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Feiz-Haddad MH, Moradkhani MA, Sefat F, Ali SA. The molecular and histopathological investigations of TLR2 rs5743708 and TLR4 (rs4986790 and rs4986791) polymorphisms effects on cutaneous leishmaniasis lesions. Exp Parasitol 2024; 267:108857. [PMID: 39521237 DOI: 10.1016/j.exppara.2024.108857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 09/09/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
Cutaneous leishmaniasis (CL), a zoonotic and neglected disease, is prevalent in numerous regions, particularly in tropical and sub-tropical countries. In Iran, endemic foci of leishmaniasis exist in specific regions, with zoonotic cutaneous leishmaniasis (ZCL) caused by Leishmania major being common in most rural areas. Toll-like receptors (TLRs) play a crucial role in both innate and adaptive immunities, and the investigation of TLR2 rs5743708 and TLR4 (rs4986790 and rs4986791) polymorphisms in parasitic diseases can have significant implications for patient treatment. In the present study, a total of 88 leishmaniasis patients using the patients' lesions from Khuzestan province health-treatment centers, Iran, including 50 cases (56.8%; Central region) and 38 cases (43.2%; Western region) underwent examination between the years 2022 and 2023. Two direct smears from the lesions of each patient were prepared and one of the smears was stained with Giemsa for parasitological examination. Among the 88 patients, the highest frequency was observed in the 21-30 years' age group (35.2%), while the lowest was in the 11-20 years' age group (10.2%). No statistically significant relationship was found between gender and age (P > 0.05). Following disease confirmation via microscopic examination, TLR2 rs5743708 and TLR4 (rs4986790 and rs4986791) polymorphisms in the patients were assessed using PCR-RFLP. Fragments of 264, 249, and 406 base pairs were successfully amplified, targeting the TLR2 and TLR4 genes, respectively. Out of the 88 leishmaniasis patients, 14 cases (15.9%) exhibited polymorphisms. Notably, all individuals in the polymorphism group carried both the TLR2 rs5743708 homozygous and the TLR4 rs4986791 heterozygous genotype combinations. There were no observations of TLR2 rs5743708 heterozygous, TLR4 rs4986790 heterozygous and homozygous and TLR4 rs4986791 homozygous genotypes within the polymorphism group. Biopsies from lesions for all contributors were prepared for histopathological examination. All patients with polymorphism showed larger lesions than patients without polymorphism (P < 0.05). Histophatological study showed abnormal cases in patients with polymorphism including mild hyperkeratosis, mild acanthosis, focal parakeratosis in the epithelium surface and mild hyperpigmentation of melanocytes in the basal layer. Furthermore, a strong infiltration of immune cells such as PMNs and a small number of lymphocytes was observed in the epidermal region of patients with polymorphisms. There was no statistically significant relationship between age and the quantity of lesions (P > 0.05). Additionally, some regions of the epidermal surface layer displayed pustule formation in patients with polymorphisms. No significant difference was discerned in the dermal layers of patients with polymorphisms compared to other patients. Considering that all patients with polymorphisms concurrently had TLR2 rs5743708 homozygous and TLR4 rs4986791 heterozygous genotype combinations, the anomalies observed in conjunction with histological changes in the skin lesions of patients with CL may plausibly be linked to the polymorphisms. Nonetheless, a more expansive dataset involving a larger population is imperative to comprehensively elucidate the pathogenesis of the Leishmania parasite and the potential impact of TLR2 rs5743708 and TLR4 (rs4986790 and rs4986791) gene polymorphisms in individuals afflicted with CL across diverse geographical locales.
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Affiliation(s)
- Mohammad-Hossein Feiz-Haddad
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Department of Parasitology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad-Ali Moradkhani
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Department of Parasitology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Farshid Sefat
- Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford, UK; Interdisciplinary Research Center in Polymer Science & Technology (Polymer IRC), University of Bradford, Bradford, UK
| | - S A Ali
- Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
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Gomes FDC, Galhardo DDR, Navegante ACG, dos Santos GS, Dias HAAL, Dias Júnior JRL, Pierre ME, Luz MO, de Melo Neto JS. Bioinformatics analysis to identify the relationship between human papillomavirus-associated cervical cancer, toll-like receptors and exomes: A genetic epidemiology study. PLoS One 2024; 19:e0305760. [PMID: 39208235 PMCID: PMC11361573 DOI: 10.1371/journal.pone.0305760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 06/04/2024] [Indexed: 09/04/2024] Open
Abstract
INTRODUCTION Genetic variants may influence Toll-like receptor (TLR) signaling in the immune response to human papillomavirus (HPV) infection and lead to cervical cancer. In this study, we investigated the pattern of TLR expression in the transcriptome of HPV-positive and HPV-negative cervical cancer samples and looked for variants potentially related to TLR gene alterations in exomes from different populations. MATERIALS AND METHODS A cervical tissue sample from 28 women, which was obtained from the Gene Expression Omnibus database, was used to examine TLR gene expression. Subsequently, the transcripts related to the TLRs that showed significant gene expression were queried in the Genome Aggregation Database to search for variants in more than 5,728 exomes from different ethnicities. RESULTS Cancer and HPV were found to be associated (p<0.0001). TLR1(p = 0.001), TLR3(p = 0.004), TLR4(221060_s_at)(p = 0.001), TLR7(p = 0.001;p = 0.047), TLR8(p = 0.002) and TLR10(p = 0.008) were negatively regulated, while TLR4(1552798_at)(p<0.0001) and TLR6(p = 0.019) were positively regulated in HPV-positive patients (p<0.05). The clinical significance of the variants was statistically significant for TLR1, TLR3, TLR6 and TLR8 in association with ethnicity. Genetic variants in different TLRs have been found in various ethnic populations. Variants of the TLR gene were of the following types: TLR1(5_prime_UTR), TLR4(start_lost), TLR8(synonymous;missense) and TLR10(3_prime_UTR). The "missense" variant was found to have a risk of its clinical significance being pathogenic in South Asian populations (OR = 56,820[95%CI:40,206,80,299]). CONCLUSION The results of this study suggest that the variants found in the transcriptomes of different populations may lead to impairment of the functional aspect of TLRs that show significant gene expression in cervical cancer samples caused by HPV.
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Affiliation(s)
- Fabiana de Campos Gomes
- Postgraduate Program in Collective Health in the Amazon (PPGSCA), Federal University of Pará (UFPA), Belém, Pará, Brazil
- Faculty of Medicine CERES (FACERES), São José do Rio Preto, São Paulo, Brazil
| | - Deizyane dos Reis Galhardo
- Postgraduate Program in Collective Health in the Amazon (PPGSCA), Federal University of Pará (UFPA), Belém, Pará, Brazil
| | | | - Gabriela Sepêda dos Santos
- Postgraduate Program in Collective Health in the Amazon (PPGSCA), Federal University of Pará (UFPA), Belém, Pará, Brazil
| | | | - José Ribamar Leal Dias Júnior
- Postgraduate Program in Collective Health in the Amazon (PPGSCA), Federal University of Pará (UFPA), Belém, Pará, Brazil
| | - Marie Esther Pierre
- Postgraduate Program in Collective Health in the Amazon (PPGSCA), Federal University of Pará (UFPA), Belém, Pará, Brazil
| | - Marlucia Oliveira Luz
- Postgraduate Program in Collective Health in the Amazon (PPGSCA), Federal University of Pará (UFPA), Belém, Pará, Brazil
| | - João Simão de Melo Neto
- Postgraduate Program in Collective Health in the Amazon (PPGSCA), Federal University of Pará (UFPA), Belém, Pará, Brazil
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Salamaikina S, Kulabukhova E, Korchagin V, Khokhlova O, Mironov K, Akimkin V. Toll-Like Receptor Genes and Risk of Latent Tuberculosis Infection in People Infected with HIV-1. Viruses 2024; 16:1371. [PMID: 39339847 PMCID: PMC11436194 DOI: 10.3390/v16091371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 08/26/2024] [Indexed: 09/30/2024] Open
Abstract
The purpose of this study was to determine the contribution of genetic factors, i.e., the level of expression and polymorphisms of Toll-like receptors (TLR), to the susceptibility of latent tuberculosis infection in a Russian cohort of individuals infected with HIV. The patients (n = 317) with confirmed HIV infection were divided into two groups according to the results of the STANDARD E TB-Feron test: 63 cases with a latent TB infection and 274 controls without LTBI. Total DNA and RNA were isolated from whole-blood samples. SNP genotyping and expression levels of five TLR genes (TLR1, TLR2, TLR4, TLR6, and TLR8) were determined by means of real-time PCR. There were no significant differences in the expression levels of the TLRs between the case and control groups. In addition, we did not observe any significant association between the analyzed SNPs and the susceptibility of Latent tuberculosis infection (LTBI) in patients with HIV. However, patients from an entire cohort with the rs4986790-GG (TLR4) and rs5743708-GG (TLR2) genotypes were characterized by lower CD4 T-cell counts compared to carriers of alternative alleles. Moreover, we found a significant risk of a hazardous drop in the CD4 T-cell count below 350 cells/mm3 associated with the rs4986790-G (TLR4) allele. Latent tuberculosis infection in individuals infected with HIV does not significantly modify the level of TLR gene expression.
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Affiliation(s)
- Svetlana Salamaikina
- Central Research Institute of Epidemiology Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing Russian Federation, 111123 Moscow, Russia
| | - Ekaterina Kulabukhova
- Central Research Institute of Epidemiology Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing Russian Federation, 111123 Moscow, Russia
- Medical Institute, The Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia
| | - Vitaly Korchagin
- Central Research Institute of Epidemiology Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing Russian Federation, 111123 Moscow, Russia
| | - Olga Khokhlova
- Central Research Institute of Epidemiology Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing Russian Federation, 111123 Moscow, Russia
| | - Konstantin Mironov
- Central Research Institute of Epidemiology Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing Russian Federation, 111123 Moscow, Russia
| | - Vasiliy Akimkin
- Central Research Institute of Epidemiology Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing Russian Federation, 111123 Moscow, Russia
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Gutiérrez-Romero KJ, Falfán-Valencia R, Ramírez-Venegas A, Hernández-Zenteno RDJ, Flores-Trujillo F, Sansores-Martínez R, Ramos-Martínez E, Pérez-Rubio G. Altered levels of IFN-γ, IL-4, and IL-5 depend on the TLR4 rs4986790 genotype in COPD smokers but not those exposed to biomass-burning smoke. Front Immunol 2024; 15:1411408. [PMID: 39139567 PMCID: PMC11319291 DOI: 10.3389/fimmu.2024.1411408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 07/10/2024] [Indexed: 08/15/2024] Open
Abstract
Introduction Chronic obstructive pulmonary disease (COPD) is associated with tobacco smoking and biomass-burning smoke exposure. Toll-like receptor 4 (TLR4) single-nucleotide polymorphisms (SNPs) may contribute to its pathogenesis. The study aimed to assess the association of rs4986790 and rs4986791 in the TLR4 gene in a Mexican mestizo population with COPD secondary to tobacco smoking (COPD-TS) and biomass-burning smoke (COPD-BBS) and to evaluate whether the genotypes of risk affect cytokine serum levels. Materials and methods We enrolled 2,092 participants and divided them into two comparisons according to their environmental exposure. SNPs were genotyped using TaqMan probes. Serum cytokine levels (IL-4, IL-5, IL-6, IL-10, and INF-γ) were quantified by ELISA. Results The rs4986790 AA genotype in COPD-TS was associated with a higher COPD risk (OR = 3.53). Haplotype analysis confirmed this association, identifying a block containing the rs4986790 allele (A-C, OR = 3.11). COPD-TS exhibited elevated IL-6, IL-4, and IL-5 levels compared with smokers without COPD (SWOC), whereas COPD-BBS displayed higher IFN-γ, IL-6, and IL-10 levels. The AA carriers in the COPD-TS group had elevated IL-4, IL-5, and IFN-γ compared with carriers of AG or GG. Conclusion The rs4986790 common allele and the A-C haplotype (rs4986790-rs4986791) were associated with a higher COPD risk in smokers; COPD patients carrying the AA genotype showed increased pro-inflammatory cytokines.
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Affiliation(s)
| | - Ramcés Falfán-Valencia
- HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico
| | - Alejandra Ramírez-Venegas
- Tobacco Smoking and COPD Research Department, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico
| | - Rafael De Jesus Hernández-Zenteno
- Tobacco Smoking and COPD Research Department, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico
| | - Fernando Flores-Trujillo
- Tobacco Smoking and COPD Research Department, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico
| | | | - Espiridión Ramos-Martínez
- Experimental Medicine Research Unit, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Gloria Pérez-Rubio
- HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico
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Huang Y, Zhou W, Liu S, Zeng D, Zhou W. Association between polymorphisms and atopic dermatitis susceptibility: A systematic review and meta-analysis. Gene 2024; 913:148397. [PMID: 38513928 DOI: 10.1016/j.gene.2024.148397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 03/13/2024] [Accepted: 03/18/2024] [Indexed: 03/23/2024]
Abstract
AIM Atopic dermatitis (AD) is a chronic pruritic inflammatory skin disease that is closely linked to genetic factors. Previous studies have revealed numerous single nucleotide polymorphisms (SNPs) that been related to susceptibility to AD; however, the results are conflicting. Therefore, a meta-analysis was conducted to assess the associations of these polymorphisms and AD risk. MATERIAL AND METHODS PubMed, Web of Science, Embase, Cochrane Library, and China National Knowledge Infrastructure databases were retrieved to identify eligible studies, with selected polymorphisms being reported in a minimum of three separate studies. The Newcastle-Ottawa Scale (NOS) was used to evaluate study quality. Review Manager 5.3 and STATA 14.0 were used to perform the meta-analysis. RESULTS After screening, 64 studies involving 13 genes (24 SNPs) were selected for inclusion in the meta-analysis. Nine SNPs were positively correlated with AD susceptibility [filaggrin (FLG) R501X, FLG 2282del4, chromosome 11q13.5 rs7927894, interleukin (IL)-17A rs2275913, IL-18 -137 G/C, Toll-like receptor 2 (TLR2) rs5743708, TLR2 A-16934 T, serine protease inhibitor Kazal type-5 (SPINK5) Asn368Ser, interferon-γ (IFN-γ) T874A] and one was negatively associated with AD susceptibility (IL-4 -1098 T/G). The 14 remaining SNPs were not significantly associated with AD susceptibility. CONCLUSIONS Nine SNPs that may be risk factors and one SNP that may be a protective factor for AD were identified, providing a reference for AD prediction, prevention, and therapy.
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Affiliation(s)
- Yunxia Huang
- Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Department of Allergy, Chongqing General Hospital, Chongqing 400014, China
| | - Wei Zhou
- Department of Allergy, Chongqing General Hospital, Chongqing 400014, China
| | - Shunan Liu
- Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Department of Allergy, Chongqing General Hospital, Chongqing 400014, China
| | - Dan Zeng
- Department of Allergy, Chongqing General Hospital, Chongqing 400014, China
| | - Weikang Zhou
- Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Department of Allergy, Chongqing General Hospital, Chongqing 400014, China.
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Kaliappan A, Ramakrishnan S, Thomas P, Verma SK, Panwar K, Singh M, Dey S, Mohan Chellappa M. Polymorphism in the leucine-rich repeats of TLR7 in different breeds of chicken and in silico analysis of its effect on TLR7 structure and function. Gene 2024; 912:148373. [PMID: 38490513 DOI: 10.1016/j.gene.2024.148373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 03/02/2024] [Accepted: 03/12/2024] [Indexed: 03/17/2024]
Abstract
Chicken toll-like receptor 7 (chTLR7) is a viral sensing pattern recognition receptor and detects ssRNA. The ligand binding site comprises leucine-rich repeats (LRRs) located in the ectodomain of chTLR7. Hence, any polymorphism in the binding site would modify its functional interaction with the ligand, resulting in varied strength of immune response. This study first aimed to compare the single nucleotide polymorphisms (SNPs) associated with the ligand binding site of TLR7 in three indigenous chicken breeds namely Aseel, Kadaknath, Nicobari along with an exotic breed White Leghorn. Four synonymous SNPs (P123P, I171I, N339N and L421L) and four non-synonymous SNPs (I121V, S135T, F356S and S447G) were identified among various breeds. We employed in silico tools to screen the pathogenic nsSNPs and one nsSNP was identified as having potential impact on chTLR7 protein. Moreover, sequence and structure-based methods were used to determine the effect of nsSNPs on protein stability. It revealed I121V, F356S, and S447G as decreasing the stability while S135T increasing the stability of chTLR7. Additionally, docking analysis confirmed that I121V and F356S reduced the binding affinity of ligands (R-848 and polyU) to chTLR7 protein. The results suggest that the nsSNPs found in this study could alter the ligand binding of chTLR7 and modify the immune response between different breeds further contributing to disease susceptibility or resistance. Further, in vitro and in vivo studies are needed to analyze the effect of these SNPs on susceptibility or resistance against various viral diseases in poultry.
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Affiliation(s)
- Abinaya Kaliappan
- Immunology Section, ICAR - Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh 243 122, India
| | - Saravanan Ramakrishnan
- Immunology Section, ICAR - Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh 243 122, India.
| | - Prasad Thomas
- Division of Bacteriology and Mycology, ICAR - Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh 243 122, India
| | - Surya Kant Verma
- Immunology Section, ICAR - Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh 243 122, India
| | - Khushboo Panwar
- Immunology Section, ICAR - Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh 243 122, India
| | - Mithilesh Singh
- Immunology Section, ICAR - Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh 243 122, India
| | - Sohini Dey
- Recombinant DNA Laboratory, Division of Veterinary Biotechnology, ICAR - Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh 243 122, India
| | - Madhan Mohan Chellappa
- Recombinant DNA Laboratory, Division of Veterinary Biotechnology, ICAR - Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh 243 122, India
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Kaushik G, Vashishtha R, Verma C, Sharma S, Kumar V. Genetic Variation in Toll-Like Receptors (TLRs) 2, 4, and 9 Influences HIV Disease Progression Toward Active TB and AIDS. J Inflamm Res 2024; 17:3283-3291. [PMID: 38800599 PMCID: PMC11128240 DOI: 10.2147/jir.s451431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Accepted: 03/25/2024] [Indexed: 05/29/2024] Open
Abstract
Background Toll-like receptors (TLRs) are identified as one of the key components of the innate immune system. The objective of this study was to explore the influence of genetic variability in these TLRs on human immunodeficiency virus (HIV) disease progression with and without tuberculosis (TB) co-infection. Materials and Methods This prospective, cross-sectional, and longitudinal study included 373 HIV-positive patients without TB infection. This study aimed to examine the genetic variation in TLRs (TLR2, TLR4, and TLR9) between patients with HIV-1 infection and those who progressed to active TB during the two years of follow-up. Results During the two year follow-up of 373 positive patients, 98 patients progressed to active TB/AIDS (acquired immunodeficiency syndrome). When comparing 98 HIV patients who developed active TB/AIDS to 275 HIV patients who did not, it was discovered that the frequency of the A allele in TLR9 was considerably higher (p <0.001) in HIV patients progressed to active TB/AIDS. Ninety eight HIV individuals who advanced to active TB/AIDS showed a significantly higher frequency of the AA genotype in TLR9 than did in HIV patients who had no TB/AIDS (p <0.001). Conclusion The increased association of the AA genotype of TLR9 in HIV patients who progressed to active TB during follow-up suggests that HIV-positive patients with the AA genotype of TLR9 have increased susceptibility towards TB during the disease progression.
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Affiliation(s)
- Gaurav Kaushik
- School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
- Department of Medicine, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Richa Vashishtha
- Department of Medicine, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Chaitenya Verma
- Department of Pathology, Wexner Medical Center, Ohio State University, Columbus, OH, USA
| | - Shipra Sharma
- Shri Guru Ram Rai Institute of Medical & Health Sciences, Dehradun, Uttarakhand, 248001, India
| | - Vinay Kumar
- Pennsylvania State University Hershey Medical Center, 500 University Dr, Hershey, PA, 17033, USA
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Bhardwaj A, Prasad D, Mukherjee S. Role of toll-like receptor in the pathogenesis of oral cancer. Cell Biochem Biophys 2024; 82:91-105. [PMID: 37853249 DOI: 10.1007/s12013-023-01191-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 10/06/2023] [Indexed: 10/20/2023]
Abstract
Toll-like receptors are important molecules of innate immunity. They are known as pattern recognition receptors. They recognise certain molecules known as pathogen-associated molecular pattern on a pathogen and release chemicals that causes inflammation. Toll-like receptors (TLR) help in the removal of the infected cell and thus stop the spread of infection and are being studied for their association with cancer. Oral carcinoma has emerged as a major problem of our country today; it is found ranks first in men and third in women. Toll-like receptors have been implicated in the development of cancer. Certain polymorphisms in toll-like receptor can make a cell more susceptible to develop oral cancer. The identification of toll-like receptors and the different genotypes that are involved in the development of cancer can be utilised for using them as biomarkers of the disease. The study revealed that toll-like receptors like TLR7 and TLR5 are found to have a role in suppression of oral cancer while toll-like receptors like TLR4 and TLR2 are found to be associated with the progression of oral cancer. Toll-like receptors can turn out as important target molecules in the future in designing therapeutic strategies for oral cancer.
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Affiliation(s)
- Ananya Bhardwaj
- Amity Institute of Biotechnology, Amity University Uttar Pradesh Lucknow Campus, Lucknow, Uttar Pradesh, India
| | - Divya Prasad
- Amity Institute of Biotechnology, Amity University Uttar Pradesh Lucknow Campus, Lucknow, Uttar Pradesh, India
| | - Sayali Mukherjee
- Amity Institute of Biotechnology, Amity University Uttar Pradesh Lucknow Campus, Lucknow, Uttar Pradesh, India.
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Zhang C, Yu L, Xiong T, Zhang Y, Liu J, Zhang J, He P, Xi Y, Jiang Y. Exploring a Potential Causal Link Between Dietary Intake and Chronic Obstructive Pulmonary Disease: A Two-Sample Mendelian Randomization Study. Int J Chron Obstruct Pulmon Dis 2024; 19:297-308. [PMID: 38292139 PMCID: PMC10826572 DOI: 10.2147/copd.s445706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 01/14/2024] [Indexed: 02/01/2024] Open
Abstract
Background Chronic Obstructive Pulmonary Disease (COPD), the most prevalent chronic respiratory condition, significantly impairs patients' quality of life. The pivotal element in disease management lies in prevention, underscoring the paramount importance of employing a scientific approach to investigate early prevention strategies for COPD. Methods This study delved into the causal link between 28 dietary intakes and COPD employing two-sample Mendelian randomization. We primarily utilized the Inverse Variance Weighted (IVW) method as the main outcome, complemented by Weighted Median (WM), MR-Egger method, along with several sensitivity analysis techniques, all accompanied by visual representations. Results We identified higher odds of COPD following exposure to green beans (OR=1.381, 95% CI=1.119-1.704, P=0.003) and pork intake (OR=2.657, 95% CI=1.203-5.868, P=0.016). In contrast, the odds of developing COPD were lower following exposure to dried fruit (OR=0.481, 95% CI=0.283-0.819, P=0.007), cereal (OR=0.560, 95% CI=0.356-0.880, P=0.012), and whole egg consumption (OR=0.700, 95% CI=0.504-0.972, P=0.033). Conclusion In light of our study's findings, we anticipate that strategically modifying dietary choices may offer an avenue for early COPD prevention in the future.
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Affiliation(s)
- Chenwei Zhang
- Department of Pulmonary and Critical Care Medicine, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
| | - Lu Yu
- Department of Pulmonary and Critical Care Medicine, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
| | - Tao Xiong
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
| | - Yukai Zhang
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
| | - Juan Liu
- Department of Pulmonary and Critical Care Medicine, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
| | - Jingfen Zhang
- Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
| | - Peiyun He
- Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
| | - Yujia Xi
- Department of Urology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
| | - Yi Jiang
- Department of Pulmonary and Critical Care Medicine, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
- NHC Key Laboratory of Pneumoconiosis, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
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Vlk AM, Prantner D, Shirey KA, Perkins DJ, Buzza MS, Thumbigere-Math V, Keegan AD, Vogel SN. M2a macrophages facilitate resolution of chemically-induced colitis in TLR4-SNP mice. mBio 2023; 14:e0120823. [PMID: 37768050 PMCID: PMC10653841 DOI: 10.1128/mbio.01208-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 07/18/2023] [Indexed: 09/29/2023] Open
Abstract
IMPORTANCE Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, impacts millions of individuals worldwide and severely impairs the quality of life for patients. Dysregulation of innate immune signaling pathways reduces barrier function and exacerbates disease progression. Macrophage (Mφ) signaling pathways are potential targets for IBD therapies. While multiple treatments are available for IBD, (i) not all patients respond, (ii) responses may diminish over time, and (iii) treatments often have undesirable side effects. Genetic studies have shown that the inheritance of two co-segregating SNPs expressed in the innate immune receptor, TLR4, is associated with human IBD. Mice expressing homologous SNPs ("TLR4-SNP" mice) exhibited more severe colitis than WT mice in a DSS-induced colonic inflammation/repair model. We identified a critical role for M2a "tissue repair" Mφ in the resolution of colitis. Our findings provide insight into potential development of novel therapies targeting Mφ signaling pathways that aim to alleviate the debilitating symptoms experienced by individuals with IBD.
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Affiliation(s)
- Alexandra M. Vlk
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Daniel Prantner
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Kari Ann Shirey
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Darren J. Perkins
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
- University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, Maryland, USA
| | - Marguerite S. Buzza
- Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Vivek Thumbigere-Math
- Division of Periodontics, University of Maryland School of Dentistry, Baltimore, Maryland, USA
| | - Achsah D. Keegan
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Stefanie N. Vogel
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
- University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, Maryland, USA
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11
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Bakaros E, Voulgaridi I, Paliatsa V, Gatselis N, Germanidis G, Asvestopoulou E, Alexiou S, Botsfari E, Lygoura V, Tsachouridou O, Mimtsoudis I, Tseroni M, Sarrou S, Mouchtouri VA, Dadouli K, Kalala F, Metallidis S, Dalekos G, Hadjichristodoulou C, Speletas M. Innate Immune Gene Polymorphisms and COVID-19 Prognosis. Viruses 2023; 15:1784. [PMID: 37766191 PMCID: PMC10537595 DOI: 10.3390/v15091784] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 08/19/2023] [Accepted: 08/19/2023] [Indexed: 09/29/2023] Open
Abstract
COVID-19 is characterized by a heterogeneous clinical presentation and prognosis. Risk factors contributing to the development of severe disease include old age and the presence of comorbidities. However, the genetic background of the host has also been recognized as an important determinant of disease prognosis. Considering the pivotal role of innate immunity in the control of SARS-CoV-2 infection, we analyzed the possible contribution of several innate immune gene polymorphisms (including TLR2-rs5743708, TLR4-rs4986790, TLR4-rs4986791, CD14-rs2569190, CARD8-rs1834481, IL18-rs2043211, and CD40-rs1883832) in disease severity and prognosis. A total of 249 individuals were enrolled and further divided into five (5) groups, according to the clinical progression scale provided by the World Health Organization (WHO) (asymptomatic, mild, moderate, severe, and critical). We identified that elderly patients with obesity and/or diabetes mellitus were more susceptible to developing pneumonia and respiratory distress syndrome after SARS-CoV-2 infection, while the IL18-rs1834481 polymorphism was an independent risk factor for developing pneumonia. Moreover, individuals carrying either the TLR2-rs5743708 or the TLR4-rs4986791 polymorphisms exhibited a 3.6- and 2.5-fold increased probability for developing pneumonia and a more severe disease, respectively. Our data support the notion that the host's genetic background can significantly affect COVID-19 clinical phenotype, also suggesting that the IL18-rs1834481, TLR2-rs5743708, and TLR4-rs4986791 polymorphisms may be used as molecular predictors of COVID-19 clinical phenotype.
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Affiliation(s)
- Evangelos Bakaros
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece; (E.B.); (V.P.); (E.A.); (S.A.); (E.B.); (S.S.); (F.K.)
| | - Ioanna Voulgaridi
- Laboratory of Hygiene and Epidemiology, Faculty of Medicine, University of Thessaly, 41222 Larissa, Greece; (I.V.); (V.A.M.); (K.D.); (C.H.)
| | - Vassiliki Paliatsa
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece; (E.B.); (V.P.); (E.A.); (S.A.); (E.B.); (S.S.); (F.K.)
| | - Nikolaos Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, Full Member of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, 41110 Larissa, Greece; (N.G.); (V.L.); (G.D.)
| | - Georgios Germanidis
- First Internal Medicine Department, Infectious Diseases Division, AHEPA Hospital, Medical School, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (G.G.); (O.T.); (I.M.); (S.M.)
| | - Evangelia Asvestopoulou
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece; (E.B.); (V.P.); (E.A.); (S.A.); (E.B.); (S.S.); (F.K.)
| | - Stamatia Alexiou
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece; (E.B.); (V.P.); (E.A.); (S.A.); (E.B.); (S.S.); (F.K.)
| | - Elli Botsfari
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece; (E.B.); (V.P.); (E.A.); (S.A.); (E.B.); (S.S.); (F.K.)
| | - Vasiliki Lygoura
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, Full Member of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, 41110 Larissa, Greece; (N.G.); (V.L.); (G.D.)
| | - Olga Tsachouridou
- First Internal Medicine Department, Infectious Diseases Division, AHEPA Hospital, Medical School, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (G.G.); (O.T.); (I.M.); (S.M.)
| | - Iordanis Mimtsoudis
- First Internal Medicine Department, Infectious Diseases Division, AHEPA Hospital, Medical School, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (G.G.); (O.T.); (I.M.); (S.M.)
| | - Maria Tseroni
- National Public Health Organization, 15123 Athens, Greece;
| | - Styliani Sarrou
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece; (E.B.); (V.P.); (E.A.); (S.A.); (E.B.); (S.S.); (F.K.)
| | - Varvara A. Mouchtouri
- Laboratory of Hygiene and Epidemiology, Faculty of Medicine, University of Thessaly, 41222 Larissa, Greece; (I.V.); (V.A.M.); (K.D.); (C.H.)
| | - Katerina Dadouli
- Laboratory of Hygiene and Epidemiology, Faculty of Medicine, University of Thessaly, 41222 Larissa, Greece; (I.V.); (V.A.M.); (K.D.); (C.H.)
| | - Fani Kalala
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece; (E.B.); (V.P.); (E.A.); (S.A.); (E.B.); (S.S.); (F.K.)
| | - Simeon Metallidis
- First Internal Medicine Department, Infectious Diseases Division, AHEPA Hospital, Medical School, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (G.G.); (O.T.); (I.M.); (S.M.)
| | - George Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, Full Member of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, 41110 Larissa, Greece; (N.G.); (V.L.); (G.D.)
| | - Christos Hadjichristodoulou
- Laboratory of Hygiene and Epidemiology, Faculty of Medicine, University of Thessaly, 41222 Larissa, Greece; (I.V.); (V.A.M.); (K.D.); (C.H.)
| | - Matthaios Speletas
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece; (E.B.); (V.P.); (E.A.); (S.A.); (E.B.); (S.S.); (F.K.)
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12
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Salamaikina S, Korchagin V, Kulabukhova E, Mironov K, Zimina V, Kravtchenko A, Akimkin V. Association of Toll-Like Receptor Gene Polymorphisms with Tuberculosis in HIV-Positive Participants. EPIGENOMES 2023; 7:15. [PMID: 37606452 PMCID: PMC10443360 DOI: 10.3390/epigenomes7030015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/20/2023] [Accepted: 07/21/2023] [Indexed: 08/23/2023] Open
Abstract
Genetic factors in the HIV-background may play a significant role in the susceptibility to secondary diseases, like tuberculosis, which is the leading cause in mortality of HIV-positive people. Toll-like receptors (TLRs) are considered to be receptors for adaptive immunity, and polymorphisms in TLR genes can influence the activity of the immune response to infection. We conducted a case-control study of the association of TLR gene polymorphisms with the risk of tuberculosis coinfection in a multi-country sample of HIV-positive participants. Our study revealed certain associations between TLR4 and TLR6 polymorphisms and HIV-tuberculosis coinfection. We also found that the analyzed TLR1 and TLR4 polymorphisms were linked with the decline in CD4+ cell count, which is a predictor of disease progression in HIV-infected individuals. Our findings confirm that TLR gene polymorphisms are factors that may contribute to development of HIV-tuberculosis coinfection. However, the essence of the observed associations remains unclear, since it can also include both environmental factors and epigenetic mechanisms of gene expression regulation.
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Affiliation(s)
- Svetlana Salamaikina
- Central Research Institute of Epidemiology Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing Russian Federation, Novogireevskaya Str. 3a, 111123 Moscow, Russia
| | - Vitaly Korchagin
- Central Research Institute of Epidemiology Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing Russian Federation, Novogireevskaya Str. 3a, 111123 Moscow, Russia
| | - Ekaterina Kulabukhova
- Central Research Institute of Epidemiology Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing Russian Federation, Novogireevskaya Str. 3a, 111123 Moscow, Russia
- Medical Institute, The Peoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya Str. 6, 117198 Moscow, Russia
| | - Konstantin Mironov
- Central Research Institute of Epidemiology Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing Russian Federation, Novogireevskaya Str. 3a, 111123 Moscow, Russia
| | - Vera Zimina
- Medical Institute, The Peoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya Str. 6, 117198 Moscow, Russia
| | - Alexey Kravtchenko
- Central Research Institute of Epidemiology Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing Russian Federation, Novogireevskaya Str. 3a, 111123 Moscow, Russia
| | - Vasily Akimkin
- Central Research Institute of Epidemiology Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing Russian Federation, Novogireevskaya Str. 3a, 111123 Moscow, Russia
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13
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Lionakis MS. Exploiting antifungal immunity in the clinical context. Semin Immunol 2023; 67:101752. [PMID: 37001464 PMCID: PMC10192293 DOI: 10.1016/j.smim.2023.101752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Indexed: 03/31/2023]
Abstract
The continuous expansion of immunocompromised patient populations at-risk for developing life-threatening opportunistic fungal infections in recent decades has helped develop a deeper understanding of antifungal host defenses, which has provided the foundation for eventually devising immune-based targeted interventions in the clinic. This review outlines how genetic variation in certain immune pathway-related genes may contribute to the observed clinical variability in the risk of acquisition and/or severity of fungal infections and how immunogenetic-based patient stratification may enable the eventual development of personalized strategies for antifungal prophylaxis and/or vaccination. Moreover, this review synthesizes the emerging cytokine-based, cell-based, and other immunotherapeutic strategies that have shown promise as adjunctive therapies for boosting or modulating tissue-specific antifungal immune responses in the context of opportunistic fungal infections.
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Affiliation(s)
- Michail S Lionakis
- From the Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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14
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Fuess LE, Bolnick DI. Single-Cell RNA Sequencing Reveals Microevolution of the Stickleback Immune System. Genome Biol Evol 2023; 15:evad053. [PMID: 37039516 PMCID: PMC10116603 DOI: 10.1093/gbe/evad053] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 03/16/2023] [Accepted: 03/23/2023] [Indexed: 04/12/2023] Open
Abstract
The risk and severity of pathogen infections in humans, livestock, or wild organisms depend on host immune function, which can vary between closely related host populations or even among individuals. This immune variation can entail between-population differences in immune gene coding sequences, copy number, or expression. In recent years, many studies have focused on population divergence in immunity using whole-tissue transcriptomics. But, whole-tissue transcriptomics cannot distinguish between evolved differences in gene regulation within cells, versus changes in cell composition within the focal tissue. Here, we leverage single-cell transcriptomic approaches to document signatures of microevolution of immune system structure in a natural system, the three-spined stickleback (Gasterosteus aculeatus). We sampled nine adult fish from three populations with variability in resistance to a cestode parasite, Schistocephalus solidus, to create the first comprehensive immune cell atlas for G. aculeatus. Eight broad immune cell types, corresponding to major vertebrate immune cells, were identified. We were also able to document significant variation in both abundance and expression profiles of the individual immune cell types among the three populations of fish. Furthermore, we demonstrate that identified cell type markers can be used to reinterpret traditional transcriptomic data: we reevaluate previously published whole-tissue transcriptome data from a quantitative genetic experimental infection study to gain better resolution relating infection outcomes to inferred cell type variation. Our combined study demonstrates the power of single-cell sequencing to not only document evolutionary phenomena (i.e., microevolution of immune cells) but also increase the power of traditional transcriptomic data sets.
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Affiliation(s)
- Lauren E Fuess
- Department of Biology, Texas State University
- Department of Ecology and Evolutionary Biology, University of Connecticut
| | - Daniel I Bolnick
- Department of Ecology and Evolutionary Biology, University of Connecticut
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15
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Habibabadi HM, Parsania M, Pourfathollah AA, Sharifi Z. Association of HTLV-1 infection prevalence with TLR7 single nucleotide polymorphisms (rs179008 & rs179009) in asymptomatic blood donors in Khorasan Province of Iran. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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16
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Hattori T, Saito T, Miyamoto H, Kajihara M, Igarashi M, Takada A. Single Nucleotide Variants of the Human TIM-1 IgV Domain with Reduced Ability to Promote Viral Entry into Cells. Viruses 2022; 14:v14102124. [PMID: 36298679 PMCID: PMC9611583 DOI: 10.3390/v14102124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/18/2022] [Accepted: 09/21/2022] [Indexed: 11/29/2022] Open
Abstract
Human T-cell immunoglobulin mucin 1 (hTIM-1) is known to promote cellular entry of enveloped viruses. Previous studies suggested that the polymorphisms of hTIM-1 affected its function. Here, we analyzed single nucleotide variants (SNVs) of hTIM-1 to determine their ability to promote cellular entry of viruses using pseudotyped vesicular stomatitis Indiana virus (VSIV). We obtained hTIM-1 sequences from a public database (Ensembl genome browser) and identified 35 missense SNVs in 3 loops of the hTIM-1 immunoglobulin variable (IgV) domain, which had been reported to interact with the Ebola virus glycoprotein (GP) and phosphatidylserine (PS) in the viral envelope. HEK293T cells transiently expressing wildtype hTIM-1 or its SNV mutants were infected with VSIVs pseudotyped with filovirus or arenavirus GPs, and their infectivities were compared. Eleven of the thirty-five SNV substitutions reduced the efficiency of hTIM-1-mediated entry of pseudotyped VSIVs. These SNV substitutions were found not only around the PS-binding pocket but also in other regions of the molecule. Taken together, our findings suggest that some SNVs of the hTIM-1 IgV domain have impaired ability to interact with PS and/or viral GPs in the viral envelope, which may affect the hTIM-1 function to promote viral entry into cells.
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Affiliation(s)
- Takanari Hattori
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
| | - Takeshi Saito
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
| | - Hiroko Miyamoto
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
| | - Masahiro Kajihara
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
| | - Manabu Igarashi
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
- International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
| | - Ayato Takada
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
- International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
- Department of Disease Control, School of Veterinary Medicine, University of Zambia, Lusaka 10101, Zambia
- One Health Research Center, Hokkaido University, Sapporo 001-0020, Japan
- Correspondence: ; Tel.: +81-11-706-9502; Fax: +81-11-706-7310
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17
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Association of Toll-like receptors polymorphisms with the risk of acute lymphoblastic leukemia in the Brazilian Amazon. Sci Rep 2022; 12:15159. [PMID: 36071076 PMCID: PMC9452670 DOI: 10.1038/s41598-022-19130-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 08/24/2022] [Indexed: 11/29/2022] Open
Abstract
Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children in childhood. Single-nucleotide polymorphism (SNPs) in key molecules of the immune system, such as Toll-like receptors (TLRs) and CD14 molecules, are associated with the development of several diseases. However, their role in ALL is unknown. A case–control study was performed with 152 ALL patients and 187 healthy individuals to investigate the role of SNPs in TLRs and the CD14 gene in ALL. In this study, TLR6 C > T rs5743810 [OR: 3.20, 95% CI: 1.11–9.17, p = 0.003) and TLR9 C > T rs187084 (OR: 2.29, 95% CI: 1.23–4.26, p = 0.000) seems to be a risk for development of ALL. In addition, the TLR1 T > G rs5743618 and TLR6 C > T rs5743810 polymorphisms with protection against death (OR: 0.17, 95% IC: 0.04–0.79, p = 0.008; OR: 0.48, 95% IC: 0.24–0.94, p = 0.031, respectively). Our results show that SNPs in TLRs genes may be involved in the pathogenesis of ALL and may influence clinical prognosis; however, further studies are necessary to elucidate the role of TLR1, TLR4, TLR5, TLR6, TLR9 and CD14 polymorphisms in this disease.
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18
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Single Nucleotide Polymorphisms of Toll-like Receptor 4 in Hepatocellular Carcinoma-A Single-Center Study. Int J Mol Sci 2022; 23:ijms23169430. [PMID: 36012696 PMCID: PMC9409058 DOI: 10.3390/ijms23169430] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 08/15/2022] [Accepted: 08/18/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver tumor leading to significant morbidity and mortality; its exact genetic background is largely unrecognized. Toll-like receptor-4 (TLR4) reacts with lipopolysaccharides, molecules found in the outer membrane of Gram-negative bacteria. In damaged liver, TLR4 expression is upregulated, leading to hepatic inflammation and injury. We tried to investigate the role of the two most common single-nucleotide polymorphisms (SNPs) of TLR4 in HCC-genesis. Aged > 18 years old, cirrhotic patients were included in this study. Exclusion criteria were non-HCC tumors and HIV co-infection. TLR4 SNPs association with HCC occurrence was the primary endpoint, and associations with all-cause and liver-related mortality, as well as time durations between diagnosis of cirrhosis and HCC development or death and diagnosis of HCC and death were secondary endpoints. A total of 52 out of 260 included patients had or developed HCC. TLR4 SNPs showed no correlation with primary or secondary endpoints, except for the shorter duration between HCC development and death in patients with TLR4 mutations. Overall, TLR4 SNPs showed no correlation with carcinogenesis or deaths in patients with liver cirrhosis; patients with TLR4 SNPs that developed HCC had lower survival rates, a finding that should be further evaluated.
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19
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The link between genetic variation and variability in vaccine responses: a narrative review. JOURNAL OF BIO-X RESEARCH 2022. [DOI: 10.1097/jbr.0000000000000122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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20
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Xu Y, Xue W, Gao H, Cui J, Zhao L, You C. Association of toll-like receptors single nucleotide polymorphisms with HBV and HCV infection: research status. PeerJ 2022; 10:e13335. [PMID: 35462764 PMCID: PMC9029363 DOI: 10.7717/peerj.13335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 04/04/2022] [Indexed: 01/13/2023] Open
Abstract
Background Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections have become increasingly severe worldwide and are a threat to public health. There have been a number of studies conducted recently on the relationship of single nucleotide polymorphisms (SNPs) to innate immune receptor genes such as toll-like receptors (TLRs). Some literature suggests that SNPs of TLRs are associated with HBV and HCV infection. We summarized the role of TLRs gene polymorphisms associated with HBV and HCV infections and explored their possible mechanisms of action. Methodology PubMed and Web of Science were used to perform the literature review. Related articles and references were identified and used to analyze the role of TLRs gene polymorphism in HBV and HCV infection. Results TLRs gene polymorphisms may have beneficial or detrimental effects in HBV and HCV infection, and some SNPs can affect disease progression or prognosis. They affect the disease state by altering gene expression or protein synthesis; however, the mechanism of action is not clearly understood. Conclusions Single nucleotide polymorphisms of TLRs play a role in HBV and HCV infection, but the mechanism of action still needs to be explored in future studies.
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Affiliation(s)
- Yaxin Xu
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China
| | - Wentao Xue
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China
| | - Hongwei Gao
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China
| | - Jiabo Cui
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China
| | - Lingzhi Zhao
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China
| | - Chongge You
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China
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21
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Lansdon P, Carlson M, Ackley BD. Wild-type Caenorhabditis elegans isolates exhibit distinct gene expression profiles in response to microbial infection. BMC Genomics 2022; 23:229. [PMID: 35321659 PMCID: PMC8943956 DOI: 10.1186/s12864-022-08455-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 02/28/2022] [Indexed: 11/20/2022] Open
Abstract
The soil-dwelling nematode Caenorhabditis elegans serves as a model system to study innate immunity against microbial pathogens. C. elegans have been collected from around the world, where they, presumably, adapted to regional microbial ecologies. Here we use survival assays and RNA-sequencing to better understand how two isolates from disparate climates respond to pathogenic bacteria. We found that, relative to N2 (originally isolated in Bristol, UK), CB4856 (isolated in Hawaii), was more susceptible to the Gram-positive microbe, Staphylococcus epidermidis, but equally susceptible to Staphylococcus aureus as well as two Gram-negative microbes, Providencia rettgeri and Pseudomonas aeruginosa. We performed transcriptome analysis of infected worms and found gene-expression profiles were considerably different in an isolate-specific and microbe-specific manner. We performed GO term analysis to categorize differential gene expression in response to S. epidermidis. In N2, genes that encoded detoxification enzymes and extracellular matrix proteins were significantly enriched, while in CB4856, genes that encoded detoxification enzymes, C-type lectins, and lipid metabolism proteins were enriched, suggesting they have different responses to S. epidermidis, despite being the same species. Overall, discerning gene expression signatures in an isolate by pathogen manner can help us to understand the different possibilities for the evolution of immune responses within organisms.
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Affiliation(s)
- Patrick Lansdon
- Department of Molecular Biosciences, University of Kansas, 5004 Haworth Hall, 1200 Sunnyside Ave, KS, 66045, Lawrence, USA
| | - Maci Carlson
- Department of Molecular Biosciences, University of Kansas, 5004 Haworth Hall, 1200 Sunnyside Ave, KS, 66045, Lawrence, USA
| | - Brian D Ackley
- Department of Molecular Biosciences, University of Kansas, 5004 Haworth Hall, 1200 Sunnyside Ave, KS, 66045, Lawrence, USA.
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Anywaine Z, Lule SA, Hansen C, Warimwe G, Elliott A. Clinical manifestations of Rift Valley fever in humans: Systematic review and meta-analysis. PLoS Negl Trop Dis 2022; 16:e0010233. [PMID: 35333856 PMCID: PMC8986116 DOI: 10.1371/journal.pntd.0010233] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 04/06/2022] [Accepted: 02/03/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Rift Valley fever (RVF) is an emerging, neglected, mosquito-borne viral zoonosis associated with significant morbidity, mortality and expanding geographical scope. The clinical signs and symptoms in humans are non-specific and case definitions vary. We reviewed and analysed the clinical manifestations of RVF in humans. METHODS In this systematic review and meta-analysis we searched on different dates, the Embase (from 1947 to 13th October 2019), Medline (1946 to 14th October 2019), Global Health (1910 to 15th October 2019), and Web of Science (1970 to 15th October 2019) databases. Studies published in English, reporting frequency of symptoms in humans, and laboratory confirmed RVF were included. Animal studies, studies among asymptomatic volunteers, and single case reports for which a proportion could not be estimated, were excluded. Quality assessment was done using a modified Hoy and Brooks et al tool, data was extracted, and pooled frequency estimates calculated using random effects meta-analysis. RESULTS Of the 3765 articles retrieved, less than 1% (32 articles) were included in the systematic review and meta-analysis. Nine RVF clinical syndromes were reported including the general febrile, renal, gastrointestinal, hepatic, haemorrhagic, visual, neurological, cardio-pulmonary, and obstetric syndromes. The most common clinical manifestations included fever (81%; 95% Confidence Interval (CI) 69-91; [26 studies, 1286 patients]), renal failure (41%; 23-59; [4, 327]), nausea (38%; 12-67; [6, 325]), jaundice (26%; 16-36; [15, 393]), haemorrhagic disease (26%; 17-36; [16, 277]), partial blindness (24%; 7-45; [11, 225]), encephalitis (21%; 11-33; [4, 327]), cough (4%; 0-17; [4, 11]), and miscarriage (54%) respectively. Death occurred in 21% (95% CI 14-29; [16 studies, 328 patients]) of cases, most of whom were hospitalised. DISCUSSION This study delineates the complex symptomatology of human RVF disease into syndromes. This approach is likely to improve case definitions and detection rates, impact outbreak control, increase public awareness about RVF, and subsequently inform 'one-health' policies. This study provides a pooled estimate of the proportion of RVF clinical manifestations alongside a narrative description of clinical syndromes. However, most studies reviewed were case series with small sample sizes and enrolled mostly in-patients and out-patients, and captured symptoms either sparsely or using broad category terms.
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Affiliation(s)
- Zacchaeus Anywaine
- Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
- * E-mail:
| | - Swaib Abubaker Lule
- Institute for Global Health, University College London, London, United Kingdom
| | - Christian Hansen
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
- MRC International Statistics & Epidemiology Group, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - George Warimwe
- Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom
- KEMRI WellcomeTrust Research Programme, Kilifi, Kenya
| | - Alison Elliott
- Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
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23
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Elloumi N, Tahri S, Fakhfakh R, Abida O, Mahfoudh N, Hachicha H, Marzouk S, Bahloul Z, Masmoudi H. Role of innate immune receptors TLR4 and TLR2 polymorphisms in systemic lupus erythematosus susceptibility. Ann Hum Genet 2022; 86:137-144. [PMID: 35128637 DOI: 10.1111/ahg.12458] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 12/29/2021] [Accepted: 01/04/2022] [Indexed: 01/22/2023]
Abstract
AIM Through their recognition of various bacterial cell wall components, TLR2 and TLR4 participate in the innate response and modulate the activation of adaptive immunity. Therefore, the genetic background of these receptors might play a crucial role in autoimmune diseases such as systemic lupus erythematosus (SLE). In this study, we investigated the possible association between polymorphisms within TLR2 and TLR4 genes with SLE susceptibility. MATERIAL AND METHODS A total of 100 SLE patients and 200 unrelated healthy controls of the Tunisian population were enrolled in the study.TLR4rs4986790, TLR4rs4986791, and TLR2rs5743708 genotyping were performed using a polymerase chain reaction-restriction fragment length polymorphism method. The number of guanine-thymine (GT) repeat microsatellite in the intron 2 of TLR2 gene was analyzed by sequencing. RESULTS We reported a lack of allelic and genotypic association between SNPs of TLR4 and TLR2 genes and SLE pathogenesis. No correlation was found with any SLE features. However, SLE susceptibility was associated with the GT repeat microsatellite polymorphism in the human TLR2 gene. Further subclassification of alleles into three subclasses revealed a significant association between the long-sized repeats ((GT) >23) and SLE. CONCLUSION Though the results showed the absence of genetic association of TLR4 and TLR2 SNPs with the risk of developing SLE, we have identified a protective association between the microsatellite polymorphism in intron 2 of the TLR2 gene and SLE. Functionally, these (GT)n repeats may confer modifying effects or susceptibility to certain inflammatory conditions.
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Affiliation(s)
- Nesrine Elloumi
- Research laboratory LR18/SP12 auto-immunity, cancer and immunogenetics, Immunology Department, Habib Bourguiba university Hospital, University of Sfax, Sfax, Tunisia
| | - Safa Tahri
- Research laboratory LR18/SP12 auto-immunity, cancer and immunogenetics, Immunology Department, Habib Bourguiba university Hospital, University of Sfax, Sfax, Tunisia
| | - Raouia Fakhfakh
- Research laboratory LR18/SP12 auto-immunity, cancer and immunogenetics, Immunology Department, Habib Bourguiba university Hospital, University of Sfax, Sfax, Tunisia
| | - Olfa Abida
- Research laboratory LR18/SP12 auto-immunity, cancer and immunogenetics, Immunology Department, Habib Bourguiba university Hospital, University of Sfax, Sfax, Tunisia
| | - Nadia Mahfoudh
- Immunology Department, Hedi Chaker University Hospital, University of Sfax, Sfax, Tunisia
| | - Hend Hachicha
- Research laboratory LR18/SP12 auto-immunity, cancer and immunogenetics, Immunology Department, Habib Bourguiba university Hospital, University of Sfax, Sfax, Tunisia
| | - Sameh Marzouk
- Internal Medicine Department, Hedi Chaker Hospital, University of Sfax, Sfax, Tunisia
| | - Zouhir Bahloul
- Internal Medicine Department, Hedi Chaker Hospital, University of Sfax, Sfax, Tunisia
| | - Hatem Masmoudi
- Research laboratory LR18/SP12 auto-immunity, cancer and immunogenetics, Immunology Department, Habib Bourguiba university Hospital, University of Sfax, Sfax, Tunisia
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24
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Taha SI, Shata AK, El-Sehsah EM, Mohamed MF, Moustafa NM, Youssef MK. Comparison of COVID-19 characteristics in Egyptian patients according to their Toll-Like Receptor-4 (Asp299Gly) polymorphism. LE INFEZIONI IN MEDICINA 2022; 30:96-103. [PMID: 35350262 PMCID: PMC8929736 DOI: 10.53854/liim-3001-11] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 01/06/2022] [Indexed: 04/21/2023]
Abstract
BACKGROUND Toll-like receptor (TLR)-4 plays a vital role in recognizing viral particles, activating the innate immune system, and producing pro-inflammatory cytokines. OBJECTIVES This cross-sectional study aimed to compare COVID-19 severity, progression, and fate according to TLR-4 (Asp299Gly) polymorphism in Egyptian patients. METHODS A total of 145 COVID-19 patients were included in this study. TLR-4 (Asp299Gly) genotyping was done using the PCR restriction fragment length polymorphism (PCR-RFLP) approach. RESULTS The most commonly encountered TLR-4 genotype in relation to the amino acid at position 299 was the wild-type AA (73.1%); meanwhile, the homozygous mutant GG genotype (8.3%) was the least encountered. At hospital admission, 85.8% of the AA group had free (with no ground glass opacities) chest computed tomography (CT) examination, and 16.0% were asymptomatic. On the other hand, of the AG and GG groups, 81.5% and 83.3%, respectively showed bilateral ground-glass opacities in chest CT, as well as 25.9% and 75.0%, respectively were dyspneic. Values of the total leucocytic count, C-reactive protein (CRP), ferritin, and D dimer increased in the AA<AG<GG sequence. In contrast, hemoglobin values and the absolute lymphocyte counts decreased in the AA>AG>GG sequence. ICU admission (83.3%) and in-hospital death (33.3%) rates were significantly higher in the GG group. CONCLUSIONS In COVID-19 patients, the TLR-4 mutant G allele may be associated with a more aggressive disease course and in-hospital death. New therapeutic alternatives could be aimed at this area.
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Affiliation(s)
- Sara I Taha
- Department of Clinical Pathology/Immunology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Aalaa K Shata
- Department of Pulmonary Medicine, Faculty of Medicine, Ain Shams university, Cairo, Egypt
| | - Eman M El-Sehsah
- Department of Medical Microbiology and Immunology, Mansoura Faculty of Medicine, Mansoura, Egypt
| | - Manar F Mohamed
- Department of Internal Medicine, Allergy and Clinical Immunology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Nouran M Moustafa
- Basic Medical Science Department, College of Medicine, Dar Al Uloom University, Riyadh, Saudi Arabia
- Medical Microbiology and Immunology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mariam K Youssef
- Department of Clinical Pathology/Hematology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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25
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Tian Z, Li Z, Guo T, Li H, Mu Y. Atorvastatin suppresses lipopolysaccharide-induced inflammation in human coronary artery endothelial cells. BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-979020200001181092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Zhen Tian
- Northeast Agricultural University, China; Harbin Medical University, China
| | | | - Tian Guo
- Harbin Medical University, China
| | - He Li
- Harbin Medical University, China
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26
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Rajput N, Gahlay GK. Identification and in silico Characterization of Deleterious Single Nucleotide Variations in Human ZP2 Gene. Front Cell Dev Biol 2021; 9:763166. [PMID: 34869353 PMCID: PMC8635754 DOI: 10.3389/fcell.2021.763166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 10/25/2021] [Indexed: 12/15/2022] Open
Abstract
ZP2, an important component of the zona matrix, surrounds mammalian oocytes and facilitates fertilization. Recently, some studies have documented the association of mutations in genes encoding the zona matrix with the infertile status of human females. Single nucleotide polymorphisms are the most common type of genetic variations observed in a population and as per the dbSNP database, around 5,152 SNPs are reported to exist in the human ZP2 (hZP2) gene. Although a wide range of computational tools are publicly available, yet no computational studies have been done to date to identify and analyze structural and functional effects of deleterious SNPs on hZP2. In this study, we conducted a comprehensive in silico analysis of all the SNPs found in hZP2. Six different computational tools including SIFT and PolyPhen-2 predicted 18 common nsSNPs as deleterious of which 12 were predicted to most likely affect the structure/functional properties. These were either present in the N-term region crucial for sperm-zona interaction or in the zona domain. 31 additional SNPs in both coding and non-coding regions were also identified. Interestingly, some of these SNPs have been found to be present in infertile females in some recent studies.
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Affiliation(s)
- Neha Rajput
- Department of Molecular Biology and Biochemistry, Guru Nanak Dev University, Amritsar, INDIA
| | - Gagandeep Kaur Gahlay
- Department of Molecular Biology and Biochemistry, Guru Nanak Dev University, Amritsar, INDIA
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27
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Aboussahoud WS, Smith H, Stevens A, Wangsaputra I, Hunter HR, Kimber SJ, Seif MW, Brison DR. The expression and activity of Toll-like receptors in the preimplantation human embryo suggest a new role for innate immunity. Hum Reprod 2021; 36:2661-2675. [PMID: 34517414 PMCID: PMC8450873 DOI: 10.1093/humrep/deab188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 07/02/2021] [Indexed: 11/18/2022] Open
Abstract
STUDY QUESTION Is the innate immunity system active in early human embryo development? SUMMARY ANSWER The pattern recognition receptors and innate immunity Toll-like receptor (TLR) genes are widely expressed in preimplantation human embryos and the pathway appears to be active in response to TLR ligands. WHAT IS KNOWN ALREADY Early human embryos are highly sensitive to their local environment, however relatively little is known about how embryos detect and respond to specific environmental cues. While the maternal immune response is known to be key to the establishment of pregnancy at implantation, the ability of human embryos to detect and signal the presence of pathogens is unknown. STUDY DESIGN, SIZE, DURATION Expression of TLR family and related genes in human embryos was assessed by analysis of published transcriptome data (n = 40). Day 5 (D-5) human embryos (n = 25) were cultured in the presence of known TLR ligands and gene expression and cytokine production measured compared to controls. PARTICIPANTS/MATERIALS, SETTING, METHODS Human embryos surplus to treatment requirements were donated with informed consent from several ART centres. Embryos were cultured to Day 6 (D-6) in the presence of the TLR3 and TLR5 ligands Poly (I: C) and flagellin, with gene expression measured by quantitative PCR and cytokine release into medium measured using cytometric bead arrays. MAIN RESULTS AND THE ROLE OF CHANCE TLR and related genes, including downstream signalling molecules, were expressed variably at all human embryo developmental stages. Results showed the strongest expression in the blastocyst for TLRs 9 and 5, and throughout development for TLRs 9, 5, 2, 6 and 7. Stimulation of Day 5 blastocysts with TLR3 and TLR5 ligands Poly (I: C) and flagellin produced changes in mRNA expression levels of TLR genes, including the hyaluronan-mediated motility receptor (HMMR), TLR5, TLR7, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and monocyte chemoattractant Protein-1 (MCP-1) (P < 0.05, P < 0.001 compared to unstimulated controls), and release into culture medium of cytokines and chemokines, notably IL8 (P = 0.00005 and 0.01277 for flagellin and Poly (I: C), respectively). LIMITATIONS, REASONS FOR CAUTION This was a descriptive and experimental study which suggests that the TLR system is active in human embryos and capable of function, but does not confirm any particular role. Although we identified embryonic transcripts for a range of TLR genes, the expression patterns were not always consistent across published studies and expression levels of some genes were low, leaving open the possibility that these were expressed from the maternal rather than embryonic genome. WIDER IMPLICATIONS OF THE FINDINGS This is the first report of the expression and activity of a number of components of the innate immunity TLR system in human embryos. Understanding the role of TLRs during preimplantation human development may be important to reveal immunological mechanisms and potential clinical markers of embryo quality and pregnancy initiation during natural conception and in ART. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by the Ministry of Higher Education, The State of Libya, the UK Medical Research Council, and the NIHR Local Comprehensive Research Network and NIHR Manchester Clinical Research Facility and the European Union's Horizon 2020 Research and Innovation Programmes under the Marie Skłodowska-Curie Grant Agreement No. 812660 (DohART-NET). In accordance with H2020 rules, no new human embryos were sacrificed for research activities performed from the EU funding, which concerned only in silico analyses of recorded time-lapse and transcriptomics datasets. None of the authors has any conflict of interest to declare. TRIAL REGISTRATION NUMBER n/a.
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Affiliation(s)
- Wedad S Aboussahoud
- Division of Developmental Biology and Medicine, Maternal and Fetal Health Research Centre, School of Medical Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK
- Maternal and Fetal Health Research Centre, St. Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
| | - Helen Smith
- Division of Developmental Biology and Medicine, Maternal and Fetal Health Research Centre, School of Medical Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK
| | - Adam Stevens
- Division of Developmental Biology and Medicine, Maternal and Fetal Health Research Centre, School of Medical Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK
- Maternal and Fetal Health Research Centre, St. Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
| | - Ivan Wangsaputra
- Division of Developmental Biology and Medicine, Maternal and Fetal Health Research Centre, School of Medical Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK
- Maternal and Fetal Health Research Centre, St. Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
| | - Helen R Hunter
- Department of Reproductive Medicine, Old St. Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
| | - Susan J Kimber
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK
| | - Mourad W Seif
- Division of Developmental Biology and Medicine, Maternal and Fetal Health Research Centre, School of Medical Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK
- Department of Reproductive Medicine, Old St. Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
| | - Daniel R Brison
- Department of Reproductive Medicine, Old St. Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
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28
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Richard K, Piepenbrink KH, Shirey KA, Gopalakrishnan A, Nallar S, Prantner DJ, Perkins DJ, Lai W, Vlk A, Toshchakov VY, Feng C, Fanaroff R, Medvedev AE, Blanco JCG, Vogel SN. A mouse model of human TLR4 D299G/T399I SNPs reveals mechanisms of altered LPS and pathogen responses. J Exp Med 2021; 218:211550. [PMID: 33216117 PMCID: PMC7685774 DOI: 10.1084/jem.20200675] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 09/01/2020] [Accepted: 10/09/2020] [Indexed: 12/12/2022] Open
Abstract
Two cosegregating single-nucleotide polymorphisms (SNPs) in human TLR4, an A896G transition at SNP rs4986790 (D299G) and a C1196T transition at SNP rs4986791 (T399I), have been associated with LPS hyporesponsiveness and differential susceptibility to many infectious or inflammatory diseases. However, many studies failed to confirm these associations, and transfection experiments resulted in conflicting conclusions about the impact of these SNPs on TLR4 signaling. Using advanced protein modeling from crystallographic data of human and murine TLR4, we identified homologous substitutions of these SNPs in murine Tlr4, engineered a knock-in strain expressing the D298G and N397I TLR4 SNPs homozygously, and characterized in vivo and in vitro responses to TLR4 ligands and infections in which TLR4 is implicated. Our data provide new insights into cellular and molecular mechanisms by which these SNPs decrease the TLR4 signaling efficiency and offer an experimental approach to confirm or refute human data possibly confounded by variables unrelated to the direct effects of the SNPs on TLR4 functionality.
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Affiliation(s)
- Katharina Richard
- Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, MD
| | - Kurt H Piepenbrink
- Department of Food Science and Technology, Department of Biochemistry, University of Nebraska, Lincoln, NE
| | - Kari Ann Shirey
- Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, MD
| | - Archana Gopalakrishnan
- Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, MD
| | - Shreeram Nallar
- Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, MD
| | - Daniel J Prantner
- Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, MD
| | - Darren J Perkins
- Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, MD
| | - Wendy Lai
- Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, MD
| | - Alexandra Vlk
- Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, MD
| | - Vladimir Y Toshchakov
- Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, MD
| | - Chiguang Feng
- Center for Vaccine Development, University of Maryland, School of Medicine, Baltimore, MD
| | - Rachel Fanaroff
- Department of Anatomical Pathology, University of Maryland Medical Center, Baltimore, MD
| | - Andrei E Medvedev
- Department of Immunology, University of Connecticut Health Center, Farmington, CT
| | | | - Stefanie N Vogel
- Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, MD
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29
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Mandal A, Kumar M, Kumar A, Sen A, Das P, Das S. TLR4 and TLR9 polymorphism: Probable role in susceptibility among the population of Bihar for Indian visceral leishmaniasis. Innate Immun 2021; 27:493-500. [PMID: 33910419 PMCID: PMC8504264 DOI: 10.1177/1753425920965658] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Genetic variations in the host TLRs genes play an important role in susceptibility and/or resistance to visceral leishmaniasis by altering the host-pathogen interaction. In this study, we investigated the association between polymorphisms of TLR4 (Asp299Gly, Thr399Ile) and TLR-9 (T-1237C), with susceptibility to visceral leishmaniasis. A bi-directional PCR amplification of specific alleles technique was used to characterize the distribution of TLR4 (Asp299Gly and Thr399Ile) and TLR9 (T-1237C) polymorphisms. A total of 60 samples were randomly selected from confirmed visceral leishmaniasis patients and 24 endemic healthy volunteers. The samples were genotyped and allele frequencies were determined. We observed that TLR4 Asp299Gly and Thr399Ile genotypes were more frequent in visceral leishmaniasis patients (10% and 15% respectively) compared to controls (4.2% and 8.3% respectively). However, the differences were not significant in TLR4 Asp299Gly and Thr399Ile alleles and genotypes. In the case of TLR9, we observed the frequency of T1237C genotype was higher in visceral leishmaniasis patients (43.3%) than in healthy controls (33.3%). Statistically significant differences were observed in TLR9 T1237C alleles and genotypes. We concluded that TLR9 T1237C, but not TLR4, gene polymorphisms can be regarded as contributors to visceral leishmaniasis susceptibility among the Indian population of Bihar state.
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Affiliation(s)
- Abhishek Mandal
- Department of Molecular Biology, Indian Council of Medical Research-Rajendra Memorial Research Institute of Medical Sciences, Patna, India
| | - Manish Kumar
- Department of Molecular Biology, Indian Council of Medical Research-Rajendra Memorial Research Institute of Medical Sciences, Patna, India
| | - Ashish Kumar
- Department of Biochemistry, Indian Council of Medical Research-Rajendra Memorial Research Institute of Medical Sciences, Patna, India
| | - Abhik Sen
- Department of Molecular Biology, Indian Council of Medical Research-Rajendra Memorial Research Institute of Medical Sciences, Patna, India
| | - Pradeep Das
- Department of Molecular Biology, Indian Council of Medical Research-Rajendra Memorial Research Institute of Medical Sciences, Patna, India
| | - Sushmita Das
- Department of Microbiology, All India Institute of Medical Sciences, Patna, India
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30
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Wang M, Li L, Xiao S, Chen W, Hu F, Li F, Guo P, Chen X, Cai W, Tang X. The Association of TLR2, TLR3, and TLR9 Gene Polymorphisms With Susceptibility to Talaromycosis Among Han Chinese AIDS Patients in Guangdong. Front Cell Infect Microbiol 2021; 11:625461. [PMID: 33777838 PMCID: PMC7991721 DOI: 10.3389/fcimb.2021.625461] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 02/15/2021] [Indexed: 11/13/2022] Open
Abstract
Background Talaromycosis (TM) caused by Talaromyces marneffei (T. marneffei) is a growing public health concern. Although Toll-like receptor (TLR) genes play a critical role in the host defense against fungal infection, the influence of polymorphisms in these genes on the susceptibility of acquired immune deficiency syndrome (AIDS) patients to TM remains unknown. This study aims to uncover the associations of single nucleotide polymorphisms (SNPs) in TLR genes with TM susceptibility among patients with AIDS. Methods Altogether 200 AIDS patients complicated with TM, 200 matched AIDS patients without TM, and 76 healthy controls (HCs) were enrolled in this case-control study. In total, 23 SNPs in the TLR2, TLR4, and TLR9 genes, which may influence the susceptibility of AIDS patients to TM, were checked by the time of flight mass spectrometry (TOF/MS) method among these Han Chinese subjects. Results No significant differences in genotype or allele frequencies of selected SNPs were found among the TM group, Non-TM group, and HC group. Haplotype analysis also demonstrated no correlation of these SNPs with TM. However, subgroup analysis showed that the genotype TT and the T allele in TLR2 SNP rs1339 were more frequent in typical TM cases than controls (50.0 vs. 35.8%, 70.5 vs. 59.7%); the frequency of the GT genotype in TLR2 SNP rs7656411 was markedly higher in severe TM cases compared to controls (57.8 vs. 34.4%). Conclusion Our results demonstrate a genetic connection of TLR2 SNPs rs1339 and rs7656411 with an increased susceptibility and severity of TM among Han Chinese populations.
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Affiliation(s)
- Min Wang
- The First Affiliated Hospital, Jinan University, Guangzhou, China.,Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Linghua Li
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Saiyin Xiao
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China.,Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, China
| | - Wanshan Chen
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Fengyu Hu
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Feng Li
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Pengle Guo
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Xiejie Chen
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Weiping Cai
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Xiaoping Tang
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
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31
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Djuric O, Andjelkovic M, Vreca M, Skakic A, Pavlovic S, Novakovic I, Jovanovic B, Skodric-Trifunovic V, Markovic-Denic L. Genetic variants in TNFA, LTA, TLR2 and TLR4 genes and risk of sepsis in patients with severe trauma: nested case-control study in a level-1 trauma centre in SERBIA. Injury 2021; 52:419-425. [PMID: 33436266 DOI: 10.1016/j.injury.2020.12.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 12/20/2020] [Accepted: 12/29/2020] [Indexed: 02/02/2023]
Abstract
INTRODUCTION Single nucleotide variants (SNVs) represent important genetic risk factors for susceptibility to posttraumatic sepsis and a potential target for immunotherapy. We aimed to evaluate the association between 8 different SNVs within tumor necrosis factor alpha (TNFA), lymphotoxin alpha (LTA) and Toll-like receptor (TLR2 and TLR4) genes and the risk of posttraumatic sepsis. METHODS Nested case-control study was conducted in the emergency department of the Clinical Centre of Serbia including 228 traumatized patients (44 with sepsis and 184 without sepsis). To compare the results of trauma subjects with the data from the general population, a control group of 101 healthy persons was included in the study. Genotyping of TNFA (rs1800629 and rs361525), LTA (rs909253), TLR2 (rs3804099, rs4696480 and rs3804100), and TLR4 (rs4986790 and rs4986791) was performed for all patients within all three groups using the real-time PCR method. MutationTaster database and in silico software SIFT were used to predict the variant pathogenic effect. RESULTS Carriage of the G allele of the TNFA rs1800629 gene variant (OR 2.1, 95%CI 1.06-4.16) and T allele-carriage of the TLR4 rs4986791 genetic variant (OR 3.02, 95%CI 1.31-6.57) were associated with significantly higher risk of sepsis in trauma patients when compared to the general population prone to sepsis and traumatized patients without developing a sepsis, respectively. Of these two variants, only variant in TLR4 gene (rs4986791) has been labeled as disease causing by both the MutationTaster database and the in-silico software SIFT, which further supports the role of this variant in various pathologies including sepsis. For the remaining six variants no significant association with the susceptibility to sepsis was detected. CONCLUSIONS Carriage of the G allele of the TNFA rs1800629 gene variant and T allele-carriage of the TLR4 rs4986791 genetic variant confer significant risk of posttraumatic sepsis. TLR4 gene variants (rs4986790 and rs4986791) has been labelled as disease causing.
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Affiliation(s)
- Olivera Djuric
- Institute of Epidemiology, Faculty of medicine, University of Belgrade, Belgrade, Serbia.
| | - Marina Andjelkovic
- Laboratory for Molecular Biomedicine, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Serbia
| | - Misa Vreca
- Laboratory for Molecular Biomedicine, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Serbia
| | - Anita Skakic
- Laboratory for Molecular Biomedicine, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Serbia
| | - Sonja Pavlovic
- Laboratory for Molecular Biomedicine, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Serbia
| | - Ivana Novakovic
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Bojan Jovanovic
- Department of Surgery and Anesthesia, School of Medicine, University of Belgrade, Belgrade, Serbia; Center for Anesthesia and Resuscitation, Clinical Center of Serbia, Belgrade, Serbia
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Natama HM, Rovira-Vallbona E, Krit M, Guetens P, Sorgho H, Somé MA, Traoré-Coulibaly M, Valéa I, Mens PF, Schallig HDFH, Berkvens D, Kestens L, Tinto H, Rosanas-Urgell A. Genetic variation in the immune system and malaria susceptibility in infants: a nested case-control study in Nanoro, Burkina Faso. Malar J 2021; 20:94. [PMID: 33593344 PMCID: PMC7885350 DOI: 10.1186/s12936-021-03628-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 02/03/2021] [Accepted: 02/05/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Genetic polymorphisms in the human immune system modulate susceptibility to malaria. However, there is a paucity of data on the contribution of immunogenetic variants to malaria susceptibility in infants, who present differential biological features related to the immaturity of their adaptive immune system, the protective effect of maternal antibodies and fetal haemoglobin. This study investigated the association between genetic variation in innate immune response genes and malaria susceptibility during the first year of life in 656 infants from a birth cohort survey performed in Nanoro, Burkina Faso. METHODS Seventeen single nucleotide polymorphisms (SNPs) in 11 genes of the immune system previously associated with different malaria phenotypes were genotyped using TaqMan allelic hybridization assays in a Fluidigm platform. Plasmodium falciparum infection and clinical disease were documented by active and passive case detection. Case-control association analyses for both alleles and genotypes were carried out using univariate and multivariate logistic regression. For cytokines showing significant SNP associations in multivariate analyses, cord blood supernatant concentrations were measured by quantitative suspension array technology (Luminex). RESULTS Genetic variants in IL-1β (rs1143634) and FcγRIIA/CD32 (rs1801274)-both in allelic, dominant and co-dominant models-were significantly associated with protection from both P. falciparum infection and clinical malaria. Furthermore, heterozygote individuals with rs1801274 SNP in FcγRIIA/CD32 showed higher IL-1RA levels compared to wild-type homozygotes (P = 0.024), a cytokine whose production is promoted by the binding of IgG immune complexes to Fcγ receptors on effector immune cells. CONCLUSIONS These findings indicate that genetic polymorphisms in genes driving innate immune responses are associated to malaria susceptibility during the first year of life, possibly by modulating production of inflammatory mediators.
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Affiliation(s)
- Hamatandi Magloire Natama
- Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
- Unité de Recherche Clinique de Nanoro, Institut de Recherche en Sciences de La Santé, Nanoro, Burkina Faso.
- Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
| | | | - Meryam Krit
- Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
| | - Pieter Guetens
- Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
| | - Hermann Sorgho
- Unité de Recherche Clinique de Nanoro, Institut de Recherche en Sciences de La Santé, Nanoro, Burkina Faso
| | - M Athanase Somé
- Unité de Recherche Clinique de Nanoro, Institut de Recherche en Sciences de La Santé, Nanoro, Burkina Faso
| | - Maminata Traoré-Coulibaly
- Unité de Recherche Clinique de Nanoro, Institut de Recherche en Sciences de La Santé, Nanoro, Burkina Faso
| | - Innocent Valéa
- Unité de Recherche Clinique de Nanoro, Institut de Recherche en Sciences de La Santé, Nanoro, Burkina Faso
| | - Petra F Mens
- Department of Medical Microbiology-Parasitology Unit, Academic Medical Centre, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - Henk D F H Schallig
- Department of Medical Microbiology-Parasitology Unit, Academic Medical Centre, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - Dirk Berkvens
- Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
| | - Luc Kestens
- Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
- Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Halidou Tinto
- Unité de Recherche Clinique de Nanoro, Institut de Recherche en Sciences de La Santé, Nanoro, Burkina Faso
- Centre Muraz, Bobo Dioulasso, Burkina Faso
| | - Anna Rosanas-Urgell
- Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
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Ma PY, Tan JE, Hee EW, Yong DWX, Heng YS, Low WX, Wu XH, Cletus C, Kumar Chellappan D, Aung K, Yong CY, Liew YK. Human Genetic Variation Influences Enteric Fever Progression. Cells 2021; 10:cells10020345. [PMID: 33562108 PMCID: PMC7915608 DOI: 10.3390/cells10020345] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/02/2021] [Accepted: 02/04/2021] [Indexed: 01/06/2023] Open
Abstract
In the 21st century, enteric fever is still causing a significant number of mortalities, especially in high-risk regions of the world. Genetic studies involving the genome and transcriptome have revealed a broad set of candidate genetic polymorphisms associated with susceptibility to and the severity of enteric fever. This review attempted to explain and discuss the past and the most recent findings on human genetic variants affecting the progression of Salmonella typhoidal species infection, particularly toll-like receptor (TLR) 4, TLR5, interleukin (IL-) 4, natural resistance-associated macrophage protein 1 (NRAMP1), VAC14, PARK2/PACRG, cystic fibrosis transmembrane conductance regulator (CFTR), major-histocompatibility-complex (MHC) class II and class III. These polymorphisms on disease susceptibility or progression in patients could be related to multiple mechanisms in eliminating both intracellular and extracellular Salmonella typhoidal species. Here, we also highlighted the limitations in the studies reported, which led to inconclusive results in association studies. Nevertheless, the knowledge obtained through this review may shed some light on the development of risk prediction tools, novel therapies as well as strategies towards developing a personalised typhoid vaccine.
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Affiliation(s)
- Pei Yee Ma
- School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia;
| | - Jing En Tan
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Edd Wyn Hee
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Dylan Wang Xi Yong
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Yi Shuan Heng
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Wei Xiang Low
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Xun Hui Wu
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Christy Cletus
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, International Medical University, Kuala Lumpur 57000, Malaysia;
| | - Kyan Aung
- Department of Pathology, International Medical University, Kuala Lumpur 57000, Malaysia;
| | - Chean Yeah Yong
- Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia;
| | - Yun Khoon Liew
- Department of Life Sciences, International Medical University, Kuala Lumpur 57000, Malaysia;
- Correspondence:
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Ramos RI, Shaw MA, Foshag L, Stern SL, Rahimzadeh N, Elashoff D, Hoon DSB. Genetic Variants in Immune Related Genes as Predictors of Responsiveness to BCG Immunotherapy in Metastatic Melanoma Patients. Cancers (Basel) 2020; 13:cancers13010091. [PMID: 33396862 PMCID: PMC7795941 DOI: 10.3390/cancers13010091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 12/12/2020] [Accepted: 12/25/2020] [Indexed: 02/05/2023] Open
Abstract
Simple Summary The study objective was to determine if an SNP (single nucleotide polymorphism)-based immune multi-gene panel has the ability to predict adjuvant BCG (Bacillus Calmette–Guérin) immunotherapy responsiveness post-tumor resection in AJCC (American Joint Committee on Cancer) stages III and IV metastatic melanoma patients. A pilot study followed by further verification and control melanoma patient cohorts involving three phase III multicenter clinical trials was used to verify if an immune gene SNP panel could identify if adjuvant BCG therapy correlates with disease outcomes. We found a specific immune gene SNP panel that could identify which patients would respond to adjuvant BCG immunotherapy, but it was not applicable in the control non-immunotherapy treated patients. These studies provide evidence that SNP immune-gene assessment has utility in predicting melanoma patient’s immunotherapy responses to adjuvant BCG immunotherapy. Abstract Adjuvant immunotherapy in melanoma patients improves clinical outcomes. However, success is unpredictable due to inherited heterogeneity of immune responses. Inherent immune genes associated with single nucleotide polymorphisms (SNPs) may influence anti-tumor immune responses. We assessed the predictive ability of 26 immune-gene SNPs genomic panels for a clinical response to adjuvant BCG (Bacillus Calmette-Guérin) immunotherapy, using melanoma patient cohorts derived from three phase III multicenter clinical trials: AJCC (American Joint Committee on Cancer) stage IV patients given adjuvant BCG (pilot cohort; n = 92), AJCC stage III patients given adjuvant BCG (verification cohort; n = 269), and AJCC stage III patients that are sentinel lymph node (SLN) positive receiving no immunotherapy (control cohort; n = 80). The SNP panel analysis demonstrated that the responder patient group had an improved disease-free survival (DFS) (hazard ratio [HR] 1.84, 95% CI 1.09–3.13, p = 0.021) in the pilot cohort. In the verification cohort, an improved overall survival (OS) (HR 1.67, 95% CI 1.07–2.67, p = 0.025) was observed. No significant differences of SNPs were observed in DFS or OS in the control patient cohort. This study demonstrates that SNP immune genes can be utilized as a predictive tool for identifying melanoma patients that are inherently responsive to BCG and potentially other immunotherapies in the future.
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Affiliation(s)
- Romela Irene Ramos
- Department of Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, CA 90404, USA; (R.I.R.); (M.A.S.); (N.R.)
| | - Misa A. Shaw
- Department of Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, CA 90404, USA; (R.I.R.); (M.A.S.); (N.R.)
| | - Leland Foshag
- Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, CA 90404, USA;
| | - Stacey L. Stern
- Department of Biostatistics, John Wayne Cancer Institute, Santa Monica, CA 90404, USA;
| | - Negin Rahimzadeh
- Department of Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, CA 90404, USA; (R.I.R.); (M.A.S.); (N.R.)
| | - David Elashoff
- Department of Medicine Statistics Core, UCLA School of Medicine, Los Angeles, CA 90024, USA;
| | - Dave S. B. Hoon
- Department of Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, CA 90404, USA; (R.I.R.); (M.A.S.); (N.R.)
- Correspondence:
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The Arg753Gln Polymorphism of Toll-Like Receptor 2 Has a Lower Occurrence in Patients with Syphilis, Suggesting Its Protective Effect in Czech and Slovak Individuals. Infect Immun 2020; 89:IAI.00503-20. [PMID: 33077622 DOI: 10.1128/iai.00503-20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 10/07/2020] [Indexed: 11/20/2022] Open
Abstract
Syphilis is a bacterial infection caused by Treponema pallidum subsp. pallidum Infection with T. pallidum subsp. pallidum and its dissemination lead to the synthesis of proinflammatory cytokines triggered by the interaction of bacterial lipoproteins with Toll-like receptor 2 (TLR2). TLR2 contains several nonsynonymous single-nucleotide polymorphisms that may impact the activation of its signaling cascade and alter the responsiveness to, or the course of, various infectious diseases, including those caused by pathogenic spirochetes. To investigate whether TLR2 polymorphism may influence susceptibility to syphilis, 221 healthy individuals with no history of syphilis (controls) and 137 patients diagnosed with syphilis (cases) were screened for the presence of the Arg753Gln polymorphism in the TLR2 gene (2258G→A; rs5743708). The Arg753Gln variant occurs at a significantly lower frequency in syphilis patients (4 of 137 [3%]) than in controls (24 of 221 [10.9%]). These data suggest that TLR2 Arg753Gln may protect from the development of syphilis due to reduced signaling.
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Zapata D, Rivera-Gutierrez HF, Parra JL, Gonzalez-Quevedo C. Low adaptive and neutral genetic diversity in the endangered Antioquia wren (Thryophilus sernai). CONSERV GENET 2020. [DOI: 10.1007/s10592-020-01313-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Culver HR, Sinha J, Prieto TR, Calo CJ, Fairbanks BD, Bowman CN. Click Nucleic Acid–DNA Binding Behavior: Dependence on Length, Sequence, and Ionic Strength. Biomacromolecules 2020; 21:4205-4211. [DOI: 10.1021/acs.biomac.0c00996] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Affiliation(s)
- Heidi R. Culver
- Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, Colorado 80309, United States
| | - Jasmine Sinha
- Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, Colorado 80309, United States
| | - Tania R. Prieto
- Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, Colorado 80309, United States
| | - Christopher J. Calo
- Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, Colorado 80309, United States
| | - Benjamin D. Fairbanks
- Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, Colorado 80309, United States
| | - Christopher N. Bowman
- Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, Colorado 80309, United States
- Department of Chemistry, University of Colorado Boulder, Boulder, Colorado 80309, United States
- Materials Science and Engineering Program, University of Colorado Boulder, Boulder, Colorado 80309, United States
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Ghartey-Kwansah G, Adu-Nti F, Aboagye B, Ankobil A, Essuman EE, Opoku YK, Abokyi S, Abu EK, Boampong JN. Autophagy in the control and pathogenesis of parasitic infections. Cell Biosci 2020; 10:101. [PMID: 32944216 PMCID: PMC7487832 DOI: 10.1186/s13578-020-00464-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 08/25/2020] [Indexed: 12/11/2022] Open
Abstract
Background Autophagy has a crucial role in the defense against parasites. The interplay existing between host autophagy and parasites has varied outcomes due to the kind of host cell and microorganism. The presence of autophagic compartments disrupt a significant number of pathogens and are further cleared by xenophagy in an autolysosome. Another section of pathogens have the capacity to outwit the autophagic pathway to their own advantage. Result To comprehend the interaction between pathogens and the host cells, it is significant to distinguish between starvation-induced autophagy and other autophagic pathways. Subversion of host autophagy by parasites is likely due to differences in cellular pathways from those of ‘classical’ autophagy and that they are controlled by parasites in a peculiar way. In xenophagy clearance at the intracellular level, the pathogens are first ubiquitinated before autophagy receptors acknowledgement, followed by labeling with light chain 3 (LC3) protein. The LC3 in LC3-associated phagocytosis (LAP) is added directly into vacuole membrane and functions regardless of the ULK, an initiation complex. The activation of the ULK complex composed of ATG13, FIP200 and ATG101causes the initiation of host autophagic response. Again, the recognition of PAMPs by conserved PRRs marks the first line of defense against pathogens, involving Toll-like receptors (TLRs). These all important immune-related receptors have been reported recently to regulate autophagy. Conclusion In this review, we sum up recent advances in autophagy to acknowledge and understand the interplay between host and parasites, focusing on target proteins for the design of therapeutic drugs. The target host proteins on the initiation of the ULK complex and PRRs-mediated recognition of PAMPs may provide strong potential for the design of therapeutic drugs against parasitic infections.
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Affiliation(s)
- George Ghartey-Kwansah
- Department of Biomedical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Frank Adu-Nti
- Department of Medical Laboratory Science, Radford University College, Accra, Ghana
| | - Benjamin Aboagye
- Department of Forensic Sciences, College of Agriculture and Natural Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Amandus Ankobil
- School of Nursing and Midwifery, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana.,Department of Epidemiology and Biostatistics, State University of New York at Albany, New York, USA
| | - Edward Eyipe Essuman
- US Food and Drugs Administration CBER, OBRR, DETTD 10903 New Hampshire Avenue, White Oak, USA
| | - Yeboah Kwaku Opoku
- Department of Biology Education, Faculty of Science, University of Education, Winneba, Ghana
| | - Samuel Abokyi
- Department of Optometry and Vision Science, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana.,School of Optometry, The Hong Kong Polytechnic University, Kowloon, Hong Kong
| | - Emmanuel Kwasi Abu
- Department of Optometry and Vision Science, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Johnson Nyarko Boampong
- Department of Biomedical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
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Yan S, Chen H, Wang Z, Zhao L. Association of two polymorphisms Asp299Gly and Thr399Ile in Toll-like receptor 4 with rheumatoid arthritis: A meta-analysis. Int J Rheum Dis 2020; 23:1117-1125. [PMID: 32558389 DOI: 10.1111/1756-185x.13890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 05/04/2020] [Accepted: 05/27/2020] [Indexed: 11/28/2022]
Abstract
Our meta-analysis aims to evaluate the association of Asp299Gly and Thr399Ile with rheumatoid arthritis (RA) susceptibility and severity. By manually searching 3 electronic databases (PubMed, Embase and Web of Science), relevant articles were collected. After checking eligibility for every study, this meta-analysis on eligible studies was performed under 5 genetic models: (1) allelic contrast; (2) heterozygous model; (3) homozygous model; (4) dominant model; (5) recessive model. In Spanish populations, a significantly decreased RA risk was identified in allelic comparison (odds ratio [OR] = 0.73, 95% CI 0.55 ~ 0.96) and dominant model (OR = 0.74, 95% CI 0.56 ~ 0.99) of Asp299Gly polymorphism. A trend of reduced risk was also observed under the heterozygous model (OR = 0.77, 95% CI 0.58 ~ 1.03). As for Thr399Ile, it might also have a protective effect on Spanish populations in allelic comparison (OR = 0.71, 95% CI 0.44 ~ 1.15). In contrast, for both Asp299Gly and Thr399Ile, a higher risk of RA was detected in Chinese Han populations. The frequency of both Asp299Gly and Thr399Ile increased in rheumatoid factor (RF)-positive subjects in Chinese patients (Asp299Gly, RF+:RF- = 0.165:0.145; Thr399Ile, RF+:RF- = 0.170:0.161) and decreased in Spanish patients (Asp299Gly, RF+:RF- = 0.060:0.073; Thr399Ile, RF+:RF- = 0.046:0.056), but not to a statistically significant extent. Our meta-analysis suggested that both Asp299Gly and Thr399Ile might have a protective effect on Spanish populations, but the 2 polymorphisms could act as a susceptible factor in Chinese Han populations. To confirm our results, further investigation concerning the functional impacts of Asp299Gly and Thr399Ile are still needed.
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Affiliation(s)
- Shunchao Yan
- Clinical Medical College of Henan University, Kaifeng, China
| | - Haobo Chen
- Basic Medical College of Henan University, Kaifeng, China
| | - Zixian Wang
- First Affiliated Hospital of Henan University, Kaifeng, China
| | - Linshan Zhao
- Clinical Medical College of Henan University, Kaifeng, China
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Hassan MO, Dix-Peek T, Duarte R, Dickens C, Naidoo S, Vachiat A, Grinter S, Manga P, Naicker S. Association of chronic inflammation and accelerated atherosclerosis among an indigenous black population with chronic kidney disease. PLoS One 2020; 15:e0232741. [PMID: 32649699 PMCID: PMC7351182 DOI: 10.1371/journal.pone.0232741] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 04/03/2020] [Indexed: 12/20/2022] Open
Abstract
Introduction Inflammation plays a major role in the development of atherosclerosis and cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. Toll-like receptor-4 (TLR4) is a major receptor for lipopolysaccharides (endotoxin) and other ligands involved in the pathogenesis of inflammation. We determined whether endotoxin levels and the presence of TLR4 polymorphisms are associated with markers of inflammation and atherosclerosis among South African CKD patients. Materials and methods Endotoxin, lipopolysaccharide binding protein (LBP), serum CD14 (sCD14), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and carotid intima media thickness (CIMT) were measured in 160 participants (120 CKD patients and 40 controls). Associations between endotoxins and CIMT in the presence of sCD14, IL-8 and MCP-1, were assessed using odds ratios. Participants were screened for the presence of Asp299Gly and Thr399Ile TLR4 polymorphisms, and CIMT and inflammatory markers were compared between subjects with and without TLR4 polymorphisms. Results Endotoxin levels correlated with sCD14 (r = 0.441, p<0.001) and MCP-1 (r = 0.388, p<0.001) levels while increased CIMT was associated with MCP-1 (r = 0.448, p<0.001), sCD14 levels (r = 0.476, p<0.001), LBP (r = 0.340, p<0.001), and IL-8 (r = 0.395, p<0.001). Atherosclerosis was associated with endotoxin levels (odds ratio: 4.95; 95% confidence interval: 2.52–9.73; p<0.001), and was predicted by higher serum levels of inflammatory markers. Analysis of patients with TLR4 polymorphisms showed reduced serum levels of inflammatory markers and CIMT values compared with the patients carrying the wild type TLR4 alleles. Conclusion The study demonstrated associations between circulating endotoxaemia, systemic inflammation and accelerated atherosclerosis among South African CKD patients, and showed that the atherogenic predictive power of endotoxaemia was significantly increased by the presence of elevated levels of inflammatory markers. Additional findings, which must be confirmed, suggest that TLR4 polymorphisms are associated with low levels of inflammatory markers and CIMT values.
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Affiliation(s)
- Muzamil Olamide Hassan
- Divisions of Nephrology, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- * E-mail:
| | - Therese Dix-Peek
- Internal Medicine Research Laboratory, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Raquel Duarte
- Internal Medicine Research Laboratory, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Caroline Dickens
- Internal Medicine Research Laboratory, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Sagren Naidoo
- Divisions of Nephrology, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Ahmed Vachiat
- Division of Cardiology, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Sacha Grinter
- Division of Cardiology, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Pravin Manga
- Division of Cardiology, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Saraladevi Naicker
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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Pathogen-associated selection on innate immunity genes (TLR4, TLR7) in a neotropical rodent in landscapes differing in anthropogenic disturbance. Heredity (Edinb) 2020; 125:184-199. [PMID: 32616896 PMCID: PMC7490709 DOI: 10.1038/s41437-020-0331-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 06/05/2020] [Accepted: 06/06/2020] [Indexed: 01/10/2023] Open
Abstract
Toll-like receptors (TLRs) form part of the innate immune system and can recognize structurally conserved pathogen-associated molecular pattern (PAMP) molecules. Their functional importance in the resistance to pathogens has been documented in laboratory experimental settings and in humans. TLR diversity, however, has been rarely investigated in wildlife species. How the genetic diversity of TLRs is associated with various pathogens and how it is shaped by habitat disturbance are understudied. Therefore, we investigated the role of genetic diversity in the functionally important parts of TLR4 and TLR7 genes in resistance towards gastrointestinal nematodes and Hepacivirus infection. We chose a generalist study species, the rodent Proechimys semispinosus, because it is highly abundant in three Panamanian landscapes that differ in their degree of anthropogenic modification. We detected only two TLR7 haplotypes that differed by one synonymous single-nucleotide polymorphism (SNP) position. The TLR4 variability was higher, and we detected four TLR4 haplotypes that differed at one synonymous SNP and at three amino acid positions within the leucine-rich repeat region. Only TLR4 haplotypes had different frequencies in each landscape. Using generalized linear models, we found evidence that nematode loads and virus prevalence were influenced by both specific TLR4 haplotypes and landscape. Here, the variable “landscape” served as a surrogate for the important influential ecological factors distinguishing landscapes in our study, i.e. species diversity and host population density. Individuals carrying the common TLR4_Ht1 haplotype were less intensely infected by the most abundant strongyle nematode. Individuals carrying the rare TLR4_Ht3 haplotype were all Hepacivirus-positive, where those carrying the rare haplotype TLR4_Ht4 were less often infected by Hepacivirus than individuals with other haplotypes. Our study highlights the role of TLR diversity in pathogen resistance and the importance of considering immune genetic as well as ecological factors in order to understand the effects of anthropogenic changes on wildlife health.
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Kong Y, Zheng J, Xu X, Chen X, Wang J, Lu L, Ye Z. A comprehensive evaluation of association between homocysteine levels and single nucleotide polymorphisms with hypertension risk: A protocol of systematic review and network meta-analysis. Medicine (Baltimore) 2020; 99:e20791. [PMID: 32590761 PMCID: PMC7328956 DOI: 10.1097/md.0000000000020791] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND According to the relevant reports that single nucleotide polymorphisms (SNPs) may contribute to change of homocysteine (HCY) levels and increase the risk of hypertension (HTN). During the inconsistent results, this meta-analysis purpose is systematically review and synthesized relevant data on HCY levels and SNPs in HTN. METHODS The systematic search database, from the following database to find out the association studies of SNPs and HTN publications up until March 2020 from the databases of PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), the Chinese Science and Technology Periodical Database (VIP) and Wan fang databases, and Chinese Biomedical Literature Database (CBM). Network meta-analysis and Thakkinstian's algorithm were used to select the most appropriate genetic model, along with false positive report probability (FPRP) for noteworthy associations. All statistical analyses were calculated with STATA software (version 14.0; StataCorp, College Station, TX). RESULTS This meta-analysis will provide high-quality evidence to the effects of SNP on HTN and levels of HCY, and find between SNPs and HTN susceptibility on in all the genetic models, and choose the best one. CONCLUSIONS This meta-analysis will research which SNP is the most correlated with HTN risk. REGISTRATION INPLASY202050002.
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Affiliation(s)
- Yixuan Kong
- Ruikang Affiliated Hospital of Guangxi University of Chinese Medicine
| | - Jinghui Zheng
- Department of Geriatrics, Ruikang Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Xiangmei Xu
- Ruikang Affiliated Hospital of Guangxi University of Chinese Medicine
| | - Xuan Chen
- Ruikang Affiliated Hospital of Guangxi University of Chinese Medicine
| | - Jie Wang
- Ruikang Affiliated Hospital of Guangxi University of Chinese Medicine
| | - Liying Lu
- Ruikang Affiliated Hospital of Guangxi University of Chinese Medicine
| | - Zhuomiao Ye
- Ruikang Affiliated Hospital of Guangxi University of Chinese Medicine
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Habibabadi HM, Parsania M, Pourfathollah AA, Haghighat S, Sharifi Z. Association of TLR3 single nucleotide polymorphisms with susceptibility to HTLV-1 infection in Iranian asymptomatic blood donors. Rev Soc Bras Med Trop 2020; 53:e20200026. [PMID: 32578708 PMCID: PMC7310369 DOI: 10.1590/0037-8682-0026-2020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 04/03/2020] [Indexed: 01/06/2023] Open
Abstract
INTRODUCTION: The human T-lymphotropic virus type 1 (HTLV-1) has a single-stranded RNA genome and expresses specific proteins that have oncogenic potential. Approximately 15 to 20 million people worldwide have been infected by this virus. Changes in protein or gene expression are the effects of single nucleotide polymorphisms (SNPs) within the Toll-like receptor 3 (TLR3) gene. The function and efficacy of signal transduction also lead to modified immune responses. The present study aimed to investigate the association of SNPs within TLR3 (rs3775291 and rs3775296) with susceptibility to HTLV-1 infection in Iranian asymptomatic blood donors. METHODS: This study was performed on 100 HTLV-1-infected asymptomatic blood donors and 118 healthy blood donors. Genomic DNA from all participants was purified and then amplified using specific PCR primers. SNPs within TLR3 were evaluated using the restriction fragmentation length polymorphism technique, and the results were analyzed using SPSS software (version 22). RESULTS: The frequencies of the TLR3 (rs3775296) CC, CA, AA genotypes were 70%, 24%, and 6% in the patient group, and 50.8%, 44.9%, and 4.2% in the control group, respectively. There was a significant difference in the frequency distribution of TLR3 (rs3775296) genotypes and alleles, but not in the frequency distribution of TLR3 (rs3775291) genotypes between the patient and control groups. CONCLUSIONS: The TLR3 SNP rs3775296 was significantly associated with HTLV-1 infection and may be a protective factor against this viral infection.
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Affiliation(s)
- Hossein Mehrabi Habibabadi
- Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Masoud Parsania
- Department of Microbiology, Faculty of Medicine, Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Ali Akbar Pourfathollah
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Setareh Haghighat
- Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Zohreh Sharifi
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
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Menendez D, Snipe J, Marzec J, Innes CL, Polack FP, Caballero MT, Schurman SH, Kleeberger SR, Resnick MA. p53-responsive TLR8 SNP enhances human innate immune response to respiratory syncytial virus. J Clin Invest 2020; 129:4875-4884. [PMID: 31430261 DOI: 10.1172/jci128626] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 08/08/2019] [Indexed: 12/15/2022] Open
Abstract
The Toll-like receptor 8 (TLR8) has an important role in innate immune responses to RNA viral infections, including respiratory syncytial virus (RSV). We previously reported that TLR8 expression was increased directly by the tumor suppressor and transcription factor p53 via a single nucleotide polymorphism (SNP) (rs3761624) in the TLR8 promoter, thereby placing TLR8 in the p53/immune axis. Because this SNP is in linkage disequilibrium with other SNPs associated with several infectious diseases, we addressed the combined influence of p53 and the SNP on downstream inflammatory signaling in response to a TLR8 cognate ssRNA ligand. Using human primary lymphocytes, p53 induction by chemotherapeutic agents such as ionizing radiation caused SNP-dependent synergistic increases in IL-6 following incubation with an ssRNA ligand, as well as TLR8 RNA and protein expression along with p53 binding at the TLR-p53 SNP site. Because TLR8 is X-linked, the increases were generally reduced in heterozygous females. We found a corresponding association of the p53-responsive allele with RSV disease severity in infants hospitalized with RSV infection. We conclude that p53 can strongly influence TLR8-mediated immune responses and that knowledge of the p53-responsive SNP can inform diagnosis and prognosis of RSV disease and other diseases that might have a TLR8 component, including cancer.
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Affiliation(s)
- Daniel Menendez
- Genome Integrity & Structural Biology Laboratory.,Immunity, Inflammation, and Disease Laboratory and
| | - Joyce Snipe
- Genome Integrity & Structural Biology Laboratory
| | | | - Cynthia L Innes
- Clinical Research Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA
| | | | | | - Shepherd H Schurman
- Clinical Research Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA
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The unleashing of the immune system in COVID-19 and sepsis: the calm before the storm? Inflamm Res 2020; 69:757-763. [PMID: 32468151 PMCID: PMC8823100 DOI: 10.1007/s00011-020-01366-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 05/19/2020] [Accepted: 05/22/2020] [Indexed: 01/08/2023] Open
Abstract
The novel coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is sorely testing health care systems and economies around the world and is rightly considered as the major health emergency in a century. Despite the course of the disease appearing to be mild in many cases, a significant proportion of symptomatic patients develop pneumonia requiring hospitalisation or progress to manifest respiratory complications leading to intensive care treatment. Potential interventions for SARS-CoV2-associated pneumonia are being tested, some of which holding promise, but as of today none of these has yet demonstrated outstanding efficacy in treating COVID-19. In this article, we discuss fresh perspectives and insights into the potential role of immune dysregulation in COVID-19 as well as similarities with systemic inflammatory response in sepsis and the rationale for exploring novel treatment options affecting host immune response.
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TLR7 Polymorphism (rs179008 and rs179009) in HIV-Infected Individual Naïve to ART. Mediators Inflamm 2020; 2020:6702169. [PMID: 32565728 PMCID: PMC7256714 DOI: 10.1155/2020/6702169] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 04/21/2020] [Indexed: 01/18/2023] Open
Abstract
Toll-like receptors (TLRs) play an important role in the innate immune response to HIV infection. Single nucleotide polymorphism (SNP) in TLR7 (Gln11Leu) gene has been associated with a rapid decline of CD4T cell count. Hence, we assessed the TLR7 (rs179008, Gln11Leu (A/T) and rs179009, IVS2-151 (A/G)) polymorphism in 150 HIV-infected individuals naïve to ART and 158 healthy controls. The genotyping of TLR7 Gln11Leu (A/T) and IVS2-151 (A/G) polymorphisms was done using the PCR-RFLP method. In univariate analysis, none of the genotype and haplotype of TLR7 Gln11Leu (A/T) and IVS2-151 (A/G) polymorphism differed significantly between HIV-infected individuals and healthy controls. The occurrence of TLR7 rs179009AG genotype in the codominant model and rs179009 AG-GG genotype in the dominant model was significantly reduced in HIV-infected individuals as compared to healthy controls (18.0% vs. 29.1%, OR = 0.42, P = 0.016; 26.7% vs. 36.7%, OR = 0.52, P = 0.016). TLR7 rs179009AG genotype was significantly underrepresented in the intermediate HIV disease stage compared with healthy controls (OR = 0.03, P = 0.04). TLR7 rs179009AG genotype expressed higher in tobacco-consuming HIV-infected individuals compared with nonusers (OR = 1.71, P = 0.47). In conclusion, rs179009 AG-GG and AG genotypes were found reduced in HIV-infected individuals as compared to healthy controls; their higher prevalence in health individuals clearly support that they are associated with reduced risk of acquisition of HIV-1 infection.
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Marchionni E, Porpora MG, Megiorni F, Piacenti I, Giovannetti A, Marchese C, Benedetti Panici P, Pizzuti A. TLR4 T399I Polymorphism and Endometriosis in a Cohort of Italian Women. Diagnostics (Basel) 2020; 10:diagnostics10050255. [PMID: 32349318 PMCID: PMC7277393 DOI: 10.3390/diagnostics10050255] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 04/20/2020] [Accepted: 04/24/2020] [Indexed: 12/12/2022] Open
Abstract
Background: Endometriosis is a widespread multifactorial disease in which environmental, genetic, and epigenetic factors contribute to the phenotype. Single Nucleotide Polymorphisms (SNPs) in genes implicated in pivotal molecular mechanisms have been investigated as susceptible risk factors in distinct populations. Among these, Toll-like receptor 4 (TLR4) represents a good candidate due to its role in the immune/inflammatory response and endometriosis pathogenesis. Methods: The TRL4 gene T399I SNP (C/T transition, rs4986791) was investigated in 236 Italian endometriosis patients and 150 controls by using the PCR-RFLP method. One-tailed Fisher’s exact test was used to compare differences between categorical variables. T399I genotype distribution was evaluated for Hardy–Weinberg equilibrium in both groups using the Chi-squared test for given probabilities. Results: Fisher’s exact test comparing C and T allele frequencies showed a difference in the frequency of T alleles between patients and controls (OR = 1.96, 95% confidence interval 0.91–4.23; p-value = 0.0552). Genotype frequencies did not show any significant difference between patients and controls. The homozygous TT genotype was observed in 2% of endometriosis women and not in controls. Conclusions: Our results show that the TLR4 rs4986791 T variant may be considered a genetic risk factor for endometriosis in Italian women. More extensive studies in other populations are needed to confirm this result.
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Affiliation(s)
- Enrica Marchionni
- Department of Experimental Medicine, Sapienza University of Rome, Policlinico Umberto I Hospital, 00161 Rome, Italy
- Correspondence: ; Tel.: +39-0649974080
| | - Maria Grazia Porpora
- Department of Maternal and Child Health and Urology, Sapienza University of Rome, Policlinico Umberto I Hospital, 00161 Rome, Italy
| | - Francesca Megiorni
- Department of Experimental Medicine, Sapienza University of Rome, Policlinico Umberto I Hospital, 00161 Rome, Italy
| | - Ilaria Piacenti
- Department of Maternal and Child Health and Urology, Sapienza University of Rome, Policlinico Umberto I Hospital, 00161 Rome, Italy
| | - Agnese Giovannetti
- Laboratory of Clinical Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
| | - Cinzia Marchese
- Department of Experimental Medicine, Sapienza University of Rome, Policlinico Umberto I Hospital, 00161 Rome, Italy
| | - Pierluigi Benedetti Panici
- Department of Maternal and Child Health and Urology, Sapienza University of Rome, Policlinico Umberto I Hospital, 00161 Rome, Italy
| | - Antonio Pizzuti
- Department of Experimental Medicine, Sapienza University of Rome, Policlinico Umberto I Hospital, 00161 Rome, Italy
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Tarragô AM, da Silva Neto PV, Ramasawmy R, Pereira GL, Toro DM, de Amorim Xabregas L, Costa AG, Victória MB, da Silva Victória F, Malheiro A. Combination of genetic polymorphisms in TLR influence cytokine profile in HCV patients treated with DAAs in the State of Amazonas. Cytokine 2020; 130:155052. [PMID: 32179425 DOI: 10.1016/j.cyto.2020.155052] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 11/26/2019] [Accepted: 02/24/2020] [Indexed: 02/08/2023]
Abstract
Hepatitis C is a public health problem and affects approximately 3% of the world's population. HCV infections have a wide spectrum of clinical manifestations, and several single nucleotide polymorphisms (SNPs) in the genes of the toll-like receptors are cited to influence the clinical outcomes. A cross-sectional study was conducted in the Amazonas State, Brazil in which SNPs in TLR4 and TLR9 genes were genotyped by PCR-RFLP in 151 HCV chronic liver disease patients and 206 healthy donors. The circulating cytokines IL-6, TNF, IL-10, IL-2, IFN-γ, IL-4 and IL-17A were measured by cytometric bead array (CBA) which revealed that the combined genotypes of TLR9 -1237T/T and -1486C/T seem to influence the cytokine profile under lipopolysaccharide (LPS) stimulation of the Th17 profile, especially among patients with advanced chronic liver disease when treated with DAAs.
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Affiliation(s)
- Andréa Monteiro Tarragô
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Amazonas, Brazil; Laboratório de Genômica, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Amazonas, Brazil; Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, Amazonas, Brazil.
| | - Pedro Vieira da Silva Neto
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Amazonas, Brazil; Laboratório de Genômica, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Amazonas, Brazil
| | - Rajendranath Ramasawmy
- Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD), Manaus, Amazonas, Brazil; Laboratório de Genômica, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Amazonas, Brazil
| | - Grenda Leite Pereira
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Amazonas, Brazil; Laboratório de Genômica, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Amazonas, Brazil
| | - Diana Mota Toro
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Amazonas, Brazil; Laboratório de Genômica, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Amazonas, Brazil
| | - Lilyane de Amorim Xabregas
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Amazonas, Brazil; Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Amazonas, Brazil; Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, Amazonas, Brazil
| | - Allyson Guimaraes Costa
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Amazonas, Brazil; Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Amazonas, Brazil; Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD), Manaus, Amazonas, Brazil; Laboratório de Genômica, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Amazonas, Brazil; Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, Amazonas, Brazil
| | - Marilú Barbieri Victória
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Amazonas, Brazil; Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD), Manaus, Amazonas, Brazil
| | - Flamir da Silva Victória
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Amazonas, Brazil; Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD), Manaus, Amazonas, Brazil
| | - Adriana Malheiro
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Amazonas, Brazil; Laboratório de Genômica, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Amazonas, Brazil; Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, Amazonas, Brazil.
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Frascaroli G, Rossini G, Maltoni V, Bartoletti M, Ortolani P, Gredmark-Russ S, Gelsomino F, Moroni A, Silenzi S, Castellani G, Sambri V, Mastroianni A, Brune W, Varani S. Genetic and Functional Characterization of Toll-Like Receptor Responses in Immunocompetent Patients With CMV Mononucleosis. Front Cell Infect Microbiol 2020; 10:386. [PMID: 32850485 PMCID: PMC7426556 DOI: 10.3389/fcimb.2020.00386] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 06/24/2020] [Indexed: 12/15/2022] Open
Abstract
Background: Human cytomegalovirus (CMV) modulates both innate and adaptive immune responses. However, limited data are available on the role of receptors of innate immunity, such as toll-like receptors (TLRs) in contributing to antiviral responses and inflammation. Objectives: The aim of this translational study was to characterize TLR responses in immunocompetent patients with primary and symptomatic CMV infection. Study Design: The study population consisted of 40 patients suffering from CMV mononucleosis and 124 blood donors included as controls. We evaluated the association between TLR2, 3, 4, 7 and 9 gene single nucleotide polymorphism (SNP) and susceptibility to symptomatic CMV infection in immunocompetent adults. Additionally, functional TLR-mediated cytokine responses in supernatants of short-term cultures of whole blood from patients with CMV mononucleosis and blood donors were evaluated. Results: TLR2 and TLR7/8 responses were altered in CMV infected patients as compared to healthy donors and were associated with the release of higher levels of the pro-inflammatory cytokines IL-6 and TNF-α, but not of the anti-inflammatory mediator IL-10. The analysis on the TLR SNPs indicated no difference between patients with CMV infection and the control group. Conclusions: No variation in the TLR2,3,4,7 and 9 genes was associated to the development of symptomatic CMV infection in immunocompetent adults. Nevertheless, TLR-mediated responses in CMV-infected patients appeared to be skewed toward a pro-inflammatory profile, which may contribute to the development of inflammatory symptoms during the CMV mononucleotic syndrome.
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Affiliation(s)
- Giada Frascaroli
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
- *Correspondence: Giada Frascaroli
| | - Giada Rossini
- Unit of Microbiology, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Virginia Maltoni
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Michele Bartoletti
- Infectious Diseases Unit, Department of Medical and Surgical Science, University of Bologna, Bologna, Italy
| | | | - Sara Gredmark-Russ
- Center for Infectious Medicine, ANA Futura, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
- Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Francesco Gelsomino
- Unit of Microbiology, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Alessandra Moroni
- Unit of Microbiology, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Silvia Silenzi
- Unit of Microbiology, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Gastone Castellani
- Department of Physics and Astronomy and Galvani Center for Biocomplexity, University of Bologna, Bologna, Italy
| | - Vittorio Sambri
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
- Unit of Microbiology, The Romagna Hub Laboratory, Pievesestina, Italy
| | - Antonio Mastroianni
- Unit of Infectious and Tropical Diseases, St. Annunziata Hospital, Cosenza, Italy
- Unit of Infectious Diseases, G.B. Morgagni-Pierantoni Hospital, Forlì, Italy
| | - Wolfram Brune
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Stefania Varani
- Unit of Microbiology, St. Orsola-Malpighi University Hospital, Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
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50
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Armstrong C, Davies RG, González‐Quevedo C, Dunne M, Spurgin LG, Richardson DS. Adaptive landscape genetics and malaria across divergent island bird populations. Ecol Evol 2019; 9:12482-12502. [PMID: 31788192 PMCID: PMC6875583 DOI: 10.1002/ece3.5700] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 08/28/2019] [Accepted: 09/02/2019] [Indexed: 12/31/2022] Open
Abstract
Environmental conditions play a major role in shaping the spatial distributions of pathogens, which in turn can drive local adaptation and divergence in host genetic diversity. Haemosporidians, such as Plasmodium (malaria), are a strong selective force, impacting survival and fitness of hosts, with geographic distributions largely determined by habitat suitability for their insect vectors. Here, we have tested whether patterns of fine-scale local adaptation to malaria are replicated across discrete, ecologically differing island populations of Berthelot's pipits Anthus berthelotii. We sequenced TLR4, an innate immunity gene that is potentially under positive selection in Berthelot's pipits, and two SNPs previously identified as being associated with malaria infection in a genome-wide association study (GWAS) in Berthelot's pipits in the Canary Islands. We determined the environmental predictors of malaria infection, using these to estimate variation in malaria risk on Porto Santo, and found some congruence with previously identified environmental risk factors on Tenerife. We also found a negative association between malaria infection and a TLR4 variant in Tenerife. In contrast, one of the GWAS SNPs showed an association with malaria risk in Porto Santo, but in the opposite direction to that found in the Canary Islands GWAS. Together, these findings suggest that disease-driven local adaptation may be an important factor in shaping variation among island populations.
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Affiliation(s)
| | | | - Catalina González‐Quevedo
- School of Biological SciencesUniversity of East AngliaNorwichUK
- Grupo Ecología y Evolución de VertebradosInstituto de BiologíaFacultad de Ciencias Exactas y NaturalesUniversidad de AntioquiaMedellínColombia
| | - Molly Dunne
- School of Biological SciencesUniversity of East AngliaNorwichUK
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