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Stewart J, Damania B. Innate Immune Recognition of EBV. Curr Top Microbiol Immunol 2025. [PMID: 40399572 DOI: 10.1007/82_2025_297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025]
Abstract
Epstein-Barr virus (EBV) is a very successful human pathogen, with ~95% seroprevalence worldwide (Mentzer et al, Nat Commun 13:1818, 2022). If contracted in early childhood, EBV infection is typically asymptomatic; however, infections in adolescence and adulthood can manifest as infectious mononucleosis (IM). The innate immune response is the first line of defense, and its function is critical for controlling EBV infection. During EBV infection, components of the virus, known as pathogen-associated molecular patterns (PAMPs), are recognized by germline-encoded pattern recognition receptors (PRRs). PRRs are found on both non-immune and immune cells including antigen-presenting cells, such as macrophages, monocytes, dendritic cells, natural killer (NK), and mast cells. PRRs are also found on B cells and epithelial cells, the primary targets of EBV infection. Without immune surveillance, EBV can transform cells inducing various malignancies. Conversely, a prolonged innate immune response can lead to chronic inflammation which increases the likelihood of cancer. This review discusses innate immune recognition of EBV and its associated diseases.
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Affiliation(s)
- Jessica Stewart
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Blossom Damania
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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Zhang HQ, Feng JH, Li SJ, Yang YX, Long Y. Risk Factors of Cytomegalovirus Retinitis Occurrence After Allogeneic Hematopoietic Stem Cell Transplantation. Ocul Immunol Inflamm 2025; 33:295-302. [PMID: 39377667 DOI: 10.1080/09273948.2024.2406310] [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: 01/26/2024] [Revised: 07/24/2024] [Accepted: 09/16/2024] [Indexed: 10/09/2024]
Abstract
PURPOSE To explore the potential risk factors for the occurrence of human cytomegalovirus (HCMV) retinitis (CMVR) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients. METHODS This is a retrospective, nested case-control study conducted in hematological patients with CMVR who underwent allo-HSCT. Patients diagnosed with CMVR after allo-HSCT were included as the case group, and those without CMVR were matched by a ratio of 1:2 and were recruited as controls. We selected 19 pre- and post-transplant indicators for univariate analysis between the cases and controls, and then Logistic regression analysis was used to calculate the odds ratio (OR) and 95% confidence intervals (CI) for exploration of risk factors of the CMVR occurrence. RESULTS A total of 1308 allo-HSCT patients from January 1, 2020 to July 31, 2023 were analyzed, and 27 patients were diagnosed CMVR with a median onset time of 222 days after transplantation. In univariate analysis, donors of stem cells source, HLA-match types (including matched sibling donor, haploidentical donor, and unrelated donor), post-transplant Epstein-Barr virus (EBV) viremia, platelet implantation time, and serostatus of CMV-IgG were more easily to develop CMVR than controls (p < 0.001, p = 0.003, p < 0.001, p = 0.032, p = 0.038, respectively). Multivariate logistic regression analysis showed that stem cells source (OR 7.823, 95% CI 1.759-34.800), HLA-match types (OR 7.452, 95% CI 1.099-50.542), and post-transplant EBV infection (OR 7.510, 95% CI 1.903-29.640) were positively associated with the onset of CMVR. CONCLUSION Stem cells derived from bone marrow and peripheral blood, HLA-match types, and post-transplant EBV viremia are important risk predictors of CMVR in allo-HSCT patients. These results suggest that clinicians should pay more attention to these indicators when formulating preventive measures pre- and post-transplant.
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Affiliation(s)
- Hai-Qing Zhang
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
- Department of Clinical Laboratory, Qingdao Women and Children's Hospital, Qingdao, China
| | - Jing-Hong Feng
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Sheng-Jun Li
- Department of Clinical Laboratory, Qingdao Women and Children's Hospital, Qingdao, China
| | - Yun-Xian Yang
- Department of Clinical Laboratory, Dali Bai Autonomous Prefecture Chinese Medicine Hospital, DaLi, China
| | - Yan Long
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
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Zhong LY, Xie C, Zhang LL, Yang YL, Liu YT, Zhao GX, Bu GL, Tian XS, Jiang ZY, Yuan BY, Li PL, Wu PH, Jia WH, Münz C, Gewurz BE, Zhong Q, Sun C, Zeng MS. Research landmarks on the 60th anniversary of Epstein-Barr virus. SCIENCE CHINA. LIFE SCIENCES 2025; 68:354-380. [PMID: 39505801 DOI: 10.1007/s11427-024-2766-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 08/15/2024] [Indexed: 11/08/2024]
Abstract
Epstein-Barr virus (EBV), the first human oncovirus discovered in 1964, has become a focal point in virology, immunology, and oncology because of its unique biological characteristics and significant role in human diseases. As we commemorate the 60th anniversary of EBV's discovery, it is an opportune moment to reflect on the major advancements in our understanding of this complex virus. In this review, we highlight key milestones in EBV research, including its virion structure and life cycle, interactions with the host immune system, association with EBV-associated diseases, and targeted intervention strategies.
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Affiliation(s)
- Lan-Yi Zhong
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Chu Xie
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Le-Le Zhang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Yan-Lin Yang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Yuan-Tao Liu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Ge-Xin Zhao
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Guo-Long Bu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Xian-Shu Tian
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Zi-Ying Jiang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Bo-Yu Yuan
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Peng-Lin Li
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Pei-Huang Wu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Wei-Hua Jia
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, 8092, Switzerland
| | - Benjamin E Gewurz
- Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Department of Microbiology, Harvard Medical School, Boston, MA, 02115, USA
- Harvard Program in Virology, Boston, MA, 02115, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA
| | - Qian Zhong
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Cong Sun
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
| | - Mu-Sheng Zeng
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
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Sikora D, Kiś J, Stępień E, Drop B, Polz-Dacewicz M. Serum TLR2 and TLR9 in Prostate Cancer Patients in Relation to EBV Status. Int J Mol Sci 2024; 25:9053. [PMID: 39201739 PMCID: PMC11354572 DOI: 10.3390/ijms25169053] [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: 06/20/2024] [Revised: 08/16/2024] [Accepted: 08/20/2024] [Indexed: 09/03/2024] Open
Abstract
The relationship between Toll-like receptors (TLRs) and prostate cancer (PCa) is complex due to the presence of the Epstein-Barr virus (EBV) infection, which has been identified as a predisposing factor for some cancers, including PCa. The present study aims to investigate these complex links by examining the levels of selected TLRs and the potential impact of EBV infection on PCa. Therefore, we examined the serum of patients with PCa. The study compared EBV(+) patients to risk groups, the Gleason score (GS), and the T-trait. Additionally, the correlation between TLR and antibody levels was examined. The results indicated that higher levels of TLR-2 and TLR-9 were observed in more advanced PCa. The findings of this study may contribute to a deeper understanding of the role of viral infections in PCa and provide information on future strategies for the diagnosis, prevention, and treatment of these malignancies.
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Affiliation(s)
- Dominika Sikora
- Department of Virology with Viral Diagnostics Laboratory, Medical University of Lublin, 20-093 Lublin, Poland; (E.S.); (M.P.-D.)
| | - Jacek Kiś
- 1st Clinical Military Hospital with Outpatient Clinic in Lublin, 20-049 Lublin, Poland;
| | - Ewa Stępień
- Department of Virology with Viral Diagnostics Laboratory, Medical University of Lublin, 20-093 Lublin, Poland; (E.S.); (M.P.-D.)
| | - Bartłomiej Drop
- Department of Medical Informatics and Statistics with e-Health Lab, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Małgorzata Polz-Dacewicz
- Department of Virology with Viral Diagnostics Laboratory, Medical University of Lublin, 20-093 Lublin, Poland; (E.S.); (M.P.-D.)
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Liu W, Hu H, Li C, Li Y, Mao P, Fan B. Genetics of causal relationships between circulating inflammatory proteins and postherpetic neuralgia: a bidirectional Mendelian randomization study. Front Neurol 2024; 15:1405694. [PMID: 38974683 PMCID: PMC11225550 DOI: 10.3389/fneur.2024.1405694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Accepted: 06/05/2024] [Indexed: 07/09/2024] Open
Abstract
Objective According to data from several observational studies, there is a strong association between circulating inflammatory cytokines and postherpetic neuralgia (PHN), but it is not clear whether this association is causal or confounding; therefore, the main aim of the present study was to analyze whether circulating inflammatory proteins have a bidirectional relationship with PHN at the genetic inheritance level using a Mendelian randomization (MR) study. Methods The Genome-Wide Association Study (GWAS) database was used for our analysis. We gathered data on inflammation-related genetic variation from three GWASs of human cytokines. These proteins included 91 circulating inflammatory proteins, tumor necrosis factor-alpha (TNF-α), macrophage inflammatory protein 1b (MIP-1b), and CXC chemokine 13 (CXCL13). The PHN dataset was obtained from the FinnGen biobank analysis round 5, and consisted of 1,413 cases and 275,212 controls. We conducted a two-sample bidirectional MR study using the TwoSampleMR and MRPRESSO R packages (version R.4.3.1). Our main analytical method was inverse variance weighting (IVW), and we performed sensitivity analyses to assess heterogeneity and pleiotropy, as well as the potential influence of individual SNPs, to validate our findings. Results According to our forward analysis, five circulating inflammatory proteins were causally associated with the development of PHN: interleukin (IL)-18 was positively associated with PHN, and IL-13, fibroblast growth factor 19 (FGF-19), MIP-1b, and stem cell growth factor (SCF) showed reverse causality with PHN. Conversely, we found that PHN was closely associated with 12 inflammatory cytokines, but no significant correlation was found among the other inflammatory factors. Among them, only IL-18 had a bidirectional causal relationship with PHN. Conclusion Our research advances the current understanding of the role of certain inflammatory biomarker pathways in the development of PHN. Additional verification is required to evaluate the viability of these proteins as targeted inflammatory factors for PHN-based treatments.
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Affiliation(s)
- WenHui Liu
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - HuiMin Hu
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Chen Li
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - YiFan Li
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Peng Mao
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - BiFa Fan
- Department of Pain Management, China-Japan Friendship Hospital, Beijing, China
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Chen PK, Chen YM, Chen HH, Liao TL, Chang SH, Yeo KJ, Huang PH, Chen DY. Association of the Reduced Levels of Monocyte Chemoattractant Protein-1 with Herpes Zoster in Rheumatoid Arthritis Patients Treated with Janus Kinase Inhibitors in a Single-Center Cohort. Microorganisms 2024; 12:974. [PMID: 38792802 PMCID: PMC11124047 DOI: 10.3390/microorganisms12050974] [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: 03/27/2024] [Revised: 05/06/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
Anti-interferon (IFN)-γ autoantibodies are linked to varicella zoster virus (VZV) infection. Given the elevated risks of herpes zoster (HZ) in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKis), we aimed to examine the relationship between anti-IFN-γ autoantibodies with HZ development in JAKi-treated patients. Serum titers of anti-IFN-γ autoantibodies, plasma levels of IFN-γ, monocyte chemoattractant protein-1 (MCP-1), and IFN-γ-inducible protein-10 (IP-10) were measured by ELISA. Among the 66 enrolled RA patients, 24 developed new-onset HZ. Significantly lower MCP-1 levels were observed in patients with HZ compared to those without (median, 98.21 pg/mL, interquartile range (IQR) 77.63-150.30 pg/mL versus 142.3 pg/mL, IQR 106.7-175.6 pg/mL, p < 0.05). There was no significant difference in anti-IFN-γ titers, IFN-γ levels, or IP-10 levels between patients with and without HZ. Three of 24 patients with HZ had severe HZ with multi-dermatomal involvement. Anti-IFN-γ titers were significantly higher in patients with severe HZ than in those with non-severe HZ (median 24.8 ng/mL, IQR 21.0-38.2 ng/mL versus 10.5 ng/mL, IQR 9.9-15.0 ng/mL, p < 0.005). Our results suggest an association between reduced MCP-1 levels and HZ development in JAKi-treated RA patients. High-titer anti-IFN-γ autoantibodies may be related to severe HZ in these patients.
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Affiliation(s)
- Po-Ku Chen
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung 404, Taiwan; (P.-K.C.); (S.-H.C.); (K.-J.Y.); (P.-H.H.)
- College of Medicine, China Medical University, Taichung 404, Taiwan
- Translational Medicine Laboratory, Rheumatology and Immunology Center, China Medical University Hospital, Taichung 404, Taiwan
| | - Yi-Ming Chen
- Division of Translational Medicine, Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan;
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan; (H.-H.C.); (T.-L.L.)
| | - Hsin-Hua Chen
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan; (H.-H.C.); (T.-L.L.)
- Department of Industrial Engineering and Enterprise Information, Tunghai University, Taichung 407, Taiwan
- Big Data Center, National Chung Hsing University, Taichung 402, Taiwan
| | - Tsai-Ling Liao
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan; (H.-H.C.); (T.-L.L.)
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan
- Ph.D. Program in Translational Medicine, Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Shih-Hsin Chang
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung 404, Taiwan; (P.-K.C.); (S.-H.C.); (K.-J.Y.); (P.-H.H.)
- College of Medicine, China Medical University, Taichung 404, Taiwan
- Ph.D. Program in Translational Medicine, Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Kai-Jieh Yeo
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung 404, Taiwan; (P.-K.C.); (S.-H.C.); (K.-J.Y.); (P.-H.H.)
- College of Medicine, China Medical University, Taichung 404, Taiwan
| | - Po-Hao Huang
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung 404, Taiwan; (P.-K.C.); (S.-H.C.); (K.-J.Y.); (P.-H.H.)
- College of Medicine, China Medical University, Taichung 404, Taiwan
| | - Der-Yuan Chen
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung 404, Taiwan; (P.-K.C.); (S.-H.C.); (K.-J.Y.); (P.-H.H.)
- College of Medicine, China Medical University, Taichung 404, Taiwan
- Translational Medicine Laboratory, Rheumatology and Immunology Center, China Medical University Hospital, Taichung 404, Taiwan
- Institute of Clinical Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan
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Yi M, Niu Y, Liu S, Chen Y, Jiao B, Wang Y, Du H, Mei G, Duan H, Han J, Dai Y. Herpesvirus activated NF-κB-mediated antigen processing and presentation to aggravate trichloroethylene-induced hypersensitivity dermatitis. Toxicol Lett 2024; 393:47-56. [PMID: 38242488 DOI: 10.1016/j.toxlet.2024.01.010] [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: 07/10/2023] [Revised: 01/15/2024] [Accepted: 01/15/2024] [Indexed: 01/21/2024]
Abstract
Trichloroethylene-induced hypersensitivity dermatitis (TIHD) is a delayed hypersensitivity response that is affected by genetic and environmental factors. Occupational exposure to trichloroethylene (TCE) enhances antigen presentation, leading to hypersensitivity in workers with the HLA-B* 13:01 allele. Several studies have observed the activation of herpesviruses, such as EpsteinBarr virus (EBV), in TIHD patients. However, the underlying mechanisms remain unclear. Toll-like receptors (TLRs) play a pivotal role in the pathogenesis of herpesvirus infection. This study aimed to explore whether TLRs serve as a shared mechanism for both herpesvirus and allergenic chemicals. In this study, HLA-B* 13:01-transfected Hmy2. A C1R cell model was constructed, and cells were treated with TCOH and EBV to explore the possible mechanisms. We established a mouse model of dermatitis and used a TLR4 agonist to verify the effect of herpesvirus on TIHD. The results showed that EBV and TCOH synergistically enhance antigen processing and presentation via the TLR2/NF-κB axis. Furthermore, TLR4 agonist further aggravated skin lesions and liver damage in TCE-sensitized mice through TLR4/NF-κB axis-mediated antigen processing and presentation. Together, this study indicates that viral infection further aggravates the inflammatory response in TIHD based on environment-gene interactions.
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Affiliation(s)
- Mengnan Yi
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050, China
| | - Yong Niu
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050, China
| | - Shuai Liu
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050, China
| | - Yuanyuan Chen
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050, China
| | - Bo Jiao
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050, China
| | - Yican Wang
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050, China
| | - Haijun Du
- Key Laboratory for Infectious Disease Control and Prevention, National Institute for viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
| | - Guoyong Mei
- Key Laboratory for Infectious Disease Control and Prevention, National Institute for viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
| | - Huawei Duan
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050, China
| | - Jun Han
- Key Laboratory for Infectious Disease Control and Prevention, National Institute for viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
| | - Yufei Dai
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050, China; National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing 100021, China.
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Guiouillier F, Derely J, Salvadori A, Pochard J, Le Goff J, Martinez T, Raffin F, Laitselart P, Beaucreux C, Priou S, Conan PL, Foissaud V, Servonnet A, Vest P, Boutonnet M, de Rudnicki S, Bigaillon C, Libert N. Reactivation of Epstein-Barr virus among intensive care patients: a prospective observational study. Intensive Care Med 2024; 50:418-426. [PMID: 38436725 DOI: 10.1007/s00134-024-07345-3] [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: 10/11/2023] [Accepted: 02/02/2024] [Indexed: 03/05/2024]
Abstract
PURPOSE Herpesvirus reactivation has been documented among patients in the intensive care unit (ICU) and is associated with increased morbidity and mortality, particularly for cytomegalovirus (CMV). Epstein-Barr virus (EBV) has been poorly studied despite >95% of the population being seropositive. Our preliminary study suggested an association between EBV reactivation and increased morbidity and mortality. This study aimed to investigate this association among patients admitted to the ICU. METHODS In this multicenter prospective study, polymerase chain reaction was performed to quantify EBV in patients upon ICU admission and then twice a week during their stay. Follow-up was 90 days. RESULTS The study included 129 patients; 70 (54.3%) had EBV reactivation. On day 90, there was no difference in mortality rates between patients with and without reactivation (25.7% vs 15.3%, p = 0.22). Patients with EBV reactivation at admission had increased mortality compared with those without reactivation and those with later reactivation. EBV reactivation was associated with increased morbidity. Patients with EBV reactivation had fewer ventilator-free days at day 28 than those without reactivation (18 [1-22] vs. 21 days [5-26], p = 0.037) and a higher incidence of acute respiratory distress syndrome (34.3% vs. 17%, p = 0.04), infections (92.9% vs. 78%, p = 0.03), and septic shock (58.6% vs. 32.2%, p = 0.004). More patients with EBV reactivation required renal replacement therapy (30% vs. 11.9%, p = 0.02). EBV reactivation was also associated with a more inflammatory immune profile. CONCLUSION While EBV reactivation was not associated with increased 90-day mortality, it was associated with significantly increased morbidity.
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Affiliation(s)
- François Guiouillier
- Service d'Anesthésie-Réanimation, Hôpital d'Instruction des Armées Percy, Clamart, France
| | - Jean Derely
- Service d'Anesthésie-Réanimation, Hôpital d'Instruction des Armées Percy, Clamart, France
| | - Alexandre Salvadori
- Service d'Anesthésie-Réanimation, Hôpital d'Instruction des Armées Bégin, Saint Mandé, France
| | - Jonas Pochard
- Service d'Anesthésie-réanimation Chirurgicale, Hôpital de Bicêtre, Université Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France
| | - Jérôme Le Goff
- Département des Agents Infectieux, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Thibault Martinez
- Service d'Anesthésie-Réanimation, Hôpital d'Instruction des Armées Percy, Clamart, France
| | - Florent Raffin
- Institut de Recherche Biomédicale des Armées, Unité d'Analyses Biologiques, Brétigny sur Orge, France
| | - Philippe Laitselart
- Service d'Anesthésie-Réanimation, Hôpital d'Instruction des Armées Percy, Clamart, France
| | - Charlotte Beaucreux
- Service d'Anesthésie-Réanimation, Hôpital d'Instruction des Armées Bégin, Saint Mandé, France
| | - Sonia Priou
- CentraleSupelec, Université Paris Saclay, Laboratoire Génie Industriel, Gif-Sur-Yvette, France
| | - Pierre-Louis Conan
- Service de maladie infectieuse, Hôpital d'Instruction des Armées Bégin, Saint Mandé, France
| | - Vincent Foissaud
- Service de biologie médicale, Hôpital d'Instruction des Armées Percy, Clamart, France
| | - Aurélie Servonnet
- Institut de Recherche Biomédicale des Armées, Unité d'Analyses Biologiques, Brétigny sur Orge, France
| | - Philippe Vest
- Service de biologie médicale, Hôpital d'Instruction des Armées Percy, Clamart, France
| | - Mathieu Boutonnet
- Service d'Anesthésie-Réanimation, Hôpital d'Instruction des Armées Percy, Clamart, France
| | - Stéphane de Rudnicki
- Service d'Anesthésie-Réanimation, Hôpital d'Instruction des Armées Percy, Clamart, France
| | - Christine Bigaillon
- Service de biologie médicale, Hôpital d'Instruction des Armées Bégin, Saint Mandé, France
| | - Nicolas Libert
- Service d'Anesthésie-Réanimation, Hôpital d'Instruction des Armées Percy, Clamart, France.
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9
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Li D, Ren J, Zhu G, Wu P, Yang W, Ru Y, Feng T, Liu H, Zhang J, Peng J, Tian H, Liu X, Zheng H. Deletions of MGF110-9L and MGF360-9L from African swine fever virus are highly attenuated in swine and confer protection against homologous challenge. J Biol Chem 2023; 299:104767. [PMID: 37142221 PMCID: PMC10236468 DOI: 10.1016/j.jbc.2023.104767] [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: 07/28/2022] [Revised: 04/23/2023] [Accepted: 04/25/2023] [Indexed: 05/06/2023] Open
Abstract
African swine fever, caused by a large icosahedral DNA virus (African swine fever virus, ASFV), is a highly contagious disease in domestic and feral swine, thus posing a significant economic threat to the global swine industry. Currently, there are no effective vaccines or the available methods to control ASFV infection. Attenuated live viruses with deleted virulence factors are considered to be the most promising vaccine candidates; however, the mechanism by which these attenuated viruses confer protection is unclear. Here, we used the Chinese ASFV CN/GS/2018 as a backbone and used homologous recombination to generate a virus in which MGF110-9L and MGF360-9L, two genes antagonize host innate antiviral immune response, were deleted (ASFV-ΔMGF110/360-9L). This genetically modified virus was highly attenuated in pigs and provided effective protection of pigs against parental ASFV challenge. Importantly, we found ASFV-ΔMGF110/360-9L infection induced higher expression of Toll-like receptor 2 (TLR2) mRNA compared with parental ASFV as determined by RNA-Seq and RT-PCR analysis. Further immunoblotting results showed that parental ASFV and ASFV-ΔMGF110/360-9L infection inhibited Pam3CSK4-triggered activating phosphorylation of proinflammatory transcription factor NF-κB subunit p65 and phosphorylation of NF-κB inhibitor IκBα levels, although NF-κB activation was higher in ASFV-ΔMGF110/360-9L-infected cells compared with parental ASFV-infected cells. Additionally, we show overexpression of TLR2 inhibited ASFV replication and the expression of ASFV p72 protein, whereas knockdown of TLR2 had the opposite effect. Our findings suggest that the attenuated virulence of ASFV-ΔMGF110/360-9L might be mediated by increased NF-κB and TLR2 signaling.
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Affiliation(s)
- Dan Li
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Jingjing Ren
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Guoqiang Zhu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Panxue Wu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Wenping Yang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Yi Ru
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Tao Feng
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Huanan Liu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Jing Zhang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Jiangling Peng
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Hong Tian
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Xiangtao Liu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Haixue Zheng
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
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10
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Yao Y, Kong W, Yang L, Ding Y, Cui H. Immunity and Immune Evasion Mechanisms of Epstein-Barr Virus. Viral Immunol 2023; 36:303-317. [PMID: 37285188 DOI: 10.1089/vim.2022.0200] [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] [Indexed: 06/08/2023] Open
Abstract
Epstein-Barr virus (EBV) is the first human oncogenic virus to be identified, which evades the body's immune surveillance through multiple mechanisms that allow long-term latent infection. Under certain pathological conditions, EBVs undergo a transition from the latent phase to the lytic phase and cause targeted dysregulation of the host immune system, leading to the development of EBV-related diseases. Therefore, an in-depth understanding of the mechanism of developing an immune response to EBV and the evasion of immune recognition by EBV is important for the understanding of the pathogenesis of EBV, which is of great significance for finding strategies to prevent EBV infection, and developing a therapy to treat EBV-associated diseases. In this review, we will discuss the molecular mechanisms of host immunological responses to EBV infection and the mechanisms of EBV-mediated immune evasion during chronic active infection.
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Affiliation(s)
- Yanqing Yao
- Department of Pediatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Weijing Kong
- Department of Pediatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lijun Yang
- Department of Pediatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yingxue Ding
- Department of Pediatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hong Cui
- Department of Pediatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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11
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Villarroel-Espindola F, Ejsmentewicz T, Gonzalez-Stegmaier R, Jorquera RA, Salinas E. Intersections between innate immune response and gastric cancer development. World J Gastroenterol 2023; 29:2222-2240. [PMID: 37124883 PMCID: PMC10134417 DOI: 10.3748/wjg.v29.i15.2222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/07/2022] [Accepted: 03/13/2023] [Indexed: 04/14/2023] Open
Abstract
Worldwide, gastric cancer (GC) is the fifth most commonly diagnosed malignancy. It has a reduced prevalence but has maintained its poor prognosis being the fourth leading cause of deaths related to cancer. The highest mortality rates occur in Asian and Latin American countries, where cases are usually diagnosed at advanced stages. Overall, GC is viewed as the consequence of a multifactorial process, involving the virulence of the Helicobacter pylori (H. pylori) strains, as well as some environmental factors, dietary habits, and host intrinsic factors. The tumor microenvironment in GC appears to be chronically inflamed which promotes tumor progression and reduces the therapeutic opportunities. It has been suggested that inflammation assessment needs to be measured qualitatively and quantitatively, considering cell-infiltration types, availability of receptors to detect damage and pathogens, and presence or absence of aggressive H. pylori strains. Gastrointestinal epithelial cells express several Toll-like receptors and determine the first defensive line against pathogens, and have been also described as mediators of tumorigenesis. However, other molecules, such as cytokines related to inflammation and innate immunity, including immune checkpoint molecules, interferon-gamma pathway and NETosis have been associated with an increased risk of GC. Therefore, this review will explore innate immune activation in the context of premalignant lesions of the gastric epithelium and established gastric tumors.
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Affiliation(s)
- Franz Villarroel-Espindola
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
| | - Troy Ejsmentewicz
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
| | - Roxana Gonzalez-Stegmaier
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
| | - Roddy A Jorquera
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
| | - Esteban Salinas
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
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12
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Rex V, Zargari R, Stempel M, Halle S, Brinkmann MM. The innate and T-cell mediated immune response during acute and chronic gammaherpesvirus infection. Front Cell Infect Microbiol 2023; 13:1146381. [PMID: 37065193 PMCID: PMC10102517 DOI: 10.3389/fcimb.2023.1146381] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 03/20/2023] [Indexed: 04/03/2023] Open
Abstract
Immediately after entry into host cells, viruses are sensed by the innate immune system, leading to the activation of innate antiviral effector mechanisms including the type I interferon (IFN) response and natural killer (NK) cells. This innate immune response helps to shape an effective adaptive T cell immune response mediated by cytotoxic T cells and CD4+ T helper cells and is also critical for the maintenance of protective T cells during chronic infection. The human gammaherpesvirus Epstein-Barr virus (EBV) is a highly prevalent lymphotropic oncovirus that establishes chronic lifelong infections in the vast majority of the adult population. Although acute EBV infection is controlled in an immunocompetent host, chronic EBV infection can lead to severe complications in immunosuppressed patients. Given that EBV is strictly host-specific, its murine homolog murid herpesvirus 4 or MHV68 is a widely used model to obtain in vivo insights into the interaction between gammaherpesviruses and their host. Despite the fact that EBV and MHV68 have developed strategies to evade the innate and adaptive immune response, innate antiviral effector mechanisms still play a vital role in not only controlling the acute infection but also shaping an efficient long-lasting adaptive immune response. Here, we summarize the current knowledge about the innate immune response mediated by the type I IFN system and NK cells, and the adaptive T cell-mediated response during EBV and MHV68 infection. Investigating the fine-tuned interplay between the innate immune and T cell response will provide valuable insights which may be exploited to design better therapeutic strategies to vanquish chronic herpesviral infection.
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Affiliation(s)
- Viktoria Rex
- Institute of Genetics, Technische Universität Braunschweig, Braunschweig, Germany
| | - Razieh Zargari
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Markus Stempel
- Institute of Genetics, Technische Universität Braunschweig, Braunschweig, Germany
- Virology and Innate Immunity Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Stephan Halle
- Institute of Immunology, Hannover Medical School, Hannover, Germany
- Institute of Clinical Chemistry, Hannover Medical School, Hannover, Germany
- *Correspondence: Stephan Halle, ; Melanie M. Brinkmann,
| | - Melanie M. Brinkmann
- Institute of Genetics, Technische Universität Braunschweig, Braunschweig, Germany
- Virology and Innate Immunity Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
- *Correspondence: Stephan Halle, ; Melanie M. Brinkmann,
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13
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Casco A, Johannsen E. EBV Reactivation from Latency Is a Degrading Experience for the Host. Viruses 2023; 15:726. [PMID: 36992435 PMCID: PMC10054251 DOI: 10.3390/v15030726] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/06/2023] [Accepted: 03/08/2023] [Indexed: 03/15/2023] Open
Abstract
During reactivation from latency, gammaherpesviruses radically restructure their host cell to produce virion particles. To achieve this and thwart cellular defenses, they induce rapid degradation of cytoplasmic mRNAs, suppressing host gene expression. In this article, we review mechanisms of shutoff by Epstein-Barr virus (EBV) and other gammaherpesviruses. In EBV, canonical host shutoff is accomplished through the action of the versatile BGLF5 nuclease expressed during lytic reactivation. We explore how BGLF5 induces mRNA degradation, the mechanisms by which specificity is achieved, and the consequences for host gene expression. We also consider non-canonical mechanisms of EBV-induced host shutoff. Finally, we summarize the limitations and barriers to accurate measurements of the EBV host shutoff phenomenon.
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Affiliation(s)
- Alejandro Casco
- Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53705, USA
| | - Eric Johannsen
- Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53705, USA
- Department of Medicine, Division of Infectious Diseases, University of Wisconsin, Madison, WI 53705, USA
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14
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Broussard G, Ni G, Zhang Z, Li Q, Cano P, Dittmer DP, Damania B. Barrier-to-autointegration factor 1 promotes gammaherpesvirus reactivation from latency. Nat Commun 2023; 14:434. [PMID: 36746947 PMCID: PMC9902469 DOI: 10.1038/s41467-023-35898-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 01/06/2023] [Indexed: 02/08/2023] Open
Abstract
Gammaherpesviruses, including Kaposi sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are DNA viruses that are globally associated with human cancers and establish lifelong latency in the human population. Detection of gammaherpesviral infection by the cGAS-STING innate immune DNA-sensing pathway is critical for suppressing viral reactivation from latency, a process that promotes viral pathogenesis and transmission. We report that barrier-to-autointegration factor 1 (BAF)-mediated suppression of the cGAS-STING signaling pathway is necessary for reactivation of KSHV and EBV. We demonstrate a role for BAF in destabilizing cGAS expression and show that inhibiting BAF expression in latently infected, reactivating, or uninfected cells leads to increased type I interferon-mediated antiviral responses and decreased viral replication. Furthermore, BAF overexpression resulted in decreased cGAS expression at the protein level. These results establish BAF as a key regulator of the lifecycle of gammaherpesviruses and a potential target for treating viral infections and malignancies.
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Affiliation(s)
- Grant Broussard
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Guoxin Ni
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Zhigang Zhang
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Qian Li
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Patricio Cano
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Dirk P Dittmer
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Blossom Damania
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
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15
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Vojdani A, Vojdani E, Saidara E, Maes M. Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID. Viruses 2023; 15:v15020400. [PMID: 36851614 PMCID: PMC9967513 DOI: 10.3390/v15020400] [Citation(s) in RCA: 63] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 01/24/2023] [Accepted: 01/28/2023] [Indexed: 02/04/2023] Open
Abstract
A novel syndrome called long-haul COVID or long COVID is increasingly recognized in a significant percentage of individuals within a few months after infection with SARS-CoV-2. This disorder is characterized by a wide range of persisting, returning or even new but related symptoms that involve different tissues and organs, including respiratory, cardiac, vascular, gastrointestinal, musculo-skeletal, neurological, endocrine and systemic. Some overlapping symptomatologies exist between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Very much like with long ME/CFS, infections with herpes family viruses, immune dysregulation, and the persistence of inflammation have been reported as the most common pattern for the development of long COVID. This review describes several factors and determinants of long COVID that have been proposed, elaborating mainly on viral persistence, reactivation of latent viruses such as Epstein-Barr virus and human herpesvirus 6 which are also associated with the pathology of ME/CFS, viral superantigen activation of the immune system, disturbance in the gut microbiome, and multiple tissue damage and autoimmunity. Based on these factors, we propose diagnostic strategies such as the measurement of IgG and IgM antibodies against SARS-CoV-2, EBV, HHV-6, viral superantigens, gut microbiota, and biomarkers of autoimmunity to better understand and manage this multi-factorial disorder that continues to affect millions of people in the world.
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Affiliation(s)
- Aristo Vojdani
- Immunosciences Lab, Inc., Los Angeles, CA 90035, USA
- Cyrex Laboratories, LLC, Phoenix, AZ 85034, USA
- Correspondence: ; Tel.: +1-310-657-1077
| | | | - Evan Saidara
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel
| | - Michael Maes
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand
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16
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Hatton AA, Guerra FE. Scratching the Surface Takes a Toll: Immune Recognition of Viral Proteins by Surface Toll-like Receptors. Viruses 2022; 15:52. [PMID: 36680092 PMCID: PMC9863796 DOI: 10.3390/v15010052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 12/22/2022] [Accepted: 12/22/2022] [Indexed: 12/29/2022] Open
Abstract
Early innate viral recognition by the host is critical for the rapid response and subsequent clearance of an infection. Innate immune cells patrol sites of infection to detect and respond to invading microorganisms including viruses. Surface Toll-like receptors (TLRs) are a group of pattern recognition receptors (PRRs) that can be activated by viruses even before the host cell becomes infected. However, the early activation of surface TLRs by viruses can lead to viral clearance by the host or promote pathogenesis. Thus, a plethora of research has attempted to identify specific viral ligands that bind to surface TLRs and mediate progression of viral infection. Herein, we will discuss the past two decades of research that have identified specific viral proteins recognized by cell surface-associated TLRs, how these viral proteins and host surface TLR interactions affect the host inflammatory response and outcome of infection, and address why controversy remains regarding host surface TLR recognition of viral proteins.
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Affiliation(s)
- Alexis A. Hatton
- Department of Microbiology & Cell Biology, Montana State University, Bozeman, MT 59718, USA
| | - Fermin E. Guerra
- Department of Laboratory Medicine & Pathology, University of Washington, Seattle, WA 98195, USA
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17
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Co-infection of porcine deltacoronavirus and porcine epidemic diarrhea virus induces early TRAF6-mediated NF-κB and IRF7 signaling pathways through TLRs. Sci Rep 2022; 12:19443. [PMID: 36376395 PMCID: PMC9660140 DOI: 10.1038/s41598-022-24190-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 11/11/2022] [Indexed: 11/16/2022] Open
Abstract
Porcine deltacoronavirus (PDCoV) and porcine epidemic diarrhea virus (PEDV) infect the small intestine and cause swine enteric coronavirus disease. The mucosal innate immune system is the first line of defense against viral infection. The modulatory effect of PDCoV and PEDV coinfection on antiviral signaling cascades of the intestinal mucosa has not been reported. Here, we investigate the gene expression levels of pattern recognition receptors, downstream inflammatory signaling pathway molecules, and associated cytokines on the intestinal mucosa of neonatal piglets either infected with a single- or co-infected with PDCoV and PEDV using real-time PCR. The results demonstrate that single-PEDV regulates the noncanonical NF-κB signaling pathway through RIG-I regulation. In contrast, single-PDCoV and PDCoV/PEDV coinfection regulate proinflammatory and regulatory cytokines through TRAF6-mediated canonical NF-κB and IRF7 signaling pathways through TLRs. Although PDCoV/PEDV coinfection demonstrated an earlier modulatory effect in these signaling pathways, the regulation of proinflammatory and regulatory cytokines was observed simultaneously during single viral infection. These results suggested that PDCoV/PEDV coinfection may have synergistic effects that lead to enhanced viral evasion of the mucosal innate immune response.
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18
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Cui X, Liu L, Li J, Liu Y, Liu Y, Hu D, Zhang R, Huang S, Jiang Z, Wang Y, Qu Y, Pang SW, Lam RHW. A Microfluidic Platform Revealing Interactions between Leukocytes and Cancer Cells on Topographic Micropatterns. BIOSENSORS 2022; 12:963. [PMID: 36354472 PMCID: PMC9687854 DOI: 10.3390/bios12110963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 10/27/2022] [Accepted: 10/31/2022] [Indexed: 06/16/2023]
Abstract
Immunoassay for detailed analysis of immune-cancer intercellular interactions can achieve more promising diagnosis and treatment strategies for cancers including nasopharyngeal cancer (NPC). In this study, we report a microfluidic live-cell immunoassay integrated with a microtopographic environment to meet the rising demand for monitoring intercellular interactions in different tumor microenvironments. The developed assay allows: (1) coculture of immune cells and cancer cells on tunable (flat or micrograting) substrates, (2) simultaneous detection of different cytokines in a wide working range of 5-5000 pg/mL, and (3) investigation of migration behaviors of mono- and co-cultured cells on flat/grating platforms for revealing the topography-induced intercellular and cytokine responses. Cytokine monitoring was achieved on-chip by implementing a sensitive and selective microbead-based sandwich assay with an antibody on microbeads, target cytokines, and the matching fluorescent-conjugated detection antibody in an array of active peristaltic mixer-assisted cytokine detection microchambers. Moreover, this immunoassay requires a low sample volume down to 0.5 μL and short assay time (30 min) for on-chip cytokine quantifications. We validated the biocompatibility of the co-culture strategy between immune cells and NPC cells and compared the different immunological states of undifferentiated THP-1 monocytic cells or PMA-differentiated THP-1 macrophages co-culturing with NP460 and NPC43 on topographical and planar substrates, respectively. Hence, the integrated microfluidic platform provides an efficient, broad-range and precise on-chip cytokine detection approach, eliminates the manual sampling procedures and allows on-chip continuous cytokine monitoring without perturbing intercellular microenvironments on different topographical ECM substrates, which has the potential of providing clinical significance in early immune diagnosis, personalized immunotherapy, and precision medicine.
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Affiliation(s)
- Xin Cui
- Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, Jinan University, Guangzhou 519070, China
| | - Lelin Liu
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong 999077, China
- Research Center of Biological Computation, Zhejiang Laboratory, Hangzhou 311100, China
| | - Jiyu Li
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong 999077, China
| | - Yi Liu
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong 999077, China
| | - Ya Liu
- BGI-Shenzhen, Shenzhen 518083, China
| | | | - Ruolin Zhang
- Department of Electrical Engineering, City University of Hong Kong, Hong Kong 999077, China
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong 999077, China
| | - Siping Huang
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong 999077, China
| | - Zhongning Jiang
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong 999077, China
| | - Yuchao Wang
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong 999077, China
| | - Yun Qu
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong 999077, China
| | - Stella W. Pang
- Department of Electrical Engineering, City University of Hong Kong, Hong Kong 999077, China
- Centre for Biosystems, Neuroscience, and Nanotechnology, City University of Hong Kong, Hong Kong 999077, China
| | - Raymond H. W. Lam
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong 999077, China
- Centre for Biosystems, Neuroscience, and Nanotechnology, City University of Hong Kong, Hong Kong 999077, China
- Centre for Robotics and Automation, City University of Hong Kong, Hong Kong 999077, China
- Shenzhen Research Institute, City University of Hong Kong, Shenzhen 518057, China
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19
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Omoboyede V, Ibrahim O, Umar HI, Bello T, Adedeji AA, Khalid A, Fayojegbe ES, Ayomide AB, Chukwuemeka PO. Designing a vaccine-based therapy against Epstein-Barr virus-associated tumors using immunoinformatics approach. Comput Biol Med 2022; 150:106128. [PMID: 36179514 DOI: 10.1016/j.compbiomed.2022.106128] [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: 05/23/2022] [Revised: 08/05/2022] [Accepted: 09/18/2022] [Indexed: 11/26/2022]
Abstract
Epstein-Barr virus (EBV) is widely known due to its role in the etiology of infectious mononucleosis. However, it is the first oncovirus that was identified and has been implicated in the etiology of several types of cancers. Globally, EBV infection is associated with more than 200, 000 new cancer cases and 150, 000 deaths yearly. A prophylactic or therapeutic vaccine targeting tumors associated with EBV infection is currently lacking. Therefore, this study aimed to develop a multiepitope-based polyvalent vaccine against EBV-associated tumors using immunoinformatics approach. The latency-associated proteins (LAP) of three strains of the virus were used in this study. Potential epitopes predicted from the proteins were analyzed and selected based on several predicted properties. Thirty viable B-cell and T-cell epitopes were selected and conjugated using various linkers alongside beta-defensin 3 as an adjuvant and pan HLA DR-binding epitope (PADRE) sequence to improve the immunogenicity of the vaccine construct. Molecular docking studies of the vaccine construct against toll-like receptors (TLRs) showed it is capable of inducing immune response via recognition by TLRs while immune simulation studies showed it could induce both cellular and humoral immune responses. Furthermore, molecular dynamics study of the complex formed by the vaccine candidate and TLR-4 showed that the complex was stable. Ultimately, the designed vaccine showed desirable properties based on in silico evaluation; however, experimental studies are needed to validate the efficacy of the vaccine against EBV-associated tumors.
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Affiliation(s)
- Victor Omoboyede
- Department of Biochemistry, School of Sciences (SOS), Federal University of Technology Akure, P.M.B 704, Akure, Nigeria; Computer Aided Therapeutics Laboratory (CATL) Group, School of Sciences (SOS), Federal University of Technology Akure, P.M.B 704, Akure, Nigeria; Computer Aided Therapeutics and Drug Design (CATDD) Group, School of Sciences (SOS), Federal University of Technology Akure, P.M.B 704, Akure, Nigeria.
| | - Ochapa Ibrahim
- Computer Aided Therapeutics and Drug Design (CATDD) Group, School of Sciences (SOS), Federal University of Technology Akure, P.M.B 704, Akure, Nigeria; Faculty of Pharmaceutical Sciences, Ahmadu Bello University, Zaria, Kaduna State, Nigeria.
| | - Haruna Isiyaku Umar
- Department of Biochemistry, School of Sciences (SOS), Federal University of Technology Akure, P.M.B 704, Akure, Nigeria; Computer Aided Therapeutics and Drug Design (CATDD) Group, School of Sciences (SOS), Federal University of Technology Akure, P.M.B 704, Akure, Nigeria.
| | - Taye Bello
- Department of Medical Rehabilitation, College of Health Sciences, Obafemi Awolowo University, Nigeria.
| | - Ayodeji Adeola Adedeji
- Department of Biochemistry, School of Sciences (SOS), Federal University of Technology Akure, P.M.B 704, Akure, Nigeria.
| | - Aqsa Khalid
- Research Center for Modelling and Simulation (RCMS), National University of Science and Technology (NUST), Islamabad, Pakistan.
| | | | - Adunola Blessing Ayomide
- Computer Aided Therapeutics Laboratory (CATL) Group, School of Sciences (SOS), Federal University of Technology Akure, P.M.B 704, Akure, Nigeria; Department of Biotechnology, School of Sciences (SOS), Federal University of Technology Akure, P.M.B 704, Akure, Nigeria.
| | - Prosper Obed Chukwuemeka
- Computer Aided Therapeutics Laboratory (CATL) Group, School of Sciences (SOS), Federal University of Technology Akure, P.M.B 704, Akure, Nigeria; Computer Aided Therapeutics and Drug Design (CATDD) Group, School of Sciences (SOS), Federal University of Technology Akure, P.M.B 704, Akure, Nigeria; Department of Biotechnology, School of Sciences (SOS), Federal University of Technology Akure, P.M.B 704, Akure, Nigeria.
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20
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Damania B, Kenney SC, Raab-Traub N. Epstein-Barr virus: Biology and clinical disease. Cell 2022; 185:3652-3670. [PMID: 36113467 PMCID: PMC9529843 DOI: 10.1016/j.cell.2022.08.026] [Citation(s) in RCA: 216] [Impact Index Per Article: 72.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/17/2022] [Accepted: 08/24/2022] [Indexed: 01/26/2023]
Abstract
Epstein-Barr virus (EBV) is a ubiquitous, oncogenic virus that is associated with a number of different human malignancies as well as autoimmune disorders. The expression of EBV viral proteins and non-coding RNAs contribute to EBV-mediated disease pathologies. The virus establishes life-long latency in the human host and is adept at evading host innate and adaptive immune responses. In this review, we discuss the life cycle of EBV, the various functions of EBV-encoded proteins and RNAs, the ability of the virus to activate and evade immune responses, as well as the neoplastic and autoimmune diseases that are associated with EBV infection in the human population.
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Affiliation(s)
- Blossom Damania
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Shannon C Kenney
- Department of Oncology, McArdle Laboratory for Cancer Research, and Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Nancy Raab-Traub
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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21
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Nuclear Factor Kappa B Promotes Ferritin Heavy Chain Expression in Bombyx mori in Response to B. mori Nucleopolyhedrovirus Infection. Int J Mol Sci 2022; 23:ijms231810380. [PMID: 36142290 PMCID: PMC9499628 DOI: 10.3390/ijms231810380] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/01/2022] [Accepted: 09/06/2022] [Indexed: 11/16/2022] Open
Abstract
Ferritin heavy chain (FerHCH) is a major component of ferritin and plays an important role in maintaining iron homeostasis and redox equilibrium. Our previous studies have demonstrated that the Bombyx mori ferritin heavy chain homolog (BmFerHCH) could respond to B. mori nucleopolyhedrovirus (BmNPV) infection. However, the mechanism by which BmNPV regulates the expression of BmFerHCH remains unclear. In this study, BmFerHCH increased after BmNPV infection and BmNPV infection enhanced nuclear factor kappa B (NF-κB) activity in BmN cells. An NF-κB inhibitor (PDTC) reduced the expression of the virus-induced BmFerHCH in BmN cells, and overexpression of BmRelish (NF-κB) increased the expression of virus-induced BmFerHCH in BmN cells. Furthermore, BmNPV infection enhanced BmFerHCH promoter activity. The potential NF-κB cis-regulatory elements (CREs) in the BmFerHCH promoter were screened by using the JASPAR CORE database, and two effective NF-κB CREs were identified using a dual luciferase reporting system and electrophoretic mobility shift assay (EMSA). BmRelish (NF-κB) bound to NF-κB CREs and promoted the transcription of BmFerHCH. Taken together, BmNPV promotes activation of BmRelish (NF-κB), and activated BmRelish (NF-κB) binds to NF-κB CREs of BmFerHCH promoter to enhance BmFerHCH expression. Our study provides a foundation for future research on the function of BmFerHCH in BmNPV infection.
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22
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Albanese M, Tagawa T, Hammerschmidt W. Strategies of Epstein-Barr virus to evade innate antiviral immunity of its human host. Front Microbiol 2022; 13:955603. [PMID: 35935191 PMCID: PMC9355577 DOI: 10.3389/fmicb.2022.955603] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 06/27/2022] [Indexed: 12/18/2022] Open
Abstract
Epstein-Barr virus (EBV) is a double-stranded DNA virus of the Herpesviridae family. This virus preferentially infects human primary B cells and persists in the human B cell compartment for a lifetime. Latent EBV infection can lead to the development of different types of lymphomas as well as carcinomas such as nasopharyngeal and gastric carcinoma in immunocompetent and immunocompromised patients. The early phase of viral infection is crucial for EBV to establish latency, but different viral components are sensed by cellular sensors called pattern recognition receptors (PRRs) as the first line of host defense. The efficacy of innate immunity, in particular the interferon-mediated response, is critical to control viral infection initially and to trigger a broad spectrum of specific adaptive immune responses against EBV later. Despite these restrictions, the virus has developed various strategies to evade the immune reaction of its host and to establish its lifelong latency. In its different phases of infection, EBV expresses up to 44 different viral miRNAs. Some act as viral immunoevasins because they have been shown to counteract innate as well as adaptive immune responses. Similarly, certain virally encoded proteins also control antiviral immunity. In this review, we discuss how the virus governs innate immune responses of its host and exploits them to its advantage.
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Affiliation(s)
- Manuel Albanese
- Max von Pettenkofer Institute and Gene Center, Virology, National Reference Center for Retroviruses, Faculty of Medicine, Ludwig Maximilian University of Munich, Munich, Germany
- Istituto Nazionale di Genetica Molecolare, “Romeo ed Enrica Invernizzi,” Milan, Italy
- Research Unit Gene Vectors, EBV Vaccine Development Unit, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany
| | - Takanobu Tagawa
- Research Unit Gene Vectors, EBV Vaccine Development Unit, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany
- HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Wolfgang Hammerschmidt
- Research Unit Gene Vectors, EBV Vaccine Development Unit, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany
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23
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Man SM, Jenkins BJ. Context-dependent functions of pattern recognition receptors in cancer. Nat Rev Cancer 2022; 22:397-413. [PMID: 35355007 DOI: 10.1038/s41568-022-00462-5] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/01/2022] [Indexed: 02/07/2023]
Abstract
The immune system plays a critical role in shaping all facets of cancer, from the early initiation stage through to metastatic disease and resistance to therapy. Our understanding of the importance of the adaptive arm of the immune system in antitumour immunity has led to the implementation of immunotherapy with immune checkpoint inhibitors in numerous cancers, albeit with differing efficacy. By contrast, the clinical utility of innate immunity in cancer has not been exploited, despite dysregulated innate immunity being a feature of at least one-third of all cancers associated with tumour-promoting chronic inflammation. The past two decades have seen innate immune pattern recognition receptors (PRRs) emerge as critical regulators of the immune response to microbial infection and host tissue damage. More recently, it has become apparent that in many cancer types, PRRs play a central role in modulating a vast array of tumour-inhibiting and tumour-promoting cellular responses both in immune cells within the tumour microenvironment and directly in cancer cells. Herein, we provide a comprehensive overview of the fast-evolving field of PRRs in cancer, and discuss the potential to target PRRs for drug development and biomarker discovery in a wide range of oncology settings.
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Affiliation(s)
- Si Ming Man
- Division of Immunity, Inflammation and Infection, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
- Department of Molecular and Translational Science, School of Clinical Sciences, Monash University, Clayton, VIC, Australia.
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24
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Lange PT, White MC, Damania B. Activation and Evasion of Innate Immunity by Gammaherpesviruses. J Mol Biol 2022; 434:167214. [PMID: 34437888 PMCID: PMC8863980 DOI: 10.1016/j.jmb.2021.167214] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/11/2021] [Accepted: 08/13/2021] [Indexed: 12/20/2022]
Abstract
Gammaherpesviruses are ubiquitous pathogens that establish lifelong infections in the vast majority of adults worldwide. Importantly, these viruses are associated with numerous malignancies and are responsible for significant human cancer burden. These virus-associated cancers are due, in part, to the ability of gammaherpesviruses to successfully evade the innate immune response throughout the course of infection. In this review, we will summarize the current understanding of how gammaherpesviruses are detected by innate immune sensors, how these viruses evade recognition by host cells, and how this knowledge can inform novel therapeutic approaches for these viruses and their associated diseases.
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Affiliation(s)
- Philip T Lange
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. https://twitter.com/langept
| | - Maria C White
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. https://twitter.com/maria_c_white
| | - Blossom Damania
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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25
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Transcriptomic Analysis of Fish Hosts Responses to Nervous Necrosis Virus. Pathogens 2022; 11:pathogens11020201. [PMID: 35215144 PMCID: PMC8875540 DOI: 10.3390/pathogens11020201] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/29/2022] [Accepted: 02/01/2022] [Indexed: 11/24/2022] Open
Abstract
Nervous necrosis virus (NNV) has been responsible for mass mortalities in the aquaculture industry worldwide, with great economic and environmental impact. The present review aims to summarize the current knowledge of gene expression responses to nervous necrosis virus infection in different fish species based on transcriptomic analysis data. Four electronic databases, including PubMed, Web of Science, and SCOPUS were searched, and more than 500 publications on the subject were identified. Following the application of the appropriate testing, a total of 24 articles proved eligible for this review. NNV infection of different host species, in different developmental stages and tissues, presented in the eligible publications, are described in detail, revealing and highlighting genes and pathways that are most affected by the viral infection. Those transcriptome studies of NNV infected fish are oriented in elucidating the roles of genes/biomarkers for functions of special interest, depending on each study’s specific emphasis. This review presents a first attempt to provide an overview of universal host reaction mechanisms to viral infections, which will provide us with new perspectives to overcome NNV infection to build healthier and sustainable aquaculture systems.
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26
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Yokoe S, Hasuike A, Watanabe N, Tanaka H, Karahashi H, Wakuda S, Takeichi O, Kawato T, Takai H, Ogata Y, Sato S, Imai K. Epstein-Barr Virus Promotes the Production of Inflammatory Cytokines in Gingival Fibroblasts and RANKL-Induced Osteoclast Differentiation in RAW264.7 Cells. Int J Mol Sci 2022; 23:ijms23020809. [PMID: 35054995 PMCID: PMC8775710 DOI: 10.3390/ijms23020809] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/29/2021] [Accepted: 12/29/2021] [Indexed: 01/27/2023] Open
Abstract
Periodontitis is an inflammatory condition that causes the destruction of the supporting tissues of teeth and is a major public health problem affecting more than half of the adult population worldwide. Recently, members of the herpes virus family, such as the Epstein–Barr virus (EBV), have been suggested to be involved in the etiology of periodontitis because bacterial activity alone does not adequately explain the clinical characteristics of periodontitis. However, the role of EBV in the etiology of periodontitis is unknown. This study aimed to examine the effect of inactivated EBV on the expression of inflammatory cytokines in human gingival fibroblasts (HGFs) and the induction of osteoclast differentiation. We found that extremely high levels of interleukin (IL)-6 and IL-8 were induced by inactivated EBV in a copy-dependent manner in HGFs. The levels of IL-6 and IL-8 in HGFs were higher when the cells were treated with EBV than when treated with lipopolysaccharide and lipoteichoic acid. EBV induced IκBα degradation, NF-κB transcription, and RAW264.7 cell differentiation into osteoclast-like cells. These findings suggest that even without infecting the cells, EBV contributes to inflammatory cytokine production and osteoclast differentiation by contact with oral cells or macrophage lineage, resulting in periodontitis onset and progression.
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Affiliation(s)
- Sho Yokoe
- Department of Periodontology, Nihon University School of Dentistry, Tokyo 101-8310, Japan; (S.Y.); (A.H.); (N.W.); (H.K.); (S.W.); (S.S.)
- Department of Microbiology, Nihon University School of Dentistry, Tokyo 101-8310, Japan
| | - Akira Hasuike
- Department of Periodontology, Nihon University School of Dentistry, Tokyo 101-8310, Japan; (S.Y.); (A.H.); (N.W.); (H.K.); (S.W.); (S.S.)
| | - Norihisa Watanabe
- Department of Periodontology, Nihon University School of Dentistry, Tokyo 101-8310, Japan; (S.Y.); (A.H.); (N.W.); (H.K.); (S.W.); (S.S.)
- Department of Microbiology, Nihon University School of Dentistry, Tokyo 101-8310, Japan
| | - Hideki Tanaka
- Department of Oral Health Sciences, Nihon University School of Dentistry, Tokyo 101-8310, Japan; (H.T.); (T.K.)
| | - Hiroyuki Karahashi
- Department of Periodontology, Nihon University School of Dentistry, Tokyo 101-8310, Japan; (S.Y.); (A.H.); (N.W.); (H.K.); (S.W.); (S.S.)
- Department of Microbiology, Nihon University School of Dentistry, Tokyo 101-8310, Japan
| | - Shin Wakuda
- Department of Periodontology, Nihon University School of Dentistry, Tokyo 101-8310, Japan; (S.Y.); (A.H.); (N.W.); (H.K.); (S.W.); (S.S.)
- Department of Microbiology, Nihon University School of Dentistry, Tokyo 101-8310, Japan
| | - Osamu Takeichi
- Department of Endodontics, Nihon University School of Dentistry, Tokyo 101-8310, Japan;
| | - Takayuki Kawato
- Department of Oral Health Sciences, Nihon University School of Dentistry, Tokyo 101-8310, Japan; (H.T.); (T.K.)
| | - Hideki Takai
- Department of Periodontology, Nihon University School of Dentistry at Matsudo, Chiba 271-8587, Japan; (H.T.); (Y.O.)
| | - Yorimasa Ogata
- Department of Periodontology, Nihon University School of Dentistry at Matsudo, Chiba 271-8587, Japan; (H.T.); (Y.O.)
| | - Shuichi Sato
- Department of Periodontology, Nihon University School of Dentistry, Tokyo 101-8310, Japan; (S.Y.); (A.H.); (N.W.); (H.K.); (S.W.); (S.S.)
| | - Kenichi Imai
- Department of Microbiology, Nihon University School of Dentistry, Tokyo 101-8310, Japan
- Correspondence: ; Tel.: +81-3-33219-8115
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27
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Blanco R, Carrillo-Beltrán D, Corvalán AH, Aguayo F. High-Risk Human Papillomavirus and Epstein-Barr Virus Coinfection: A Potential Role in Head and Neck Carcinogenesis. BIOLOGY 2021; 10:biology10121232. [PMID: 34943147 PMCID: PMC8698839 DOI: 10.3390/biology10121232] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 11/15/2021] [Accepted: 11/18/2021] [Indexed: 12/12/2022]
Abstract
Simple Summary A subset of carcinomas that arise in the head and neck region show a viral etiology. In fact, a subgroup of oropharyngeal cancers are caused by some types of human papillomavirus (HPV), so-called high-risk (HR)-HPVs, whereas undifferentiated nasopharyngeal carcinomas are etiologically related to Epstein–Barr virus (EBV). However, studies have reported the presence of both HR-HPV and EBV in some types of head and neck cancers. In this review, we discuss the potential contribution and role of HR-HPV/EBV coinfection in head and neck carcinogenesis, as well as the mechanisms that are potentially involved. In addition, HR-HPV/EBV interaction models are proposed. Abstract High-risk human papillomaviruses (HR-HPVs) and Epstein–Barr virus (EBV) are recognized oncogenic viruses involved in the development of a subset of head and neck cancers (HNCs). HR-HPVs are etiologically associated with a subset of oropharyngeal carcinomas (OPCs), whereas EBV is a recognized etiological agent of undifferentiated nasopharyngeal carcinomas (NPCs). In this review, we address epidemiological and mechanistic evidence regarding a potential cooperation between HR-HPV and EBV for HNC development. Considering that: (1) both HR-HPV and EBV infections require cofactors for carcinogenesis; and (2) both oropharyngeal and oral epithelium can be directly exposed to carcinogens, such as alcohol or tobacco smoke, we hypothesize possible interaction mechanisms. The epidemiological and experimental evidence suggests that HR-HPV/EBV cooperation for developing a subset of HNCs is plausible and warrants further investigation.
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Affiliation(s)
- Rancés Blanco
- Programa de Virología, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile; (R.B.); (D.C.-B.)
| | - Diego Carrillo-Beltrán
- Programa de Virología, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile; (R.B.); (D.C.-B.)
| | - Alejandro H. Corvalán
- Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, Santiago 8320000, Chile;
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28
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Gaglia MM. Anti-viral and pro-inflammatory functions of Toll-like receptors during gamma-herpesvirus infections. Virol J 2021; 18:218. [PMID: 34749760 PMCID: PMC8576898 DOI: 10.1186/s12985-021-01678-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 10/12/2021] [Indexed: 12/15/2022] Open
Abstract
Toll-like receptors (TLRs) control anti-viral responses both directly in infected cells and in responding cells of the immune systems. Therefore, they are crucial for responses against the oncogenic γ-herpesviruses Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus and the related murine virus MHV68, which directly infect immune system cells. However, since these viruses also cause lifelong persistent infections, TLRs may also be involved in modulation of inflammation during latent infection and contribute to virus-driven tumorigenesis. This review summarizes work on both of these aspects of TLR/γ-herpesvirus interactions, as well as results showing that TLR activity can drive these viruses' re-entry into the replicative lytic cycle.
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Affiliation(s)
- Marta Maria Gaglia
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, 02111, USA.
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29
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J NH, K LP, Selvaraj A, Chinnaraj S, Luke Elizabeth H. Toll like receptor (2 and 4) expression and cytokine release by human neutrophils during tuberculosis treatment-A longitudinal study. Mol Immunol 2021; 140:136-143. [PMID: 34710721 DOI: 10.1016/j.molimm.2021.10.009] [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: 05/20/2021] [Revised: 09/27/2021] [Accepted: 10/10/2021] [Indexed: 11/25/2022]
Abstract
Host innate immune responses to tuberculosis are poorly explored. Recent findings emphasize the importance of innate cells in working against Mycobacterium tuberculosis, the etiologic agent of this deadly disease. In this study we have tried to learn the role of neutrophils in building up immunity against this pathogen during therapy. We isolated neutrophils from peripheral blood of healthy volunteers and pulmonary tuberculosis patients at different phases of their treatment and cultured them withtoll like receptor ligands overnight. Toll like receptor 2 and 4 expression on neutrophils was analyzed using flow cytometry. The supernatants were used to measure cytokines. We found that in tuberculosis patients, expression of TLR2, a proven receptor of Mycobacterium tuberculosis on neutrophils, was increased throughout the duration of therapy (measured at diagnosis, second month and sixth month of therapy). This demonstrates that TLR2 expression is altered as a result of treatment, but not TLR4. Also, the chemokines IL-8 and MIP1α showed a 'dip and raise' fashion as the therapy proceeded. Even though the increase in the pro-inflammatory cytokine secretion by neutrophils seen at the end of therapy is not as expected, it definitely increases our understanding on the function of these cells during TB disease and its resolution and opens new direction in neutrophil research.
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Affiliation(s)
- Nancy Hilda J
- Department of HIV/ AIDS, National Institute for Research in Tuberculosis, Chetpet, Chennai, 600031, India.
| | - Lucia Precilla K
- Department of HIV/ AIDS, National Institute for Research in Tuberculosis, Chetpet, Chennai, 600031, India
| | - Anbalagan Selvaraj
- Department of HIV/ AIDS, National Institute for Research in Tuberculosis, Chetpet, Chennai, 600031, India
| | - Saravanan Chinnaraj
- Department of HIV/ AIDS, National Institute for Research in Tuberculosis, Chetpet, Chennai, 600031, India
| | - Hanna Luke Elizabeth
- Department of HIV/ AIDS, National Institute for Research in Tuberculosis, Chetpet, Chennai, 600031, India
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30
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How dendritic cells sense and respond to viral infections. Clin Sci (Lond) 2021; 135:2217-2242. [PMID: 34623425 DOI: 10.1042/cs20210577] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 09/15/2021] [Accepted: 09/23/2021] [Indexed: 12/26/2022]
Abstract
The ability of dendritic cells (DCs) to sense viral pathogens and orchestrate a proper immune response makes them one of the key players in antiviral immunity. Different DC subsets have complementing functions during viral infections, some specialize in antigen presentation and cross-presentation and others in the production of cytokines with antiviral activity, such as type I interferons. In this review, we summarize the latest updates concerning the role of DCs in viral infections, with particular focus on the complex interplay between DC subsets and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Despite being initiated by a vast array of immune receptors, DC-mediated antiviral responses often converge towards the same endpoint, that is the production of proinflammatory cytokines and the activation of an adaptive immune response. Nonetheless, the inherent migratory properties of DCs make them a double-edged sword and often viral recognition by DCs results in further viral dissemination. Here we illustrate these various aspects of the antiviral functions of DCs and also provide a brief overview of novel antiviral vaccination strategies based on DCs targeting.
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31
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Singh H, Koury J, Kaul M. Innate Immune Sensing of Viruses and Its Consequences for the Central Nervous System. Viruses 2021; 13:170. [PMID: 33498715 PMCID: PMC7912342 DOI: 10.3390/v13020170] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/19/2021] [Accepted: 01/20/2021] [Indexed: 12/13/2022] Open
Abstract
Viral infections remain a global public health concern and cause a severe societal and economic burden. At the organismal level, the innate immune system is essential for the detection of viruses and constitutes the first line of defense. Viral components are sensed by host pattern recognition receptors (PRRs). PRRs can be further classified based on their localization into Toll-like receptors (TLRs), C-type lectin receptors (CLR), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), NOD-like receptors (NLRs) and cytosolic DNA sensors (CDS). TLR and RLR signaling results in production of type I interferons (IFNα and -β) and pro-inflammatory cytokines in a cell-specific manner, whereas NLR signaling leads to the production of interleukin-1 family proteins. On the other hand, CLRs are capable of sensing glycans present in viral pathogens, which can induce phagocytic, endocytic, antimicrobial, and pro- inflammatory responses. Peripheral immune sensing of viruses and the ensuing cytokine response can significantly affect the central nervous system (CNS). But viruses can also directly enter the CNS via a multitude of routes, such as the nasal epithelium, along nerve fibers connecting to the periphery and as cargo of infiltrating infected cells passing through the blood brain barrier, triggering innate immune sensing and cytokine responses directly in the CNS. Here, we review mechanisms of viral immune sensing and currently recognized consequences for the CNS of innate immune responses to viruses.
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Affiliation(s)
- Hina Singh
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA; (H.S.); (J.K.)
- Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Jeffrey Koury
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA; (H.S.); (J.K.)
| | - Marcus Kaul
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA; (H.S.); (J.K.)
- Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
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Zheng W, Xu Q, Zhang Y, E X, Gao W, Zhang M, Zhai W, Rajkumar RS, Liu Z. Toll-like receptor-mediated innate immunity against herpesviridae infection: a current perspective on viral infection signaling pathways. Virol J 2020; 17:192. [PMID: 33298111 PMCID: PMC7726878 DOI: 10.1186/s12985-020-01463-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 12/01/2020] [Indexed: 12/12/2022] Open
Abstract
Background In the past decades, researchers have demonstrated the critical role of Toll-like receptors (TLRs) in the innate immune system. They recognize viral components and trigger immune signal cascades to subsequently promote the activation of the immune system. Main body Herpesviridae family members trigger TLRs to elicit cytokines in the process of infection to activate antiviral innate immune responses in host cells. This review aims to clarify the role of TLRs in the innate immunity defense against herpesviridae, and systematically describes the processes of TLR actions and herpesviridae recognition as well as the signal transduction pathways involved. Conclusions Future studies of the interactions between TLRs and herpesviridae infections, especially the subsequent signaling pathways, will not only contribute to the planning of effective antiviral therapies but also provide new molecular targets for the development of antiviral drugs.
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Affiliation(s)
- Wenjin Zheng
- School of Basic Medical Sciences, Weifang Medical University, Weifang, 261053, China
| | - Qing Xu
- School of Anesthesiology, Weifang Medical University, Weifang, 261053, China
| | - Yiyuan Zhang
- School of Basic Medical Sciences, Weifang Medical University, Weifang, 261053, China
| | - Xiaofei E
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Wei Gao
- Key Lab for Immunology in Universities of Shandong Province, School of Basic Medical Sciences, Weifang Medical University, Weifang, 261053, China
| | - Mogen Zhang
- School of Basic Medical Sciences, Weifang Medical University, Weifang, 261053, China
| | - Weijie Zhai
- School of Basic Medical Sciences, Weifang Medical University, Weifang, 261053, China
| | | | - Zhijun Liu
- Department of Medical Microbiology, School of Basic Medical Sciences, Weifang Medical University, Weifang, 261053, China.
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TLR4 896A/G and TLR9 1174G/A polymorphisms are associated with the risk of infectious mononucleosis. Sci Rep 2020; 10:13154. [PMID: 32753695 PMCID: PMC7403730 DOI: 10.1038/s41598-020-70129-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 07/21/2020] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns and activate innate and adaptive immune responses. Single nucleotide polymorphisms (SNPs) within the TLR genes may influence host–pathogen interactions and can have an impact on the progression of infectious diseases. The present study aimed to investigate the genotype distribution of TLR2 (2029C/T, rs121917864; 2258G/A, rs5743708), TLR4 (896A/G, rs4986790), and TLR9 (− 1237T/C, rs5743836; − 1486T/C, rs187084; 1174G/A, rs352139; and 2848C/T, rs352140) polymorphisms in 149 children and adolescents with infectious mononucleosis (IM) and 140 healthy individuals. The potential association of TLR SNPs with the clinical manifestations of EBV infection was also studied. The presence of TLR2, TLR4, and TLR9 SNPs was identified by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). EBV DNA loads were detected by quantitative real-time PCR assay. The TLR4 896 GG and the TLR9 1174 GA genotypes were associated with an increased risk of EBV-related IM in examined patients (p = 0.014 and p = 0.001, respectively). The heterozygous genotype of the TLR4 896A/G SNP was associated with an increased risk of elevated liver enzyme levels and leukocytosis (p < 0.05). Our preliminary study revealed that the TLR4 896A/G and the TLR9 1174G/A polymorphisms seem to be related to the course of acute EBV infection in children and adolescents.
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Plasmacytoid dendritic cells respond to Epstein-Barr virus infection with a distinct type I interferon subtype profile. Blood Adv 2020; 3:1129-1144. [PMID: 30952679 DOI: 10.1182/bloodadvances.2018025536] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 02/24/2019] [Indexed: 12/15/2022] Open
Abstract
Infectious mononucleosis, caused by infection with the human gamma-herpesvirus Epstein-Barr virus (EBV), manifests with one of the strongest CD8+ T-cell responses described in humans. The resulting T-cell memory response controls EBV infection asymptomatically in the vast majority of persistently infected individuals. Whether and how dendritic cells (DCs) contribute to the priming of this near-perfect immune control remains unclear. Here we show that of all the human DC subsets, plasmacytoid DCs (pDCs) play a central role in the detection of EBV infection in vitro and in mice with reconstituted human immune system components. pDCs respond to EBV by producing the interferon (IFN) subtypes α1, α2, α5, α7, α14, and α17. However, the virus curtails this type I IFN production with its latent EBV gene products EBNA3A and EBNA3C. The induced type I IFNs inhibit EBV entry and the proliferation of latently EBV-transformed B cells but do not influence lytic reactivation of the virus in vitro. In vivo, exogenous IFN-α14 and IFN-α17, as well as pDC expansion, delay EBV infection and the resulting CD8+ T-cell expansion, but pDC depletion does not significantly influence EBV infection. Thus, consistent with the observation that primary immunodeficiencies compromising type I IFN responses affect only alpha- and beta-herpesvirus infections, we found that EBV elicits pDC responses that transiently suppress viral replication and attenuate CD8+ T-cell expansion but are not required to control primary infection.
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35
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TLR2 on blood monocytes senses dengue virus infection and its expression correlates with disease pathogenesis. Nat Commun 2020; 11:3177. [PMID: 32576819 PMCID: PMC7311456 DOI: 10.1038/s41467-020-16849-7] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 05/27/2020] [Indexed: 12/13/2022] Open
Abstract
Vascular permeability and plasma leakage are immune-pathologies of severe dengue virus (DENV) infection, but the mechanisms underlying the exacerbated inflammation during DENV pathogenesis are unclear. Here, we demonstrate that TLR2, together with its co-receptors CD14 and TLR6, is an innate sensor of DENV particles inducing inflammatory cytokine expression and impairing vascular integrity in vitro. Blocking TLR2 prior to DENV infection in vitro abrogates NF-κB activation while CD14 and TLR6 block has a moderate effect. Moreover, TLR2 block prior to DENV infection of peripheral blood mononuclear cells prevents activation of human vascular endothelium, suggesting a potential role of the TLR2-responses in vascular integrity. TLR2 expression on CD14 + + classical monocytes isolated in an acute phase from DENV-infected pediatric patients correlates with severe disease development. Altogether, these data identify a role for TLR2 in DENV infection and provide insights into the complex interaction between the virus and innate receptors that may underlie disease pathogenesis.
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36
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How Does Epstein-Barr Virus Contribute to Chronic Periodontitis? Int J Mol Sci 2020; 21:ijms21061940. [PMID: 32178406 PMCID: PMC7139403 DOI: 10.3390/ijms21061940] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 03/10/2020] [Accepted: 03/10/2020] [Indexed: 12/21/2022] Open
Abstract
Chronic periodontitis is spreading worldwide and mutually interacts with systemic diseases like diabetes mellitus. Although periodontopathic bacteria are inevitable pathogens in their onset and progression, many cases are not ascribable to the virulence of these bacteria because the effect of plaque control is limited. In contrast, Epstein-Barr virus (EBV) in the periodontium has been correlated with chronic periodontitis and has recently been considered as a promising pathogenic candidate for this disease. However, several important questions have yet to be addressed. For instance, although EBV latently infects more than 90% of individuals over the world, why do patients with chronic periodontitis exclusively harbor progeny EBV in the oral cavity? In addition, how does latently infected or reactivated EBV in the periodontium relate to the onset or progression of chronic periodontitis? Finally, is periodontitis incurable because EBV is the pathogen for chronic periodontitis? In this review, we attempt to answer these questions by reporting the current understanding of molecular relations and mechanisms between periodontopathic bacteria and EBV reactivation in the context of how this relationship may pertain to the etiology of chronic periodontitis.
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37
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Carriere J, Rao Y, Liu Q, Lin X, Zhao J, Feng P. Post-translational Control of Innate Immune Signaling Pathways by Herpesviruses. Front Microbiol 2019; 10:2647. [PMID: 31798565 PMCID: PMC6868034 DOI: 10.3389/fmicb.2019.02647] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 10/30/2019] [Indexed: 12/21/2022] Open
Abstract
Herpesviruses constitute a large family of disease-causing DNA viruses. Each herpesvirus strain is capable of infecting particular organisms with a specific cell tropism. Upon infection, pattern recognition receptors (PRRs) recognize conserved viral features to trigger signaling cascades that culminate in the production of interferons and pro-inflammatory cytokines. To invoke a proper immune response while avoiding collateral tissue damage, signaling proteins involved in these cascades are tightly regulated by post-translational modifications (PTMs). Herpesviruses have developed strategies to subvert innate immune signaling pathways in order to ensure efficient viral replication and achieve persistent infection. The ability of these viruses to control the proteins involved in these signaling cascades post-translationally, either directly via virus-encoded enzymes or indirectly through the deregulation of cellular enzymes, has been widely reported. This ability provides herpesviruses with a powerful tool to shut off or restrict host antiviral and inflammatory responses. In this review, we highlight recent findings on the herpesvirus-mediated post-translational control along PRR-mediated signaling pathways.
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Affiliation(s)
| | | | | | | | | | - Pinghui Feng
- Section of Infection and Immunity, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, United States
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38
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Pang F, Zhang M, Li G, Zhang Z, Huang H, Li B, Wang C, Yang X, Zheng Y, An Q, Zhang L, Du L, Wang F. Integrated mRNA and miRNA profiling in NIH/3T3 cells in response to bovine papillomavirus E6 gene expression. PeerJ 2019; 7:e7442. [PMID: 31396463 PMCID: PMC6681795 DOI: 10.7717/peerj.7442] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 07/09/2019] [Indexed: 12/19/2022] Open
Abstract
Delta bovine papillomaviruses (δBPVs) mainly infect cattle and cause fibropapillomas. δBPVs encode three oncogenes, E5, E6 and E7. The effect of E6 on microRNA (miRNA) and mRNA expression profiles is not well characterized. In this study, RNA sequencing and small RNA sequencing were used to explore alterations in mRNAs and miRNAs in E6 over-expressing NIH/3T3 cells (NH-E6) compared with control cells (NH-GFP). We found that 350 genes (181 upregulated and 169 downregulated) and 54 miRNAs (26 upregulated and 28 downregulated) were differentially expressed (DE) following E6 expression. The top 20 significantly enriched GO terms in “biological process” included inflammatory response, innate immune response, immune response, immune system process, positive regulation of apoptotic process, cell adhesion, and angiogenesis. We constructed a potential miRNA-gene regulatory network from the differentially expressed genes (DEGs) and DE miRNAs. Finally, we selected 19 immune-response related DEGs and 11 DE miRNAs for qPCR validation. Of these, upregulation of 12 genes, Ccl2, Ccl7, Cxcl1, Cxcl5, Tlr2, Nfkbia, Fas, Il1rl1, Ltbp1, Rab32, and Zc3h12a, Dclk1 and downregulation of four genes, Agtr2, Ptx3, Sfrp1, and Thbs1 were confirmed. Ccl2, Ccl7, Cxcl1 and Cxcl5 were upregulated more than ten-fold in NH-E6 compared with NH-GFP. Also, upregulation of three miRNAs, mmu-miR-129-2-3p, mmu-miR-149-5p-R-2 and mmu-miR-222-3p, and downregulation of five miRNAs, mmu-miR-582-3p-R+1, mmu-miR-582-5p, mmu-miR-708-3p, mmu-miR-708-5p and mmu-miR-1197-3p, were confirmed. Our study describes changes in both mRNA and miRNA profiles in response to BPV E6 expression, providing new insights into BPV E6 oncogene functions.
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Affiliation(s)
- Feng Pang
- College of Animal Science and Technology, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Hainan University, Haikou, China
| | - Mengmeng Zhang
- College of Animal Science and Technology, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Hainan University, Haikou, China
| | - Guohua Li
- College of Animal Science and Technology, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Hainan University, Haikou, China
| | - Zhenxing Zhang
- College of Animal Science and Technology, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Hainan University, Haikou, China
| | - Haifeng Huang
- College of Animal Science and Technology, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Hainan University, Haikou, China
| | - Baobao Li
- College of Animal Science and Technology, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Hainan University, Haikou, China
| | - Chengqiang Wang
- College of Animal Science and Technology, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Hainan University, Haikou, China
| | - Xiaohong Yang
- College of Animal Science and Technology, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Hainan University, Haikou, China
| | - Yiying Zheng
- College of Animal Science and Technology, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Hainan University, Haikou, China
| | - Qi An
- College of Animal Science and Technology, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Hainan University, Haikou, China
| | - Luyin Zhang
- College of Animal Science and Technology, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Hainan University, Haikou, China
| | - Li Du
- College of Animal Science and Technology, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Hainan University, Haikou, China
| | - Fengyang Wang
- College of Animal Science and Technology, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Hainan University, Haikou, China
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39
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Hermann JK, Capadona JR. Understanding the Role of Innate Immunity in the Response to Intracortical Microelectrodes. Crit Rev Biomed Eng 2019; 46:341-367. [PMID: 30806249 DOI: 10.1615/critrevbiomedeng.2018027166] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Intracortical microelectrodes exhibit enormous potential for researching the nervous system, steering assistive devices and functional electrode stimulation systems for severely paralyzed individuals, and augmenting the brain with computing power. Unfortunately, intracortical microelectrodes often fail to consistently record signals over clinically useful periods. Biological mechanisms, such as the foreign body response to intracortical microelectrodes and self-perpetuating neuroinflammatory cascades, contribute to the inconsistencies and decline in recording performance. Unfortunately, few studies have directly correlated microelectrode performance with the neuroinflammatory response to the implanted devices. However, of those select studies that have, the role of the innate immune system remains among the most likely links capable of corroborating the results of different studies, across laboratories. Therefore, the overall goal of this review is to highlight the role of innate immunity signaling in the foreign body response to intracortical microelectrodes and hypothesize as to appropriate strategies that may become the most relevant in enabling brain-dwelling electrodes of any geometry, or location, for a range of clinical applications.
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Affiliation(s)
- John K Hermann
- Department of Biomedical Engineering, Case Western Reserve University, 2071 Martin Luther King Jr. Drive, Wickenden Bldg, Cleveland, OH 44106; Advanced Platform Technology Center, Rehabilitation Research and Development, Louis Stokes Cleveland VA Medical Center, 10701 East Blvd. Mail Stop 151 AW/APT, Cleveland, OH 44106-1702
| | - Jeffrey R Capadona
- Department of Biomedical Engineering, Case Western Reserve University, 2071 Martin Luther King Jr. Drive, Wickenden Bldg, Cleveland, OH 44106; Advanced Platform Technology Center, Rehabilitation Research and Development, Louis Stokes Cleveland VA Medical Center, 10701 East Blvd. Mail Stop 151 AW/APT, Cleveland, OH 44106-1702
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40
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Epstein-Barr Virus and Innate Immunity: Friends or Foes? Microorganisms 2019; 7:microorganisms7060183. [PMID: 31238570 PMCID: PMC6617214 DOI: 10.3390/microorganisms7060183] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 06/20/2019] [Accepted: 06/22/2019] [Indexed: 12/16/2022] Open
Abstract
Epstein–Barr virus (EBV) successfully persists in the vast majority of adults but causes lymphoid and epithelial malignancies in a small fraction of latently infected individuals. Innate immunity is the first-line antiviral defense, which EBV has to evade in favor of its own replication and infection. EBV uses multiple strategies to perturb innate immune signaling pathways activated by Toll-like, RIG-I-like, NOD-like, and AIM2-like receptors as well as cyclic GMP-AMP synthase. EBV also counteracts interferon production and signaling, including TBK1-IRF3 and JAK-STAT pathways. However, activation of innate immunity also triggers pro-inflammatory response and proteolytic cleavage of caspases, both of which exhibit proviral activity under some circumstances. Pathogenic inflammation also contributes to EBV oncogenesis. EBV activates NFκB signaling and induces pro-inflammatory cytokines. Through differential modulation of the proviral and antiviral roles of caspases and other host factors at different stages of infection, EBV usurps cellular programs for death and inflammation to its own benefits. The outcome of EBV infection is governed by a delicate interplay between innate immunity and EBV. A better understanding of this interplay will instruct prevention and intervention of EBV-associated cancers.
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Abstract
DNA viruses are linked to many infectious diseases and contribute significantly to human morbidity and mortality worldwide. Moreover, DNA viral infections are usually lifelong and hard to eradicate. Under certain circumstances, these viruses can cause fatal disease, especially in children and immunocompromised patients. An efficient innate immune response against these viruses is critical, not only as the first line of host defense against viral infection but also for mounting more specific and robust adaptive immunity against the virus. Recognition of the viral DNA genome is the very first step of this whole process and is crucial for understanding viral pathogenesis as well as for preventing and treating DNA virus-associated diseases. This review focuses on the current state of our knowledge on how human DNA viruses are sensed by the host innate immune system and how viral proteins counteract this immune response.
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Affiliation(s)
- Zhe Ma
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
| | - Guoxin Ni
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
| | - Blossom Damania
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
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42
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Vistarop AG, Cohen M, Huaman F, Irazu L, Rodriguez M, De Matteo E, Preciado MV, Chabay PA. The interplay between local immune response and Epstein-Barr virus-infected tonsillar cells could lead to viral infection control. Med Microbiol Immunol 2018; 207:319-327. [PMID: 30046954 DOI: 10.1007/s00430-018-0553-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 07/18/2018] [Indexed: 12/16/2022]
Abstract
Epstein Barr virus (EBV) gains access to the host through tonsillar crypts. Our aim was to characterize microenvironment composition around EBV+ cells in tonsils from pediatric carriers, to disclose its role on viral pathogenesis. LMP1 expression, assessed by immunohistochemistry (IHC), was used to discriminate EBV + and - zones in 41 tonsil biopsies. Three regions were defined: Subepithelial (SE), interfollicular (IF) and germinal center (GC). CD8, GrB, CD68, IL10, Foxp3, PD1, CD56 and CD4 markers were evaluated by IHC; positive cells/100 total cells were counted. CD8+, GrB+, CD68+ and IL10+ cells were prevalent in EBV+ zones at the SE region (p < 0.0001, p = 0.03, p = 0.002 and p = 0.002 respectively, Wilcoxon test). CD4+ and CD68+ cell count were higher in EBV + GC (p = 0.01 and p = 0.0002 respectively, Wilcoxon test). Increment of CD8, GrB and CD68 at the SE region could indicate a specific response that may be due to local homing at viral entry, which could be counterbalanced by IL10, an immunosuppressive cytokine. Additionally, it could be hypothesized that CD4 augment at the GC may be involved in the EBV-induced B-cell growth control at this region, in which macrophages could also participate.
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Affiliation(s)
- Aldana G Vistarop
- Molecular Biology Laboratory, Pathology Division, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina. .,Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Buenos Aires, Argentina.
| | - Melina Cohen
- Molecular Biology Laboratory, Pathology Division, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina.,Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Buenos Aires, Argentina
| | - Fuad Huaman
- Histopathological Laboratory, National Academy of Medicine, Buenos Aires, Argentina
| | - Lucia Irazu
- National Institute of Infectious Diseases, National Laboratories and Health Institutes Administration "Dr. Carlos G. Malbrán", Buenos Aires, Argentina
| | - Marcelo Rodriguez
- National Institute of Infectious Diseases, National Laboratories and Health Institutes Administration "Dr. Carlos G. Malbrán", Buenos Aires, Argentina
| | - Elena De Matteo
- Pathology Division, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina
| | - María Victoria Preciado
- Molecular Biology Laboratory, Pathology Division, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina.,Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Buenos Aires, Argentina
| | - Paola A Chabay
- Molecular Biology Laboratory, Pathology Division, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina.,Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Buenos Aires, Argentina
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43
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Hopcraft SE, Damania B. Tumour viruses and innate immunity. Philos Trans R Soc Lond B Biol Sci 2018; 372:rstb.2016.0267. [PMID: 28893934 DOI: 10.1098/rstb.2016.0267] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/12/2017] [Indexed: 12/13/2022] Open
Abstract
Host cells sense viral infection through pattern recognition receptors (PRRs), which detect pathogen-associated molecular patterns (PAMPs) and stimulate an innate immune response. PRRs are localized to several different cellular compartments and are stimulated by viral proteins and nucleic acids. PRR activation initiates signal transduction events that ultimately result in an inflammatory response. Human tumour viruses, which include Kaposi's sarcoma-associated herpesvirus, Epstein-Barr virus, human papillomavirus, hepatitis C virus, hepatitis B virus, human T-cell lymphotropic virus type 1 and Merkel cell polyomavirus, are detected by several different PRRs. These viruses engage in a variety of mechanisms to evade the innate immune response, including downregulating PRRs, inhibiting PRR signalling, and disrupting the activation of transcription factors critical for mediating the inflammatory response, among others. This review will describe tumour virus PAMPs and the PRRs responsible for detecting viral infection, PRR signalling pathways, and the mechanisms by which tumour viruses evade the host innate immune system.This article is part of the themed issue 'Human oncogenic viruses'.
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Affiliation(s)
- Sharon E Hopcraft
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Blossom Damania
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA .,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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44
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Kimura H, Cohen JI. Chronic Active Epstein-Barr Virus Disease. Front Immunol 2017; 8:1867. [PMID: 29375552 PMCID: PMC5770746 DOI: 10.3389/fimmu.2017.01867] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Accepted: 12/08/2017] [Indexed: 12/14/2022] Open
Abstract
Chronic active Epstein–Barr virus (CAEBV) disease is a rare disorder in which persons are unable to control infection with the virus. The disease is progressive with markedly elevated levels of EBV DNA in the blood and infiltration of organs by EBV-positive lymphocytes. Patients often present with fever, lymphadenopathy, splenomegaly, EBV hepatitis, or pancytopenia. Over time, these patients develop progressive immunodeficiency and if not treated, succumb to opportunistic infections, hemophagocytosis, multiorgan failure, or EBV-positive lymphomas. Patients with CAEBV in the United States most often present with disease involving B or T cells, while in Asia, the disease usually involves T or NK cells. The only proven effective treatment for the disease is hematopoietic stem cell transplantation. Current studies to find a cause of this disease focus on immune defects and genetic abnormalities associated with the disease.
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Affiliation(s)
- Hiroshi Kimura
- Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Jeffrey I Cohen
- Medical Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
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45
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Shepardson KM, Schwarz B, Larson K, Morton RV, Avera J, McCoy K, Caffrey A, Harmsen A, Douglas T, Rynda-Apple A. Induction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsids Is Toll-Like Receptor 2 Dependent. mBio 2017; 8:e01356-17. [PMID: 29138299 PMCID: PMC5686532 DOI: 10.1128/mbio.01356-17] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 10/10/2017] [Indexed: 12/25/2022] Open
Abstract
Although viruses and viral capsids induce rapid immune responses, little is known about viral pathogen-associated molecular patterns (PAMPs) that are exhibited on their surface. Here, we demonstrate that the repeating protein subunit pattern common to most virus capsids is a molecular pattern that induces a Toll-like-receptor-2 (TLR2)-dependent antiviral immune response. This early antiviral immune response regulates the clearance of subsequent bacterial superinfections, which are a primary cause of morbidities associated with influenza virus infections. Utilizing this altered susceptibility to subsequent bacterial challenge as an outcome, we determined that multiple unrelated, empty, and replication-deficient capsids initiated early TLR2-dependent immune responses, similar to intact influenza virus or murine pneumovirus. These TLR2-mediated responses driven by the capsid were not dependent upon the capsid's shape, size, origin, or amino acid sequence. However, they were dependent upon the multisubunit arrangement of the capsid proteins, because unlike intact capsids, individual capsid subunits did not enhance bacterial clearance. Further, we demonstrated that even a linear microfilament protein built from repeating protein subunits (F-actin), but not its monomer (G-actin), induced similar kinetics of subsequent bacterial clearance as did virus capsid. However, although capsids and F-actin induced similar bacterial clearance, in macrophages they required distinct TLR2 heterodimers for this response (TLR2/6 or TLR2/1, respectively) and different phagocyte populations were involved in the execution of these responses in vivo Our results demonstrate that TLR2 responds to invading viral particles that are composed of repeating protein subunits, indicating that this common architecture of virus capsids is a previously unrecognized molecular pattern.IMPORTANCE Rapid and precise pathogen identification is critical for the initiation of pathogen-specific immune responses and pathogen clearance. Bacteria and fungi express common molecular patterns on their exteriors that are recognized by cell surface-expressed host pattern recognition receptors (PRRs) prior to infection. In contrast, viral molecular patterns are primarily nucleic acids, which are recognized after virus internalization. We found that an initial antiviral immune response is induced by the repeating subunit pattern of virus exteriors (capsids), and thus, induction of this response is independent of viral infection. This early response to viral capsids required the cell surface-expressed PRR TLR2 and allowed for improved clearance of subsequent bacterial infection that commonly complicates respiratory viral infections. Since the repeating protein subunit pattern is conserved across viral capsids, this suggests that it is not easy for a virus to change without altering fitness. Targeting this vulnerability could lead to development of a universal antiviral vaccine.
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Affiliation(s)
- Kelly M Shepardson
- Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA
| | - Benjamin Schwarz
- Department of Chemistry, Indiana University, Bloomington, Indiana, USA
| | - Kyle Larson
- Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA
| | - Rachelle V Morton
- Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA
| | - John Avera
- Department of Chemistry, Indiana University, Bloomington, Indiana, USA
| | - Kimberly McCoy
- Department of Chemistry, Indiana University, Bloomington, Indiana, USA
| | - Alayna Caffrey
- Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA
| | - Ann Harmsen
- Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA
| | - Trevor Douglas
- Department of Chemistry, Indiana University, Bloomington, Indiana, USA
| | - Agnieszka Rynda-Apple
- Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA
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46
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Nath AP, Ritchie SC, Byars SG, Fearnley LG, Havulinna AS, Joensuu A, Kangas AJ, Soininen P, Wennerström A, Milani L, Metspalu A, Männistö S, Würtz P, Kettunen J, Raitoharju E, Kähönen M, Juonala M, Palotie A, Ala-Korpela M, Ripatti S, Lehtimäki T, Abraham G, Raitakari O, Salomaa V, Perola M, Inouye M. An interaction map of circulating metabolites, immune gene networks, and their genetic regulation. Genome Biol 2017; 18:146. [PMID: 28764798 PMCID: PMC5540552 DOI: 10.1186/s13059-017-1279-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 07/14/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Immunometabolism plays a central role in many cardiometabolic diseases. However, a robust map of immune-related gene networks in circulating human cells, their interactions with metabolites, and their genetic control is still lacking. Here, we integrate blood transcriptomic, metabolomic, and genomic profiles from two population-based cohorts (total N = 2168), including a subset of individuals with matched multi-omic data at 7-year follow-up. RESULTS We identify topologically replicable gene networks enriched for diverse immune functions including cytotoxicity, viral response, B cell, platelet, neutrophil, and mast cell/basophil activity. These immune gene modules show complex patterns of association with 158 circulating metabolites, including lipoprotein subclasses, lipids, fatty acids, amino acids, small molecules, and CRP. Genome-wide scans for module expression quantitative trait loci (mQTLs) reveal five modules with mQTLs that have both cis and trans effects. The strongest mQTL is in ARHGEF3 (rs1354034) and affects a module enriched for platelet function, independent of platelet counts. Modules of mast cell/basophil and neutrophil function show temporally stable metabolite associations over 7-year follow-up, providing evidence that these modules and their constituent gene products may play central roles in metabolic inflammation. Furthermore, the strongest mQTL in ARHGEF3 also displays clear temporal stability, supporting widespread trans effects at this locus. CONCLUSIONS This study provides a detailed map of natural variation at the blood immunometabolic interface and its genetic basis, and may facilitate subsequent studies to explain inter-individual variation in cardiometabolic disease.
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Affiliation(s)
- Artika P Nath
- Department of Microbiology and Immunology, The University of Melbourne, Parkville, 3010, Victoria, Australia.,Systems Genomics Lab, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Scott C Ritchie
- Systems Genomics Lab, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.,Department of Pathology, The University of Melbourne, Parkville, 3010, Victoria, Australia
| | - Sean G Byars
- Department of Pathology, The University of Melbourne, Parkville, 3010, Victoria, Australia.,School of BioSciences, The University of Melbourne, Parkville, 3010, Victoria, Australia
| | - Liam G Fearnley
- Department of Pathology, The University of Melbourne, Parkville, 3010, Victoria, Australia.,School of BioSciences, The University of Melbourne, Parkville, 3010, Victoria, Australia
| | - Aki S Havulinna
- National Institute for Health and Welfare, Helsinki, 00271, Finland.,Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, 00014, Finland
| | - Anni Joensuu
- National Institute for Health and Welfare, Helsinki, 00271, Finland
| | - Antti J Kangas
- Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, 90014, Finland
| | - Pasi Soininen
- Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, 90014, Finland.,NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, 70211, Finland
| | | | - Lili Milani
- University of Tartu, Estonian Genome Center, Tartu, 51010, Estonia
| | - Andres Metspalu
- University of Tartu, Estonian Genome Center, Tartu, 51010, Estonia
| | - Satu Männistö
- National Institute for Health and Welfare, Helsinki, 00271, Finland
| | - Peter Würtz
- Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, 90014, Finland.,Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland
| | - Johannes Kettunen
- National Institute for Health and Welfare, Helsinki, 00271, Finland.,Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, 90014, Finland.,NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, 70211, Finland.,Biocenter Oulu, University of Oulu, Oulu, 90014, Finland
| | - Emma Raitoharju
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, 33014, Tampere, Finland
| | - Mika Kähönen
- Department of Clinical Physiology, University of Tampere and Tampere University Hospital, FI-33521, Tampere, Finland
| | - Markus Juonala
- Department of Medicine, University of Turku and Division of Medicine, Turku University Hospital, FI-20520, Turku, Finland.,Murdoch Childrens Research Institute, Parkville, 3052, Victoria, Australia
| | - Aarno Palotie
- Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, 00014, Finland.,Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.,Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.,Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Mika Ala-Korpela
- Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, 90014, Finland.,NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, 70211, Finland.,Biocenter Oulu, University of Oulu, Oulu, 90014, Finland.,Computational Medicine, School of Social and Community Medicine, University of Bristol, Bristol, BS8 1TH, UK.,Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK
| | - Samuli Ripatti
- Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, 00014, Finland.,Department of Public Health, University of Helsinki, Helsinki, 00014, Finland
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, 33014, Tampere, Finland
| | - Gad Abraham
- Systems Genomics Lab, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.,Department of Pathology, The University of Melbourne, Parkville, 3010, Victoria, Australia.,School of BioSciences, The University of Melbourne, Parkville, 3010, Victoria, Australia
| | - Olli Raitakari
- Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, 20520, Finland.,Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, 20520, Finland
| | - Veikko Salomaa
- National Institute for Health and Welfare, Helsinki, 00271, Finland
| | - Markus Perola
- National Institute for Health and Welfare, Helsinki, 00271, Finland.,Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, 00014, Finland.,University of Tartu, Estonian Genome Center, Tartu, 51010, Estonia
| | - Michael Inouye
- Department of Microbiology and Immunology, The University of Melbourne, Parkville, 3010, Victoria, Australia. .,Systems Genomics Lab, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia. .,Department of Pathology, The University of Melbourne, Parkville, 3010, Victoria, Australia. .,School of BioSciences, The University of Melbourne, Parkville, 3010, Victoria, Australia.
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47
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Oh H, Hirano J, Takai H, Ogata Y. Effects of initial periodontal therapy on interleukin-1β level in gingival crevicular fluid and clinical periodontal parameters. J Oral Sci 2017; 57:67-71. [PMID: 26062853 DOI: 10.2334/josnusd.57.67] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
Inflammatory cytokines may have important roles in periodontitis. We assessed the effects of initial periodontal therapy on clinical periodontal parameters and interleukin-1β (IL-1β) level in gingival crevicular fluid (GCF) from chronic periodontitis (CP) patients. After initial screening, baseline periodontal parameters such as probing pocket depth (PPD) and bleeding on probing (BOP) were measured. GCF samples were collected from 13 shallow (≤3 mm) and deep (≥5 mm) PPD sites from 13 CP patients, and GCF volume and IL-1β concentration were determined at baseline (before scaling and root planning) and at 2 and 4 months after initial therapy. Baseline BOP rate, GCF volume, and IL-1β level were significantly higher at deep PPD sites than at shallow PPD sites. Significant improvements in PPD and BOP were observed at 2 and 4 months after periodontal initial therapy in deep PPD sites only. In contrast, GCF volume and IL-1β concentration were lower at 2 and 4 months after initial therapy at all sites. These results suggest that GCF volume and IL-1β level in samples reflect disease severity and that these variables are better than PPD and BOP as markers of gingival inflammation.
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Affiliation(s)
- Hyun Oh
- Department of Periodontology, Nihon University School of Dentistry
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48
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Review on Toll-Like Receptor Activation in Myasthenia Gravis: Application to the Development of New Experimental Models. Clin Rev Allergy Immunol 2017; 52:133-147. [PMID: 27207173 DOI: 10.1007/s12016-016-8549-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Abnormal toll-like receptor (TLR) activation and uncontrolled resolution of inflammation are suspected to play a key role in the development of autoimmune diseases. Acquired myasthenia gravis (MG) is an invalidating neuromuscular disease leading to muscle weaknesses. MG is mainly mediated by anti-acetylcholine receptor (AChR) autoantibodies, and thymic hyperplasia characterized by ectopic germinal centers is a common feature in MG. An abnormal expression of certain TLRs is observed in the thymus of MG patients associated with the overexpression of interferon (IFN)-β, the orchestrator of thymic changes in MG. Experimental models have been developed for numerous autoimmune diseases. These models are induced by animal immunization with a purified antigen solubilized in complete Freund's adjuvant (CFA) containing heat-inactivated mycobacterium tuberculosis (MTB). Sensitization against the antigen is mainly due to the activation of TLR signaling pathways by the pathogen motifs displayed by MTB, and attempts have been made to substitute the use of CFA by TLR agonists. AChR emulsified in CFA is used to induce the classical experimental autoimmune MG model (EAMG). However, the TLR4 activator lipopolysaccharide (LPS) has proved to be efficient to replace MTB and induce a sensitization against purified AChR. Poly(I:C), the well-known TLR3 agonist, is also able by itself to induce MG symptoms in mice associated with early thymic changes as observed in human MG. In this review, we discuss the abnormal expression of TLRs in MG patients and we describe the use of TLR agonists to induce EAMG in comparison with other autoimmune experimental models.
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49
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Kim JO, Kim JO, Kim WS, Oh MJ. Characterization of the Transcriptome and Gene Expression of Brain Tissue in Sevenband Grouper (Hyporthodus septemfasciatus) in Response to NNV Infection. Genes (Basel) 2017; 8:genes8010031. [PMID: 28098800 PMCID: PMC5295026 DOI: 10.3390/genes8010031] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 01/07/2017] [Accepted: 01/09/2017] [Indexed: 12/21/2022] Open
Abstract
Grouper is one of the favorite sea food resources in Southeast Asia. However, the outbreaks of the viral nervous necrosis (VNN) disease due to nervous necrosis virus (NNV) infection have caused mass mortality of grouper larvae. Many aqua-farms have suffered substantial financial loss due to the occurrence of VNN. To better understand the infection mechanism of NNV, we performed the transcriptome analysis of sevenband grouper brain tissue, the main target of NNV infection. After artificial NNV challenge, transcriptome of brain tissues of sevenband grouper was subjected to next generation sequencing (NGS) using an Illumina Hi-seq 2500 system. Both mRNAs from pooled samples of mock and NNV-infected sevenband grouper brains were sequenced. Clean reads of mock and NNV-infected samples were de novo assembled and obtained 104,348 unigenes. In addition, 628 differentially expressed genes (DEGs) in response to NNV infection were identified. This result could provide critical information not only for the identification of genes involved in NNV infection, but for the understanding of the response of sevenband groupers to NNV infection.
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Affiliation(s)
- Jong-Oh Kim
- Department of Aqualife Medicine, College of Fisheries and Ocean Science, Chonnam National University, Yeosu 550-749, Korea.
| | - Jae-Ok Kim
- Department of Aqualife Medicine, College of Fisheries and Ocean Science, Chonnam National University, Yeosu 550-749, Korea.
| | - Wi-Sik Kim
- Department of Aqualife Medicine, College of Fisheries and Ocean Science, Chonnam National University, Yeosu 550-749, Korea.
| | - Myung-Joo Oh
- Department of Aqualife Medicine, College of Fisheries and Ocean Science, Chonnam National University, Yeosu 550-749, Korea.
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50
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Schock SN, Chandra NV, Sun Y, Irie T, Kitagawa Y, Gotoh B, Coscoy L, Winoto A. Induction of necroptotic cell death by viral activation of the RIG-I or STING pathway. Cell Death Differ 2017; 24:615-625. [PMID: 28060376 DOI: 10.1038/cdd.2016.153] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 11/26/2016] [Accepted: 12/07/2016] [Indexed: 01/02/2023] Open
Abstract
Necroptosis is a form of necrotic cell death that requires the activity of the death domain-containing kinase RIP1 and its family member RIP3. Necroptosis occurs when RIP1 is deubiquitinated to form a complex with RIP3 in cells deficient in the death receptor adapter molecule FADD or caspase-8. Necroptosis may play a role in host defense during viral infection as viruses like vaccinia can induce necroptosis while murine cytomegalovirus encodes a viral inhibitor of necroptosis. To see how general the interplay between viruses and necroptosis is, we surveyed seven different viruses. We found that two of the viruses tested, Sendai virus (SeV) and murine gammaherpesvirus-68 (MHV68), are capable of inducing dramatic necroptosis in the fibrosarcoma L929 cell line. We show that MHV68-induced cell death occurs through the cytosolic STING sensor pathway in a TNF-dependent manner. In contrast, SeV-induced death is mostly independent of TNF. Knockdown of the RNA sensing molecule RIG-I or the RIP1 deubiquitin protein, CYLD, but not STING, rescued cells from SeV-induced necroptosis. Accompanying necroptosis, we also find that wild type but not mutant SeV lacking the viral proteins Y1 and Y2 result in the non-ubiquitinated form of RIP1. Expression of Y1 or Y2 alone can suppress RIP1 ubiquitination but CYLD is dispensable for this process. Instead, we found that Y1 and Y2 can inhibit cIAP1-mediated RIP1 ubiquitination. Interestingly, we also found that SeV infection of B6 RIP3-/- mice results in increased inflammation in the lung and elevated SeV-specific T cells. Collectively, these data identify viruses and pathways that can trigger necroptosis and highlight the dynamic interplay between pathogen-recognition receptors and cell death induction.
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Affiliation(s)
- Suruchi N Schock
- Department of Molecular and Cell Biology and Cancer Research Laboratory, 469 LSA, University of California, Berkeley, CA 94720-3200, USA
| | - Neha V Chandra
- Department of Molecular and Cell Biology and Cancer Research Laboratory, 469 LSA, University of California, Berkeley, CA 94720-3200, USA
| | - Yuefang Sun
- Department of Molecular and Cell Biology and Cancer Research Laboratory, 469 LSA, University of California, Berkeley, CA 94720-3200, USA
| | - Takashi Irie
- Department of Virology, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| | - Yoshinori Kitagawa
- Division of Microbiology and Infectious Diseases, Department of Pathology, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan
| | - Bin Gotoh
- Division of Microbiology and Infectious Diseases, Department of Pathology, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan
| | - Laurent Coscoy
- Department of Molecular and Cell Biology and Cancer Research Laboratory, 469 LSA, University of California, Berkeley, CA 94720-3200, USA
| | - Astar Winoto
- Department of Molecular and Cell Biology and Cancer Research Laboratory, 469 LSA, University of California, Berkeley, CA 94720-3200, USA
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