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1
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Ip WH, Bertzbach LD, Schreiner S, Dobner T. Adenovirus E1B-55K interferes with cellular IκB kinase complex subunit proteins. Front Immunol 2025; 16:1532742. [PMID: 40103806 PMCID: PMC11913716 DOI: 10.3389/fimmu.2025.1532742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 02/17/2025] [Indexed: 03/20/2025] Open
Abstract
Human adenovirus (HAdV) infections can cause high mortality rates in immunocompromised patients due to the activation of unhampered cytokine storms that are mainly induced by activation of pro-inflammatory cytokines. NF-κB is a transcription factor that is involved in numerous biological processes such as regulation of cell death and proliferation, as well as the activation of innate immune responses including the expression of pro-inflammatory cytokines, chemokines, and other immune response genes. The IKK complex plays a crucial role in the NF-κB pathway by phosphorylating and activating IκB proteins, which leads to the degradation of IκB and the subsequent release and nuclear translocation of NF-κB dimers to initiate gene transcription. The host NF-κB pathway, particularly the formation of the IKK complex, is a common target for viruses to regulate host immune responses or to utilize or inhibit its function for efficient viral replication. So far, investigations of the immune response to adenovirus infection mainly focused on transduction of adenoviral vectors or high-titer infections. Therefore, the molecular mechanism of HAdV- and HAdV gene product-mediated modulation of the NF-κB response in lytic infection is not well understood. Here, we show that HAdV-C5 infection counteracts cellular IκB kinase complex formation. Intriguingly, the IKK complex protein IKKα is targeted to the nucleus and localizes juxtaposed to viral replication centers. Furthermore, IKKα interacts with the early viral E1B-55K protein and facilitates viral replication. Together, our data provide evidence for a novel HAdV-C5 mechanism to escape host immune responses by utilizing NF-κB pathway-independent nuclear functions of IKKα to support efficient viral progeny production.
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Affiliation(s)
- Wing-Hang Ip
- Department of Viral Transformation, Leibniz Institute of Virology, Hamburg, Germany
| | - Luca D Bertzbach
- Department of Viral Transformation, Leibniz Institute of Virology, Hamburg, Germany
| | - Sabrina Schreiner
- Institute of Virology, Medical Center, University of Freiburg, Freiburg, Germany
- Institute of Virology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (Resolving Infection Susceptibility; EXC 2155), Hannover Medical School, Hannover, Germany
| | - Thomas Dobner
- Department of Viral Transformation, Leibniz Institute of Virology, Hamburg, Germany
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2
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Kalantari L, Ghotbabadi ZR, Gholipour A, Ehymayed HM, Najafiyan B, Amirlou P, Yasamineh S, Gholizadeh O, Emtiazi N. A state-of-the-art review on the NRF2 in Hepatitis virus-associated liver cancer. Cell Commun Signal 2023; 21:318. [PMID: 37946175 PMCID: PMC10633941 DOI: 10.1186/s12964-023-01351-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 10/09/2023] [Indexed: 11/12/2023] Open
Abstract
According to a paper released and submitted to WHO by IARC scientists, there would be 905,700 new cases of liver cancer diagnosed globally in 2020, with 830,200 deaths expected as a direct result. Hepatitis B virus (HBV) hepatitis C virus (HCV), and hepatitis D virus (HDV) all play critical roles in the pathogenesis of hepatocellular carcinoma (HCC), despite the rising prevalence of HCC due to non-infectious causes. Liver cirrhosis and HCC are devastating consequences of HBV and HCV infections, which are widespread worldwide. Associated with a high mortality rate, these infections cause about 1.3 million deaths annually and are the primary cause of HCC globally. In addition to causing insertional mutations due to viral gene integration, epigenetic alterations and inducing chronic immunological dysfunction are all methods by which these viruses turn hepatocytes into cancerous ones. While expanding our knowledge of the illness, identifying these pathways also give possibilities for novel diagnostic and treatment methods. Nuclear factor erythroid 2-related factor 2 (NRF2) activation is gaining popularity as a treatment option for oxidative stress (OS), inflammation, and metabolic abnormalities. Numerous studies have shown that elevated Nrf2 expression is linked to HCC, providing more evidence that Nrf2 is a critical factor in HCC. This aberrant Nrf2 signaling drives cell proliferation, initiates angiogenesis and invasion, and imparts drug resistance. As a result, this master regulator may be a promising treatment target for HCC. In addition, the activation of Nrf2 is a common viral effect that contributes to the pathogenesis, development, and chronicity of virus infection. However, certain viruses suppress Nrf2 activity, which is helpful to the virus in maintaining cellular homeostasis. In this paper, we discussed the influence of Nrf2 deregulation on the viral life cycle and the pathogenesis associated with HBV and HCV. We summed up the mechanisms for the modulation of Nrf2 that are deregulated by these viruses. Moreover, we describe the molecular mechanism by which Nrf2 is modulated in liver cancer, liver cancer stem cells (LCSCs), and liver cancer caused by HBV and HCV. Video Abstract.
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Affiliation(s)
- Leila Kalantari
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Arsalan Gholipour
- Nanotechnology Research Institute, School of Chemical Engineering, Babol Noshirvani University of Technology, Babol, Iran
| | | | - Behnam Najafiyan
- Faculty of Pharmacy, Shiraz University of Medical Science, Shiraz, Iran
| | - Parsa Amirlou
- Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | | | - Nikoo Emtiazi
- Department of Pathology, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran.
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3
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Barik S. Suppression of Innate Immunity by the Hepatitis C Virus (HCV): Revisiting the Specificity of Host-Virus Interactive Pathways. Int J Mol Sci 2023; 24:16100. [PMID: 38003289 PMCID: PMC10671098 DOI: 10.3390/ijms242216100] [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: 10/08/2023] [Revised: 10/31/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
The hepatitis C virus (HCV) is a major causative agent of hepatitis that may also lead to liver cancer and lymphomas. Chronic hepatitis C affects an estimated 2.4 million people in the USA alone. As the sole member of the genus Hepacivirus within the Flaviviridae family, HCV encodes a single-stranded positive-sense RNA genome that is translated into a single large polypeptide, which is then proteolytically processed to yield the individual viral proteins, all of which are necessary for optimal viral infection. However, cellular innate immunity, such as type-I interferon (IFN), promptly thwarts the replication of viruses and other pathogens, which forms the basis of the use of conjugated IFN-alpha in chronic hepatitis C management. As a countermeasure, HCV suppresses this form of immunity by enlisting diverse gene products, such as HCV protease(s), whose primary role is to process the large viral polyprotein into individual proteins of specific function. The exact number of HCV immune suppressors and the specificity and molecular mechanism of their action have remained unclear. Nonetheless, the evasion of host immunity promotes HCV pathogenesis, chronic infection, and carcinogenesis. Here, the known and putative HCV-encoded suppressors of innate immunity have been reviewed and analyzed, with a predominant emphasis on the molecular mechanisms. Clinically, the knowledge should aid in rational interventions and the management of HCV infection, particularly in chronic hepatitis.
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Affiliation(s)
- Sailen Barik
- EonBio, 3780 Pelham Drive, Mobile, AL 36619, USA
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4
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Pereira M, Gazzinelli RT. Regulation of innate immune signaling by IRAK proteins. Front Immunol 2023; 14:1133354. [PMID: 36865541 PMCID: PMC9972678 DOI: 10.3389/fimmu.2023.1133354] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 01/30/2023] [Indexed: 02/16/2023] Open
Abstract
The Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1R) families are of paramount importance in coordinating the early immune response to pathogens. Signaling via most TLRs and IL-1Rs is mediated by the protein myeloid differentiation primary-response protein 88 (MyD88). This signaling adaptor forms the scaffold of the myddosome, a molecular platform that employs IL-1R-associated kinase (IRAK) proteins as main players for transducing signals. These kinases are essential in controlling gene transcription by regulating myddosome assembly, stability, activity and disassembly. Additionally, IRAKs play key roles in other biologically relevant responses such as inflammasome formation and immunometabolism. Here, we summarize some of the key aspects of IRAK biology in innate immunity.
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Affiliation(s)
- Milton Pereira
- Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, United States,*Correspondence: Milton Pereira, ; Ricardo T. Gazzinelli,
| | - Ricardo T. Gazzinelli
- Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, United States,Centro de Tecnologia de Vacinas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil,Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG, Brazil,Plataforma de Medicina Translacional, Fundação Oswaldo Cruz, Ribeirão Preto, SP, Brazil,*Correspondence: Milton Pereira, ; Ricardo T. Gazzinelli,
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5
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Ciaston I, Dobosz E, Potempa J, Koziel J. The subversion of toll-like receptor signaling by bacterial and viral proteases during the development of infectious diseases. Mol Aspects Med 2022; 88:101143. [PMID: 36152458 PMCID: PMC9924004 DOI: 10.1016/j.mam.2022.101143] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/29/2022] [Accepted: 09/09/2022] [Indexed: 02/05/2023]
Abstract
Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) that respond to pathogen-associated molecular patterns (PAMPs). The recognition of specific microbial ligands by TLRs triggers an innate immune response and also promotes adaptive immunity, which is necessary for the efficient elimination of invading pathogens. Successful pathogens have therefore evolved strategies to subvert and/or manipulate TLR signaling. Both the impairment and uncontrolled activation of TLR signaling can harm the host, causing tissue destruction and allowing pathogens to proliferate, thus favoring disease progression. In this context, microbial proteases are key virulence factors that modify components of the TLR signaling pathway. In this review, we discuss the role of bacterial and viral proteases in the manipulation of TLR signaling, highlighting the importance of these enzymes during the development of infectious diseases.
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Affiliation(s)
- Izabela Ciaston
- Department of Microbiology Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Ewelina Dobosz
- Department of Microbiology Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Jan Potempa
- Department of Microbiology Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland; Department of Oral Health and Systemic Disease, University of Louisville School of Dentistry, University of Louisville, Louisville, KY, USA.
| | - Joanna Koziel
- Department of Microbiology Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
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6
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Manan A, Pirzada RH, Haseeb M, Choi S. Toll-like Receptor Mediation in SARS-CoV-2: A Therapeutic Approach. Int J Mol Sci 2022; 23:10716. [PMID: 36142620 PMCID: PMC9502216 DOI: 10.3390/ijms231810716] [Citation(s) in RCA: 7] [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: 08/20/2022] [Revised: 09/10/2022] [Accepted: 09/10/2022] [Indexed: 01/18/2023] Open
Abstract
The innate immune system facilitates defense mechanisms against pathogen invasion and cell damage. Toll-like receptors (TLRs) assist in the activation of the innate immune system by binding to pathogenic ligands. This leads to the generation of intracellular signaling cascades including the biosynthesis of molecular mediators. TLRs on cell membranes are adept at recognizing viral components. Viruses can modulate the innate immune response with the help of proteins and RNAs that downregulate or upregulate the expression of various TLRs. In the case of COVID-19, molecular modulators such as type 1 interferons interfere with signaling pathways in the host cells, leading to an inflammatory response. Coronaviruses are responsible for an enhanced immune signature of inflammatory chemokines and cytokines. TLRs have been employed as therapeutic agents in viral infections as numerous antiviral Food and Drug Administration-approved drugs are TLR agonists. This review highlights the therapeutic approaches associated with SARS-CoV-2 and the TLRs involved in COVID-19 infection.
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Affiliation(s)
- Abdul Manan
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea
| | | | - Muhammad Haseeb
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea
- S&K Therapeutics, Ajou University Campus Plaza 418, 199 Worldcup-ro, Yeongtong-gu, Suwon 16502, Korea
| | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea
- S&K Therapeutics, Ajou University Campus Plaza 418, 199 Worldcup-ro, Yeongtong-gu, Suwon 16502, Korea
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7
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Latanova A, Starodubova E, Karpov V. Flaviviridae Nonstructural Proteins: The Role in Molecular Mechanisms of Triggering Inflammation. Viruses 2022; 14:v14081808. [PMID: 36016430 PMCID: PMC9414172 DOI: 10.3390/v14081808] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/13/2022] [Accepted: 08/15/2022] [Indexed: 12/24/2022] Open
Abstract
Members of the Flaviviridae family are posing a significant threat to human health worldwide. Many flaviviruses are capable of inducing severe inflammation in humans. Flaviviridae nonstructural proteins, apart from their canonical roles in viral replication, have noncanonical functions strongly affecting antiviral innate immunity. Among these functions, antagonism of type I IFN is the most investigated; meanwhile, more data are accumulated on their role in the other pathways of innate response. This review systematizes the last known data on the role of Flaviviridae nonstructural proteins in molecular mechanisms of triggering inflammation, with an emphasis on their interactions with TLRs and RLRs, interference with NF-κB and cGAS-STING signaling, and activation of inflammasomes.
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8
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Redwan EM, Aljadawi AA, Uversky VN. Hepatitis C Virus Infection and Intrinsic Disorder in the Signaling Pathways Induced by Toll-Like Receptors. BIOLOGY 2022; 11:1091. [PMID: 36101469 PMCID: PMC9312352 DOI: 10.3390/biology11071091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 07/07/2022] [Accepted: 07/19/2022] [Indexed: 11/23/2022]
Abstract
In this study, we examined the interplay between protein intrinsic disorder, hepatitis C virus (HCV) infection, and signaling pathways induced by Toll-like receptors (TLRs). To this end, 10 HCV proteins, 10 human TLRs, and 41 proteins from the TLR-induced downstream pathways were considered from the prevalence of intrinsic disorder. Mapping of the intrinsic disorder to the HCV-TLR interactome and to the TLR-based pathways of human innate immune response to the HCV infection demonstrates that substantial levels of intrinsic disorder are characteristic for proteins involved in the regulation and execution of these innate immunity pathways and in HCV-TLR interaction. Disordered regions, being commonly enriched in sites of various posttranslational modifications, may play important functional roles by promoting protein-protein interactions and support the binding of the analyzed proteins to other partners such as nucleic acids. It seems that this system represents an important illustration of the role of intrinsic disorder in virus-host warfare.
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Affiliation(s)
- Elrashdy M. Redwan
- Biological Science Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia; (E.M.R.); (A.A.A.)
- Therapeutic and Protective Proteins Laboratory, Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology Applications, New Borg EL-Arab, Alexandria 21934, Egypt
| | - Abdullah A. Aljadawi
- Biological Science Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia; (E.M.R.); (A.A.A.)
| | - Vladimir N. Uversky
- Biological Science Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia; (E.M.R.); (A.A.A.)
- Department of Molecular Medicine and USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
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9
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Toll-like Receptor Response to Hepatitis C Virus Infection: A Recent Overview. Int J Mol Sci 2022; 23:ijms23105475. [PMID: 35628287 PMCID: PMC9141274 DOI: 10.3390/ijms23105475] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV) infection remains a major global health burden, causing chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors that detect pathogen-associated molecular patterns and activate downstream signaling to induce proinflammatory cytokine and chemokine production. An increasing number of studies have suggested the importance of TLR responses in the outcome of HCV infection. However, the exact role of innate immune responses, including TLR response, in controlling chronic HCV infection remains to be established. A proper understanding of the TLR response in HCV infection is essential for devising new therapeutic approaches against HCV infection. In this review, we discuss the progress made in our understanding of the host innate immune response to HCV infection, with a particular focus on the TLR response. In addition, we discuss the mechanisms adopted by HCV to avoid immune surveillance mediated by TLRs.
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10
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Amsden H, Kourko O, Roth M, Gee K. Antiviral Activities of Interleukin-27: A Partner for Interferons? Front Immunol 2022; 13:902853. [PMID: 35634328 PMCID: PMC9134790 DOI: 10.3389/fimmu.2022.902853] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 04/14/2022] [Indexed: 12/17/2022] Open
Abstract
Emergence of new, pandemic-level viral threats has brought to the forefront the importance of viral immunology and continued improvement of antiviral therapies. Interleukin-27 (IL-27) is a pleiotropic cytokine that regulates both innate and adaptive immune responses. Accumulating evidence has revealed potent antiviral activities of IL-27 against numerous viruses, including HIV, influenza, HBV and more. IL-27 contributes to the immune response against viruses indirectly by increasing production of interferons (IFNs) which have various antiviral effects. Additionally, IL-27 can directly interfere with viral infection both by acting similarly to an IFN itself and by modulating the differentiation and function of various immune cells. This review discusses the IFN-dependent and IFN-independent antiviral mechanisms of IL-27 and highlights the potential of IL-27 as a therapeutic cytokine for viral infection.
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Affiliation(s)
| | | | | | - Katrina Gee
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada
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11
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Chakraborty C, Sharma AR, Bhattacharya M, Lee SS. A Detailed Overview of Immune Escape, Antibody Escape, Partial Vaccine Escape of SARS-CoV-2 and Their Emerging Variants With Escape Mutations. Front Immunol 2022; 13:801522. [PMID: 35222380 PMCID: PMC8863680 DOI: 10.3389/fimmu.2022.801522] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 01/05/2022] [Indexed: 01/08/2023] Open
Abstract
The infective SARS-CoV-2 is more prone to immune escape. Presently, the significant variants of SARS-CoV-2 are emerging in due course of time with substantial mutations, having the immune escape property. Simultaneously, the vaccination drive against this virus is in progress worldwide. However, vaccine evasion has been noted by some of the newly emerging variants. Our review provides an overview of the emerging variants' immune escape and vaccine escape ability. We have illustrated a broad view related to viral evolution, variants, and immune escape ability. Subsequently, different immune escape approaches of SARS-CoV-2 have been discussed. Different innate immune escape strategies adopted by the SARS-CoV-2 has been discussed like, IFN-I production dysregulation, cytokines related immune escape, immune escape associated with dendritic cell function and macrophages, natural killer cells and neutrophils related immune escape, PRRs associated immune evasion, and NLRP3 inflammasome associated immune evasion. Simultaneously we have discussed the significant mutations related to emerging variants and immune escape, such as mutations in the RBD region (N439K, L452R, E484K, N501Y, K444R) and other parts (D614G, P681R) of the S-glycoprotein. Mutations in other locations such as NSP1, NSP3, NSP6, ORF3, and ORF8 have also been discussed. Finally, we have illustrated the emerging variants' partial vaccine (BioNTech/Pfizer mRNA/Oxford-AstraZeneca/BBIBP-CorV/ZF2001/Moderna mRNA/Johnson & Johnson vaccine) escape ability. This review will help gain in-depth knowledge related to immune escape, antibody escape, and partial vaccine escape ability of the virus and assist in controlling the current pandemic and prepare for the next.
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Affiliation(s)
- Chiranjib Chakraborty
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, India
| | - Ashish Ranjan Sharma
- Institute for Skeletal Aging and Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon-si, South Korea
| | | | - Sang-Soo Lee
- Institute for Skeletal Aging and Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon-si, South Korea
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12
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Gao Y, Nepal N, Jin SZ. Toll-like receptors and hepatitis C virus infection. Hepatobiliary Pancreat Dis Int 2021; 20:521-529. [PMID: 34419367 DOI: 10.1016/j.hbpd.2021.07.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 07/26/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is a worldwide issue. However, the current treatment for hepatitis C has many shortcomings. Toll-like receptors (TLRs) are pattern recognition receptors involved in HCV infection, and an increasing number of studies are focusing on the role of TLRs in the progression of hepatitis C. DATA SOURCES We performed a PubMed search up to January 2021 with the following keywords: hepatitis C, toll-like receptors, interferons, inflammation, and immune evasion. We also used terms such as single-nucleotide polymorphisms (SNPs), susceptibility, fibrosis, cirrhosis, direct-acting antiviral agents, agonists, and antagonists to supplement the query results. We reviewed relevant publications analyzing the correlation between hepatitis C and TLRs and the role of TLRs in HCV infection. RESULTS TLRs 1-4 and 6-9 are involved in the process of HCV infection. When the host is exposed to the HCV, TLRs, as important participants in HCV immune evasion, trigger innate immunity to remove the virus and also promote inflammation and liver fibrosis. TLR gene SNPs affect hepatitis C susceptibility, treatment, and prognosis. The contribution of each TLR to HCV is different. Drugs targeting various TLRs are developed and validated, and TLRs can synergize with classic hepatitis C drugs, including interferon and direct-acting antiviral agents, constituting a new direction for the treatment of hepatitis C. CONCLUSIONS TLRs are important receptors in HCV infection. Different TLRs induce different mechanisms of virus clearance and inflammatory response. Although TLR-related antiviral therapy strategies exist, more studies are needed to explore the clinical application of TLR-related drugs.
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Affiliation(s)
- Yang Gao
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Narayan Nepal
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Shi-Zhu Jin
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
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13
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Getachew A, Hussain M, Huang X, Li Y. Toll-like receptor 2 signaling in liver pathophysiology. Life Sci 2021; 284:119941. [PMID: 34508761 DOI: 10.1016/j.lfs.2021.119941] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 08/19/2021] [Accepted: 08/30/2021] [Indexed: 12/24/2022]
Abstract
Chronic liver diseases (CLD) are among the major cause of mortality and morbidity worldwide. Despite current achievements in the area of hepatitis virus, chronic alcohol abuse and high-fat diet are still fueling an epidemic of severe liver disease, for which, an effective therapy has yet not been discovered. In particular, the therapeutic regimens that could prevent the progression of fibrosis and, in turn, aid cirrhotic liver to develop a robust regenerative capability are intensively needed. To this context, a better understanding of the signaling pathways regulating hepatic disease development may be of critical value. In general, the liver responds to various insults with an orchestrated healing process involving variety of signaling pathways. One such pathway is the TLR2 signaling pathway, which essentially regulates adult liver pathogenesis and thus has emerged as an attractive target to treat liver disease. TLR2 is expressed by different liver cells, including Kupffer cells (KCs), hepatocytes, and hepatic stellate cells (HSCs). From a pathologic perspective, the crosstalk between antigens and TLR2 may preferentially trigger a distinctive set of signaling mechanisms in these liver cells and, thereby, induce the production of inflammatory and fibrogenic cytokines that can initiate and prolong liver inflammation, ultimately leading to fibrosis. In this review, we summarize the currently available evidence regarding the role of TLR2 signaling in hepatic disease progression. We first elaborate its pathological involvement in liver-disease states, such as inflammation, fibrosis, and cirrhosis. We then discuss how therapeutic targeting of this pathway may help to alleviate its disease-related functioning.
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Affiliation(s)
- Anteneh Getachew
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Muzammal Hussain
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Xinping Huang
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yinxiong Li
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China.
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14
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Sartorius R, Trovato M, Manco R, D'Apice L, De Berardinis P. Exploiting viral sensing mediated by Toll-like receptors to design innovative vaccines. NPJ Vaccines 2021; 6:127. [PMID: 34711839 PMCID: PMC8553822 DOI: 10.1038/s41541-021-00391-8] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 10/01/2021] [Indexed: 12/12/2022] Open
Abstract
Toll-like receptors (TLRs) are transmembrane proteins belonging to the family of pattern-recognition receptors. They function as sensors of invading pathogens through recognition of pathogen-associated molecular patterns. After their engagement by microbial ligands, TLRs trigger downstream signaling pathways that culminate into transcriptional upregulation of genes involved in immune defense. Here we provide an updated overview on members of the TLR family and we focus on their role in antiviral response. Understanding of innate sensing and signaling of viruses triggered by these receptors would provide useful knowledge to prompt the development of vaccines able to elicit effective and long-lasting immune responses. We describe the mechanisms developed by viral pathogens to escape from immune surveillance mediated by TLRs and finally discuss how TLR/virus interplay might be exploited to guide the design of innovative vaccine platforms.
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Affiliation(s)
- Rossella Sartorius
- Institute of Biochemistry and Cell Biology, C.N.R., Via Pietro Castellino 111, 80131, Naples, Italy.
| | - Maria Trovato
- Institute of Biochemistry and Cell Biology, C.N.R., Via Pietro Castellino 111, 80131, Naples, Italy
| | - Roberta Manco
- Institute of Biochemistry and Cell Biology, C.N.R., Via Pietro Castellino 111, 80131, Naples, Italy
| | - Luciana D'Apice
- Institute of Biochemistry and Cell Biology, C.N.R., Via Pietro Castellino 111, 80131, Naples, Italy.
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15
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Rai KR, Shrestha P, Yang B, Chen Y, Liu S, Maarouf M, Chen JL. Acute Infection of Viral Pathogens and Their Innate Immune Escape. Front Microbiol 2021; 12:672026. [PMID: 34239508 PMCID: PMC8258165 DOI: 10.3389/fmicb.2021.672026] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/04/2021] [Indexed: 12/15/2022] Open
Abstract
Viral infections can cause rampant disease in human beings, ranging from mild to acute, that can often be fatal unless resolved. An acute viral infection is characterized by sudden or rapid onset of disease, which can be resolved quickly by robust innate immune responses exerted by the host or, instead, may kill the host. Immediately after viral infection, elements of innate immunity, such as physical barriers, various phagocytic cells, group of cytokines, interferons (IFNs), and IFN-stimulated genes, provide the first line of defense for viral clearance. Innate immunity not only plays a critical role in rapid viral clearance but can also lead to disease progression through immune-mediated host tissue injury. Although elements of antiviral innate immunity are armed to counter the viral invasion, viruses have evolved various strategies to escape host immune surveillance to establish successful infections. Understanding complex mechanisms underlying the interaction between viruses and host’s innate immune system would help develop rational treatment strategies for acute viral infectious diseases. In this review, we discuss the pathogenesis of acute infections caused by viral pathogens and highlight broad immune escape strategies exhibited by viruses.
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Affiliation(s)
- Kul Raj Rai
- Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Prasha Shrestha
- Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Bincai Yang
- Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Yuhai Chen
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Shasha Liu
- Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Mohamed Maarouf
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Ji-Long Chen
- Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China.,CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
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16
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Yan J, Zhang Y, Su Y, Tian L, Qin P, Xu X, Zhou Y. microRNA-125a targets MAVS and TRAF6 to modulate interferon signaling and promote HCV infection. Virus Res 2021; 296:198336. [PMID: 33577860 DOI: 10.1016/j.virusres.2021.198336] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 12/30/2020] [Accepted: 02/02/2021] [Indexed: 12/20/2022]
Abstract
Hepatitis C virus (HCV) can cause chronic lifelong infections in humans, resulting in sustained hepatic inflammation, liver cirrhosis, and hepatocellular carcinoma. The clearance of HCV infections is dependent upon effective and coordinated innate and adaptive antiviral immune responses. However, HCV has evolved a range of strategies that enable it to evade or overcome the host immune response, enabling the virus to persist in susceptible hosts through mechanisms that remain to be fully clarified. Herein, we describe a novel mechanism whereby HCV can evade immune surveillance by activating microRNA (miR)-125a. Hepatocytes upregulate miR-125a following HCV infection, and serum from HCV-infected patients similarly exhibits the upregulation of this miRNA. We found that miR-125a is able to target and suppress the expression of two key genes associated with the interferon (IFN) signaling pathway - mitochondrial antiviral signaling (MAVS) and TNF receptor-associated factor 6 (TRAF6). Disrupting the expression of these genes can in turn compromise type I IFN responses to HCV. Together, our data reveal that HCV infection results in the upregulation of miR-125a, which negatively regulates IFN signaling via inhibiting the expression of MAVS and TRAF6, thereby enabling the virus to evade innate antiviral immunity. Targeting this pathway may thus represent an efficient approach to treating HCV and bolstering antiviral immune responses in infected patients.
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Affiliation(s)
- Jianguo Yan
- Department of Physiology, Guilin Medical University, Guilin, 541004, Guangxi, China
| | - Yuting Zhang
- Department of Microbiology, Guilin Medical University, Guilin, 541004, Guangxi, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541004, Guangxi, China
| | - Yan Su
- Department of Physiology, Guilin Medical University, Guilin, 541004, Guangxi, China
| | - Linlin Tian
- Department of Microbiology, Guilin Medical University, Guilin, 541004, Guangxi, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541004, Guangxi, China
| | - Peifang Qin
- Department of Microbiology, Guilin Medical University, Guilin, 541004, Guangxi, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541004, Guangxi, China
| | - Xingfeng Xu
- Department of Physiology, Guilin Medical University, Guilin, 541004, Guangxi, China
| | - Yali Zhou
- Department of Microbiology, Guilin Medical University, Guilin, 541004, Guangxi, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541004, Guangxi, China.
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17
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Sokolova TM. [Hepatitis C virus (Flaviviridae: Hepacivirus: Hepacivirus C): regulation of signaling reactions of innate immunity]. Vopr Virusol 2021; 65:307-316. [PMID: 33533227 DOI: 10.36233/0507-4088-2020-65-6-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 01/07/2021] [Indexed: 12/21/2022]
Abstract
Studying the regulation of signaling reactions of innate immunity by the hepatitis C virus (HCV) will help to reveal the causes of the transition of the acute form of the disease to a chronic course. The molecular mechanisms of activation by HCV RNA of innate immunity receptors TLR and RLR and signal transduction processes leading to the synthesis of IFN and inflammatory cytokines are considered. The inhibitory effects of non-structural and structural HCV proteins on immune signaling reactions are analyzed in detail. The information presented is the result of an analysis of literature data published in international databases mainly over the past 5 years. In conclusion, signaling receptors are proposed as targets for the development of new antiviral drugs with immunotherapeutic activity.
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Affiliation(s)
- T M Sokolova
- D.I. Ivanovsky Institute of Virology of National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya
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18
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Abdelwahab SF, Hamdy S, Osman AM, Zakaria ZA, Galal I, Sobhy M, Hashem M, Allam WR, Abdel‐Samiee M, Rewisha E, Waked I. Association of the polymorphism of the Toll-like receptor (TLR)-3 and TLR-9 genes with hepatitis C virus-specific cell-mediated immunity outcomes among Egyptian health-care workers. Clin Exp Immunol 2021; 203:3-12. [PMID: 32939755 PMCID: PMC7744502 DOI: 10.1111/cei.13514] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/29/2020] [Accepted: 09/02/2020] [Indexed: 02/05/2023] Open
Abstract
Variations in the immune response could explain resistance to hepatitis C virus (HCV) infection. Toll-like receptor gene (TLR)-3 is an innate detector of dsRNA viruses, and the TLR-9 gene recognizes bacterial and viral unmethylated cytosine-phosphate-guanosine (CpG) motifs. We previously reported that the TLR-3.rs3775290 CC genotype was associated with HCV chronicity and that the TLR-9 gene played no major role in this infection. This study identified the role of TLR-3.rs3775290 (c.1377C/T), TLR-9.rs5743836 (-1237T→C) and TLR-9.rs352140 (G2848A) gene polymorphisms in predicting the outcome of HCV-specific cell-mediated immunity (CMI) among Egyptian health-care workers (HCWs). We enrolled 265 HCWs in this study and divided them into four groups. Group 1: 140 seronegative-aviraemic HCWs; group 2: 20 seronegative-viraemic HCWs; group 3: 35 subjects with spontaneously resolved HCV infection; and group 4: 70 chronic HCV HCWs (patients). All subjects were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis for the TLR-3.rs3775290, TLR-9.rs5743836 and TLR-9.rs352140 single nucleotide polymorphisms (SNPs). We also quantified HCV-specific CMI in the four groups using an interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay in response to nine HCV genotype 4a, overlapping 15mer peptide pools covering the whole viral genome. No statistically significant difference was found between CMI-responding subjects with different HCV states and TLR-3.rs3775290 or TLR-9.rs352140 genotypes. However, there was a significant relationship between the outcome of the HCV-specific CMI and the TLR-9.rs5743836 genotype among the responding subjects (P = 0·005) and the chronic HCV patients (P = 0·044). In conclusion, TLR-9.rs5743836 SNP, but not TLR-3.rs3775290 or TLR-9.rs352140 genotypes, could predict the outcome of HCV-specific CMI responses among Egyptians infected with genotype-4.
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Affiliation(s)
- S. F. Abdelwahab
- The Egyptian Holding Company for Biological Products and Vaccines (VACSERA)GizaEgypt
- Division of MicrobiologyDepartment of Pharmaceutics and Industrial PharmacyTaif College of PharmacyAl‐Haweiah, TaifSaudi Arabia
- Department of Microbiology and ImmunologyFaculty of MedicineMinia UniversityMiniaEgypt
| | - S. Hamdy
- The Egyptian Holding Company for Biological Products and Vaccines (VACSERA)GizaEgypt
- Department of ZoologyFaculty of ScienceCairo UniversityGizaEgypt
| | - A. M. Osman
- Department of ZoologyFaculty of ScienceCairo UniversityGizaEgypt
| | - Z. A. Zakaria
- The Egyptian Holding Company for Biological Products and Vaccines (VACSERA)GizaEgypt
- Biomedical Research LaboratoryFaculty of PharmacyHeliopolis University for Sustainable DevelopmentCairoEgypt
| | - I. Galal
- The Egyptian Holding Company for Biological Products and Vaccines (VACSERA)GizaEgypt
| | - M. Sobhy
- The Egyptian Holding Company for Biological Products and Vaccines (VACSERA)GizaEgypt
| | - M. Hashem
- The Egyptian Holding Company for Biological Products and Vaccines (VACSERA)GizaEgypt
- Department of Epidemiology and Public HealthUniversity of Maryland School of MedicineBaltimoreMDUSA
| | - W. R. Allam
- The Egyptian Holding Company for Biological Products and Vaccines (VACSERA)GizaEgypt
- Centre for GenomicsUniversity of Science and TechnologyZewail City of Science and TechnologyGizaEgypt
| | - M. Abdel‐Samiee
- Department of Hepatology and GastroenterologyNational Liver InstituteMenoufia UniversityMenoufiaEgypt
| | - E. Rewisha
- Department of Hepatology and GastroenterologyNational Liver InstituteMenoufia UniversityMenoufiaEgypt
| | - I. Waked
- Department of Hepatology and GastroenterologyNational Liver InstituteMenoufia UniversityMenoufiaEgypt
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19
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Pagliari F, Marafioti MG, Genard G, Candeloro P, Viglietto G, Seco J, Tirinato L. ssRNA Virus and Host Lipid Rearrangements: Is There a Role for Lipid Droplets in SARS-CoV-2 Infection? Front Mol Biosci 2020; 7:578964. [PMID: 33134318 PMCID: PMC7579428 DOI: 10.3389/fmolb.2020.578964] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 09/03/2020] [Indexed: 12/12/2022] Open
Abstract
Since its appearance, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has immediately alarmed the World Health Organization for its very high contagiousness and the complexity of patient clinical profiles. The worldwide scientific community is today gathered in a massive effort in order to develop safe vaccines and effective therapies in the shortest possible time. Every day, new pieces of SARS-CoV-2 infective puzzle are disclosed. Based on knowledge gained with other related coronaviruses and, more in general, on single-strand RNA viruses, we highlight underexplored molecular routes in which lipids and lipid droplets (LDs) might serve essential functions in viral infections. In fact, both lipid homeostasis and the pathways connected to lipids seem to be fundamental in all phases of the coronavirus infection. This review aims at describing potential roles for lipid and LDs in host-virus interactions and suggesting LDs as new and central cellular organelles to be investigated as potential targets against SARS-CoV-2 infection.
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Affiliation(s)
- Francesca Pagliari
- Biomedical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg, Germany
| | - Maria Grazia Marafioti
- Biomedical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg, Germany
| | - Geraldine Genard
- Biomedical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg, Germany
| | - Patrizio Candeloro
- BioNEM Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Giuseppe Viglietto
- Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Joao Seco
- Biomedical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg, Germany.,Department of Physics and Astronomy, Heidelberg University, Heidelberg, Germany
| | - Luca Tirinato
- Biomedical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg, Germany.,BioNEM Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
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20
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Dash S, Aydin Y, Widmer KE, Nayak L. Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment. J Hepatocell Carcinoma 2020; 7:45-76. [PMID: 32346535 PMCID: PMC7167284 DOI: 10.2147/jhc.s221187] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 03/06/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infection is the major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). The mechanisms of HCC initiation, growth, and metastasis appear to be highly complex due to the decade-long interactions between the virus, immune system, and overlapping bystander effects of host metabolic liver disease. The lack of a readily accessible animal model system for HCV is a significant obstacle to understand the mechanisms of viral carcinogenesis. Traditionally, the primary prevention strategy of HCC has been to eliminate infection by antiviral therapy. The success of virus elimination by antiviral treatment is determined by the SVR when the HCV is no longer detectable in serum. Interferon-alpha (IFN-α) and its analogs, pegylated IFN-α (PEG-IFN-α) alone with ribavirin (RBV), have been the primary antiviral treatment of HCV for many years with a low cure rate. The cloning and sequencing of HCV have allowed the development of cell culture models, which accelerated antiviral drug discovery. It resulted in the selection of highly effective direct-acting antiviral (DAA)-based combination therapy that now offers incredible success in curing HCV infection in more than 95% of all patients, including those with cirrhosis. However, several emerging recent publications claim that patients who have liver cirrhosis at the time of DAAs treatment face the risk of HCC occurrence and recurrence after viral cure. This remains a substantial challenge while addressing the long-term benefit of antiviral medicine. The host-related mechanisms that drive the risk of HCC in the absence of the virus are unknown. This review describes the multifaceted mechanisms that create a tumorigenic environment during chronic HCV infection. In addition to the potential oncogenic programming that drives HCC after viral clearance by DAAs, the current status of a biomarker development for early prediction of cirrhosis regression and HCC detection post viral treatment is discussed. Since DAAs treatment does not provide full protection against reinfection or viral transmission to other individuals, the recent studies for a vaccine development are also reviewed.
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Affiliation(s)
- Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA70112, USA
- Southeast Louisiana Veterans Health Care System, New Orleans, LA70119, USA
- Department of Medicine, Division of Gastroenterology, Tulane University Health Sciences Center, New Orleans, LA70112, USA
| | - Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA70112, USA
| | - Kyle E Widmer
- Southeast Louisiana Veterans Health Care System, New Orleans, LA70119, USA
| | - Leela Nayak
- Southeast Louisiana Veterans Health Care System, New Orleans, LA70119, USA
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21
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Dawood RM, Moustafa RI, Abdelhafez TH, El-Shenawy R, El-Abd Y, Bader El Din NG, Dubuisson J, El Awady MK. A multiepitope peptide vaccine against HCV stimulates neutralizing humoral and persistent cellular responses in mice. BMC Infect Dis 2019; 19:932. [PMID: 31690267 PMCID: PMC6833294 DOI: 10.1186/s12879-019-4571-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 10/16/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Although DAAs hold promise to significantly reduce rates of chronic HCV infections, its eradication still requires development of an effective vaccine. Prolonged T cell responses and cross neutralizing antibodies are ideal for vaccination against the infection. We aimed to design and synthesize a 6 multi epitope peptide vaccine candidate and provide evidence for production of extended cellular and neutralizing Abs in mice. METHODS Six peptides derived from conserved epitopes in E1, E2 (n = 2),NS4B, NS5A and NS5B were designed, synthesized in a multiple antigenic peptide (MAP) form and administered w/o adjuvant to BALB/c mice as HCVp6-MAP at doses ranging from 800 ng to 16 μg. Humoral responses to structural epitopes were assayed by ELISA at different times after injection. ELISpot assay was used to evaluate IFN ɣ producing CD4+/ CD8+ T- lymphocytes at extended durations i.e. > 20 weeks. Viral neutralization by mice sera was tested for genotypes 2a (JFH1) and a chimeric 2a/4a virus (ED43/JFH1) in HCVcc culture. RESULTS HCVp6-MAP confers potent viral neutralization and specific cellular responses at > 1600 ng/ animal for at least 20 weeks. CONCLUSION We report on a promising anti HCV vaccine for future studies on permissive hosts and in clinical trials.
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Affiliation(s)
- Reham M Dawood
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt.
| | - Rehab I Moustafa
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL- Centre d'Infection et d'Immunité de Lille, F-59000, Lille, France
| | - Tawfeek H Abdelhafez
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt
| | - Reem El-Shenawy
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt
| | - Yasmine El-Abd
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt
| | - Noha G Bader El Din
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt
| | - Jean Dubuisson
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL- Centre d'Infection et d'Immunité de Lille, F-59000, Lille, France
| | - Mostafa K El Awady
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt
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22
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El Aggan H, Farahat N, El Deeb N, Zeid A, El-Shendidi A. Peripheral blood and hepatic Toll-like receptor 7 expression and interferon lambda 1 levels in chronic hepatitis C: Relation to virus replication and liver injury. Microb Pathog 2019; 131:65-74. [PMID: 30926417 DOI: 10.1016/j.micpath.2019.03.032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 03/23/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Toll-like receptor 7 (TLR7) can recognize single-stranded RNA viruses like hepatitis C virus (HCV) with subsequent induction of different interferon (IFN) types including IFN lambda (IFNL), which activate an immediate anti-viral response. However, the role of TLR7 in inflammation and fibrosis, characteristics of HCV-induced liver injury, is still controversial. The present work was designed to investigate the potential role of TLR7 and IFNL1 in chronic hepatitis C (CHC) in relation to viral replication and liver injury. METHODS Forty two treatment-naïve patients with CHC and 20 healthy subjects were enrolled in the study. TLR7 expression on peripheral blood CD14+ monocytes was studied by color flow cytometry and the frequency of TLR7+CD14+ cells was expressed as percentage of total monocyte count. Quantification of IFNL1 levels in serum was determined using enzyme-linked immunosorbant assay. Liver biopsies were examined for assessment of histological activity grade (A0-A3) and fibrosis stage (F0-F4) according to METAVIR scoring system as well as steatosis grade. Immunohistochemical staining was performed using human antibodies against TLR7 and IFNL1 and was scored semi-quantitatively (score 0-3). Hepatic expression of TLR7 and IFNL1 was further classified using a two-grade scale as low expression (score 0 or 1) and high expression (score 2 or 3). RESULTS Percentages of circulating TLR7+CD14+ monocytes and serum IFNL1 levels were significantly higher in patients with CHC than in healthy controls (P = 0.025 and P < 0.001 respectively) and were positively correlated with corresponding hepatic TLR7 and IFNL1 expression (P < 0.001 and P = 0.010 respectively). Significantly lower peripheral blood and hepatic TLR7 expression and IFNL1 levels were found in patients with viral loads between 200,000-600,000 IU/ml and >600,000 IU/ml than in those with viral load <200,000 IU/ml (P < 0.05), in patients with severe necroinflammation than in those with mild-to-moderate necroinflammation (P < 0.05) and in patients with advanced fibrosis than in those with early fibrosis (P < 0.01). Also, changes in TLR7 expression and IFNL1 production in peripheral blood and the liver were inversely correlated with serum levels of aspartate and alanine aminotransferases (P < 0.05) and HCV RNA (P < 0.01), histological activity grade (P < 0.01) and fibrosis stage (P < 0.01). By plotting receiver operating characteristics (ROC) curve, serum IFNL1 showed higher sensitivity and specificity than percentages of circulating TLR7+CD14+ monocytes in discriminating patients with CHC according to the severity of hepatic necroinflammation (area under the curve (AUC) = 0.901 vs. 0.816 respectively) and fibrosis (AUC = 0.971 vs. 0.825 respectively) at a cut-off value of 44.75 pg/ml and 10.25% respectively. CONCLUSIONS TLR7 activation and IFNL1 production in CHC may play an important role in controlling viral replication and limiting hepatic inflammation and fibrosis and their downregulation may result in viral persistence and disease progression. The immunoregulatory role of TLR7-IFNL1 pathway in the pathogenesis of chronic HCV infection should be further studied. Clinical trials with a large number of patients are needed to assess the usefulness of serum IFNL1 as a potential biomarker for severity of liver injury in chronic HCV infection and other liver diseases.
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Affiliation(s)
- Hoda El Aggan
- Department of Internal Medicine (Hepatobiliary Unit), Faculty of Medicine, University of Alexandria, Egypt.
| | - Nahla Farahat
- Department of Clinical and Chemical Pathology, Faculty of Medicine, University of Alexandria, Egypt
| | - Nevine El Deeb
- Department of Pathology, Faculty of Medicine, University of Alexandria, Egypt
| | - Ahmed Zeid
- Department of Internal Medicine (Hepatobiliary Unit), Faculty of Medicine, University of Alexandria, Egypt
| | - Assem El-Shendidi
- Department of Internal Medicine (Hepatobiliary Unit), Faculty of Medicine, University of Alexandria, Egypt
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23
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Patra T, Ray RB, Ray R. Strategies to Circumvent Host Innate Immune Response by Hepatitis C Virus. Cells 2019; 8:E274. [PMID: 30909456 PMCID: PMC6468774 DOI: 10.3390/cells8030274] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 03/15/2019] [Accepted: 03/18/2019] [Indexed: 12/13/2022] Open
Abstract
Innate immune responses generate interferons, proinflammatory cytokines, complement activation, and natural killer (NK) cell response. Ultimately, this leads to the induction of a robust virus-specific adaptive immunity. Although the host innate immune system senses and responds to eliminate virus infection, hepatitis C virus (HCV) evades immune attack and establishes persistent infection within the liver. Spontaneous clearance of HCV infection is associated with a prompt induction of innate immunity generated in an infected host. In this review, we have highlighted the current knowledge of our understanding of host⁻HCV interactions, especially for endogenous interferon production, proinflammatory response, NK cell response, and complement activation, which may impair the generation of a strong adaptive immune response for establishment of chronicity. The information may provide novel strategies in augmenting therapeutic intervention against HCV.
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Affiliation(s)
- Tapas Patra
- Departments of Internal Medicine, Saint Louis University, St. Louis, MO 63104, USA.
| | - Ratna B Ray
- Departments of Pathology, Saint Louis University, St. Louis, MO 63104, USA.
| | - Ranjit Ray
- Departments of Internal Medicine, Saint Louis University, St. Louis, MO 63104, USA.
- Molecular Microbiology & Immunology, Saint Louis University, St. Louis, MO 63104, USA.
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24
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Cao Z, Yang Q, Zheng M, Lv H, Kang K, Zhang Y. Classical swine fever virus non-structural proteins modulate Toll-like receptor signaling pathways in porcine monocyte-derived macrophages. Vet Microbiol 2019; 230:101-109. [PMID: 30827374 DOI: 10.1016/j.vetmic.2019.01.025] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 01/16/2019] [Accepted: 01/27/2019] [Indexed: 12/13/2022]
Abstract
Toll-like receptors (TLRs) are crucial activators of the innate immune response that play various roles in viral infection. Studies have confirmed that classical swine fever virus (CSFV) infection has significant effects on the expression of immune effectors participating in TLR signaling pathways; however, the involvement of CSFV-encoded proteins in TLR signaling pathways remains unclear. In this study, lentiviral individually expressing CSFV non-structural proteins (NSPs) were constructed to identify the "key proteins" that affect TLR gene expression and to analyze the impacts of these proteins on factors downstream of the TLR signaling pathways. The results indicated that Npro, NS2, NS3, NS3/4A, NS4B and NS5A all failed to induce the activation of NF-κB p65. Furthermore, NS4B was found to inhibit poly (I:C) stimulation-mediated activation of the TLR3 signaling pathway in porcine monocyte-derived macrophages (pMDMs), thereby suppressing the TRIF mRNA transcription, the IRF3 protein translation and the NF-κB p65 phosphorylation, and ultimately affecting the secretion of IL-6 and IFN-β; CSFV NS5A protein could significantly increase the activation of MyD88 and IRF7 as well as the consequent synthesis of IFN-α in pMDMs. The results suggest that CSFV NSPs affect TLR-mediated innate immune responses in pMDMs.
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Affiliation(s)
- Zhi Cao
- College of Veterinary Medicine, Northwest A&F University, Shaanxi, 712100, China; Key Laboratory of Sustainable Development of Marine Fisheries, Ministry of Agriculture, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, 266071, China
| | - Qian Yang
- Key Laboratory of Sustainable Development of Marine Fisheries, Ministry of Agriculture, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, 266071, China
| | - Minping Zheng
- College of Veterinary Medicine, Northwest A&F University, Shaanxi, 712100, China
| | - Huifang Lv
- College of Veterinary Medicine, Northwest A&F University, Shaanxi, 712100, China
| | - Kai Kang
- College of Veterinary Medicine, Northwest A&F University, Shaanxi, 712100, China
| | - Yanming Zhang
- College of Veterinary Medicine, Northwest A&F University, Shaanxi, 712100, China.
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Jannuzzi GP, de Almeida JRF, Amarante-Mendes GP, Romera LMD, Kaihami GH, Vasconcelos JR, Ferreira CP, de Almeida SR, Ferreira KS. TLR3 Is a Negative Regulator of Immune Responses Against Paracoccidioides brasiliensis. Front Cell Infect Microbiol 2019; 8:426. [PMID: 30687643 PMCID: PMC6335947 DOI: 10.3389/fcimb.2018.00426] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 11/26/2018] [Indexed: 12/12/2022] Open
Abstract
Toll-like receptors (TLRs) comprise the best-characterized pattern-recognition receptor (PRR) family able to activate distinct immune responses depending on the receptor/adaptor set assembled. TLRs, such as TLR2, TLR4 and TLR9, and their signaling were shown to be important in Paracoccidioides brasiliensis infections. However, the role of the endosomal TLR3 in experimental paracoccidioidomycosys remains obscure. In vitro assays, macrophages of the bone marrow of WT or TLR3−/− mice were differentiated for evaluation of their microbicidal activity. In vivo assays, WT or TLR3−/− mice were infected intratracheally with Paracoccidioides brasiliensis yeasts for investigation of the lung response type induced. The cytotoxic activity of CD8+ T cells was assessed by cytotoxicity assay. To confirm the importance of CD8+ T cells in the control of infection in the absence of tlr3, a depletion assay of these cells was performed. Here, we show for the first time that TLR3 modulate the infection against Paracoccidioides brasiliensis by dampening pro-inflammatory response, NO production, IFN+CD8+T, and IL-17+CD8+T cell activation and cytotoxic function, associated with granzyme B and perforin down regulation. As conclusion, we suggest that TLR3 could be used as an escape mechanism of the fungus in an experimental paracoccidioidomycosis.
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Affiliation(s)
- Grasielle Pereira Jannuzzi
- Departamento de Análises Clínicas, Faculdade de Ciências Farmacêuticas da Universidade de São Paulo, São Paulo, Brazil
| | | | - Gustavo P Amarante-Mendes
- Departamento de Imunologia, do Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Lavínia Maria Dal'Mas Romera
- Departamento de Análises Clínicas, Faculdade de Ciências Farmacêuticas da Universidade de São Paulo, São Paulo, Brazil
| | - Gilberto Hideo Kaihami
- Departamento de Química, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
| | | | - Camila Pontes Ferreira
- Centro de Terapia Molecular e Celular do Departamento de Microbiologia, Imunologia e Parasitologia da Universidade Federal de São Paulo, São Paulo, Brazil
| | - Sandro Rogério de Almeida
- Departamento de Análises Clínicas, Faculdade de Ciências Farmacêuticas da Universidade de São Paulo, São Paulo, Brazil
| | - Karen Spadari Ferreira
- Departamento de Análises Clínicas, Faculdade de Ciências Farmacêuticas da Universidade de São Paulo, São Paulo, Brazil.,Departamento de Imunologia, do Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.,Departamento de Química, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.,Departamento de Biociências da Universidade Federal de São Paulo, São Paulo, Brazil.,Centro de Terapia Molecular e Celular do Departamento de Microbiologia, Imunologia e Parasitologia da Universidade Federal de São Paulo, São Paulo, Brazil
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26
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Refolo G, Ciccosanti F, Di Rienzo M, Basulto Perdomo A, Romani M, Alonzi T, Tripodi M, Ippolito G, Piacentini M, Fimia GM. Negative Regulation of Mitochondrial Antiviral Signaling Protein-Mediated Antiviral Signaling by the Mitochondrial Protein LRPPRC During Hepatitis C Virus Infection. Hepatology 2019; 69:34-50. [PMID: 30070380 DOI: 10.1002/hep.30149] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 06/18/2018] [Indexed: 12/13/2022]
Abstract
Hepatitis C virus (HCV) is highly efficient in establishing a chronic infection, having evolved multiple strategies to suppress the host antiviral responses. The HCV nonstructural 5A (NS5A) protein, in addition to its role in viral replication and assembly, has long been known to hamper the interferon (IFN) response. However, the mechanism of this inhibitory activity of NS5A remains partly characterized. In a functional proteomic screening carried out in HCV replicon cells, we identified the mitochondrial protein LRPPRC as an NS5A binding factor. Notably, we found that downregulation of LRPPRC expression results in a significant inhibition of HCV infection, which is associated with an increased activation of the IFN response. Moreover, we showed that LRPPRC acts as a negative regulator of the mitochondrial-mediated antiviral immunity, by interacting with mitochondrial antiviral signaling protein (MAVS) and inhibiting its association with TRAF3 and TRAF6. Finally, we demonstrated that NS5A is able to interfere with MAVS activity in a LRPPRC-dependent manner. Conclusion: Overall, our results indicate that NS5A contributes to the inhibition of innate immune pathways during HCV infection by exploiting the ability of LRPPRC to inhibit MAVS-regulated antiviral signaling.
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Affiliation(s)
- Giulia Refolo
- National Institute for Infectious Diseases IRCCS 'L. Spallanzani', Rome, Italy
| | - Fabiola Ciccosanti
- National Institute for Infectious Diseases IRCCS 'L. Spallanzani', Rome, Italy
| | - Martina Di Rienzo
- National Institute for Infectious Diseases IRCCS 'L. Spallanzani', Rome, Italy
| | | | - Marta Romani
- National Institute for Infectious Diseases IRCCS 'L. Spallanzani', Rome, Italy
| | - Tonino Alonzi
- National Institute for Infectious Diseases IRCCS 'L. Spallanzani', Rome, Italy
| | - Marco Tripodi
- National Institute for Infectious Diseases IRCCS 'L. Spallanzani', Rome, Italy.,Department of Cellular Biotechnologies and Haematology, Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy
| | - Giuseppe Ippolito
- National Institute for Infectious Diseases IRCCS 'L. Spallanzani', Rome, Italy
| | - Mauro Piacentini
- National Institute for Infectious Diseases IRCCS 'L. Spallanzani', Rome, Italy.,Department of Biology, University of Rome 'Tor Vergata', Rome, Italy
| | - Gian Maria Fimia
- National Institute for Infectious Diseases IRCCS 'L. Spallanzani', Rome, Italy.,Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce, Italy
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27
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Removal of the C6 Vaccinia Virus Interferon-β Inhibitor in the Hepatitis C Vaccine Candidate MVA-HCV Elicited in Mice High Immunogenicity in Spite of Reduced Host Gene Expression. Viruses 2018; 10:v10080414. [PMID: 30096846 PMCID: PMC6116028 DOI: 10.3390/v10080414] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 08/03/2018] [Accepted: 08/07/2018] [Indexed: 12/19/2022] Open
Abstract
Hepatitis C virus (HCV) represents a major global health problem for which a vaccine is not available. Modified vaccinia virus Ankara (MVA)-HCV is a unique HCV vaccine candidate based in the modified vaccinia virus Ankara (MVA) vector expressing the nearly full-length genome of HCV genotype 1a that elicits CD8⁺ T-cell responses in mice. With the aim to improve the immune response of MVA-HCV and because of the importance of interferon (IFN) in HCV infection, we deleted in MVA-HCV the vaccinia virus (VACV) C6L gene, encoding an inhibitor of IFN-β that prevents activation of the interferon regulatory factors 3 and 7 (IRF3 and IRF7). The resulting vaccine candidate (MVA-HCV ΔC6L) expresses all HCV antigens and deletion of C6L had no effect on viral growth in permissive chicken cells. In human monocyte-derived dendritic cells, infection with MVA-HCV ΔC6L triggered severe down-regulation of IFN-β, IFN-β-induced genes, and cytokines in a manner similar to MVA-HCV, as defined by real-time polymerase chain reaction (PCR) and microarray analysis. In infected mice, both vectors had a similar profile of recruited immune cells and induced comparable levels of adaptive and memory HCV-specific CD8⁺ T-cells, mainly against p7 + NS2 and NS3 HCV proteins, with a T cell effector memory (TEM) phenotype. Furthermore, antibodies against E2 were also induced. Overall, our findings showed that while these vectors had a profound inhibitory effect on gene expression of the host, they strongly elicited CD8⁺ T cell and humoral responses against HCV antigens and to the virus vector. These observations add support to the consideration of these vectors as potential vaccine candidates against HCV.
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28
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Chen S, Yang C, Zhang W, Mahalingam S, Wang M, Cheng A. Flaviviridae virus nonstructural proteins 5 and 5A mediate viral immune evasion and are promising targets in drug development. Pharmacol Ther 2018; 190:1-14. [PMID: 29742479 DOI: 10.1016/j.pharmthera.2018.05.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Infections with viruses in the Flaviviridae family have a vast global and economic impact because of the high morbidity and mortality. The pathogenesis of Flaviviridae infections is very complex and not fully understood because these viruses can inhibit multiple immune pathways including the complement system, NK cells, and IFN induction and signalling pathways. The non-structural (NS) 5 and 5A proteins of Flaviviridae viruses are highly conserved and play an important role in resisting host immunity through various evasion mechanisms. This review summarizes the strategies used by the NS5 and 5A proteins of Flaviviridae viruses for evading the innate immune response by inhibiting pattern recognition receptor (PRR) signalling pathways (TLR/MyD88, IRF7), suppressing interferon (IFN) signalling pathways (IFN-γRs, STAT1, STAT2), and impairing the function of IFN-stimulated genes (ISGs) (e.g. protein kinase R [PKR], oligoadenylate synthase [OAS]). All of these immune evasion mechanisms depend on the interaction of NS5 or NS5A with cellular proteins, such as MyD88 and IRF7, IFN-αRs, IFN-γRs, STAT1, STAT2, PKR and OAS. NS5 is the most attractive target for the discovery of broad spectrum compounds against Flaviviridae virus infection. The methyltransferase (MTase) and RNA-dependent RNA polymerase (RdRp) activities of NS5 are the main therapeutic targets for antiviral drugs against Flaviviridae virus infection. Based on our site mapping, the sites involved in immune evasion provide some potential and promising targets for further novel antiviral therapeutics.
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Affiliation(s)
- Shun Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China.
| | - Chao Yang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Wei Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Suresh Mahalingam
- Emerging Viruses and Inflammation Research Group, Institute for Glycomics, Griffith University, Gold Coast, Australia
| | - Mingshu Wang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Anchun Cheng
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China.
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29
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Yang B, Qi X, Chen Z, Chen S, Xue Q, Jia P, Wang T, Wang J. Binding and entry of peste des petits ruminants virus into caprine endometrial epithelial cells profoundly affect early cellular gene expression. Vet Res 2018; 49:8. [PMID: 29368634 PMCID: PMC5784595 DOI: 10.1186/s13567-018-0504-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 12/18/2017] [Indexed: 12/22/2022] Open
Abstract
Peste des petits ruminants virus (PPRV), the etiological agent of peste des petits ruminants (PPR), causes an acute or subacute disease in small ruminants. Although abortion is observed in an unusually large proportion of pregnant goats during outbreaks of PPR, the pathogenic mechanism underlying remains unclear. Here, the gene expression profile of caprine endometrial epithelial cells (EECs) infected with PPRV Nigeria 75/1 was determined by DNA microarray to investigate the cellular response immediately after viral entry. The microarray analysis revealed that a total of 146 genes were significantly dysregulated by PPRV internalization within 1 h post-infection (hpi). Of these, 85 genes were upregulated and 61 genes were downregulated. Most of these genes, including NFKB1A, JUNB, and IL1A, have not previously been reported in association with PPRV infection in goats. Following viral replication (24 hpi), the expression of 307 genes were significantly upregulated and that of 261 genes were downregulated. The data for the genes differentially expressed in EECs were subjected to a time sequence profile analysis, gene network analysis and pathway analysis. The gene network analysis showed that 13 genes (EIF2AK3, IL10, TLR4, ZO3, NFKBIB, RAC1, HSP90AA1, SMAD7, ARG2, JUNB, ZFP36, APP, and IL1A) were located in the core of the network. We clearly demonstrate that PPRV infection upregulates the expression of nectin-4 after 1 hpi, which peaked at 24 hpi in EECs. In conclusion, this study demonstrates the early cellular gene expression in the caprine endometrial epithelial cells after the binding and entry of PPRV.
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Affiliation(s)
- Bo Yang
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Xuefeng Qi
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Zhijie Chen
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Shuying Chen
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Qinghong Xue
- China Institute of Veterinary Drug Control, Beijing, 100000, China
| | - Peilong Jia
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Ting Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Jingyu Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.
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30
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Liu X, Wei H, Liao S, Ye J, Zhu L, Xu Z. MicroRNA transcriptome analysis of porcine vital organ responses to immunosuppressive porcine cytomegalovirus infection. Virol J 2018; 15:16. [PMID: 29347945 PMCID: PMC5774105 DOI: 10.1186/s12985-018-0922-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 01/03/2018] [Indexed: 02/07/2023] Open
Abstract
Background Porcine cytomegalovirus (PCMV) is an immunosuppressive virus that mainly inhibits T-lymphocyte and macrophage immune functions; it has significantly damaged the farming industry. Although recent studies have shown that miRNAs play important roles in immune responses, the regulatory mechanisms of miRNAs during immunosuppressive virus infection remain unclear. Methods In this study, porcine small-RNA transcriptomes of PCMV-infected and uninfected vital organs were first characterised by high-throughput sequencing. miRDeep2 software was used to predict novel pig-encoded miRNAs. To verify the accuracy of the high-throughput sequencing results, stem-loop qRT-PCR was performed on 12 significantly DE miRNAs. The physical and functional interactions between the immune-related target genes of the DE miRNAs in PCMV-infected organs were analysed using the STRING database. Results In total, 306 annotated and 295 novel miRNAs were identified from PCMV-infected and uninfected porcine organs, respectively, through alignment with known Sus scrofa pre-miRNAs. Overall, 92, 107, 95, 77 and 111 miRNAs were significantly differentially expressed in lung, liver, spleen, kidney and thymus after PCMV infection, respectively. According to Gene Ontology enrichment analysis, target genes of the differentially expressed miRNAs associated with immune system processes, regulation of biological processes and metabolic processes were enriched in every sample. Integrated expression analysis of the differentially expressed miRNAs and their target mRNAs in PCMV-infected thymus showed that the significant differential expression of specific miRNAs under the pressure of PCMV infection in central immune organs interfered with the expression of genes involved in important immune-related signalling pathways, thus promoting the viral infection. Conclusions This is the first comprehensive analysis of the responses of host small-RNA transcriptomes to PCMV infection in vital porcine organs. It provides new insights into the regulatory mechanisms of miRNAs during infection by immunosuppressive viruses. Electronic supplementary material The online version of this article (10.1186/s12985-018-0922-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiao Liu
- Southwest University, College of Animal Science and technology, Chongqing, 400715, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province and Animal Biotechnology Center, College of Veterinary Medicine of Sichuan Agricultural University, 211#Huimin Road, Wenjiang District, Chengdu, Sichuan Province, 610000, China
| | - Haoche Wei
- College of Life Sciences, Sichuan University, Chengdu, 610000, China
| | - Shan Liao
- Southwest University, College of Animal Science and technology, Chongqing, 400715, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province and Animal Biotechnology Center, College of Veterinary Medicine of Sichuan Agricultural University, 211#Huimin Road, Wenjiang District, Chengdu, Sichuan Province, 610000, China
| | - Jianheng Ye
- Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, China
| | - Ling Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province and Animal Biotechnology Center, College of Veterinary Medicine of Sichuan Agricultural University, 211#Huimin Road, Wenjiang District, Chengdu, Sichuan Province, 610000, China
| | - Zhiwen Xu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province and Animal Biotechnology Center, College of Veterinary Medicine of Sichuan Agricultural University, 211#Huimin Road, Wenjiang District, Chengdu, Sichuan Province, 610000, China.
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31
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Innate Immune Evasion Mediated by Flaviviridae Non-Structural Proteins. Viruses 2017; 9:v9100291. [PMID: 28991176 PMCID: PMC5691642 DOI: 10.3390/v9100291] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 10/03/2017] [Accepted: 10/05/2017] [Indexed: 12/17/2022] Open
Abstract
Flaviviridae-caused diseases are a critical, emerging public health problem worldwide. Flaviviridae infections usually cause severe, acute or chronic diseases, such as liver damage and liver cancer resulting from a hepatitis C virus (HCV) infection and high fever and shock caused by yellow fever. Many researchers worldwide are investigating the mechanisms by which Flaviviridae cause severe diseases. Flaviviridae can interfere with the host’s innate immunity to achieve their purpose of proliferation. For instance, dengue virus (DENV) NS2A, NS2B3, NS4A, NS4B and NS5; HCV NS2, NS3, NS3/4A, NS4B and NS5A; and West Nile virus (WNV) NS1 and NS4B proteins are involved in immune evasion. This review discusses the interplay between viral non-structural Flaviviridae proteins and relevant host proteins, which leads to the suppression of the host’s innate antiviral immunity.
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32
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Kar P, Kumar D, Gumma PK, Chowdhury SJ, Karra VK. Down regulation of TRIF, TLR3, and MAVS in HCV infected liver correlates with the outcome of infection. J Med Virol 2017; 89:2165-2172. [PMID: 28480979 DOI: 10.1002/jmv.24849] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 04/18/2017] [Indexed: 12/19/2022]
Abstract
In virus-infected cells, pattern recognition receptors (PRRs) recruits their specific adaptor molecules, mitochondrial antiviral signaling protein (MAVS), TIR-domain-containing adapter-inducing interferon-β (TRIF), and TNF receptor associated factor (TRAF6) which induces interferon. Toll-like receptor 3 (TLR3) induces activation of the NF-kappa B (NF-κB) for interferon production. The study has been designed to assess the correlation of TLR3, MAVS, TRIF, and TRAF6 outcome of HCV infection. The 46 chronic hepatitis C (CHC) patients were screened for LFT (Liver function test), HBsAg, Anti HCV, viral load, histology, and expression of TLR3, MAVS, TRIF, and TRAF6 genes. Out of 46 CHC patients, 7 were on therapy. The 12 healthy controls were screened for LFT, HBsAg, Anti HCV and gene expressions. The gene expressions were studied in liver tissue and measured using semi-quantitative analysis of Western blots. It has been observed that the expression of TRAF6 was independent of HCV infection. The expression of TRIF, TLR3, and MAVS were significantly (P < 0.05) down regulated in CHC (N = 46) compared to healthy controls (N = 12), in high viral load (N = 21) compared to low viral load (N = 25), in HAI (Histology activity index) 1-4 (N = 12), 5-8 (N = 16), 9-12 (N = 8), 13-18 (N = 5) compared to HAI 0 (N = 5) cases. The significant reduction in the expression of TRIF, TLR3, and MAVS was observed in non-responder (N = 3) compared to responder (N = 4) after treatment (P < 0.05). The HCV viral load was positively correlated with the disease severity. The down regulation of TRIF, TLR3, and MAVS expressions in CHC correlates with the disease severity and the outcome of HCV infection.
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Affiliation(s)
- Premashis Kar
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi, India
| | - Deepak Kumar
- Department of Biotechnology and Molecular Medicine, Pt. B. D. Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana
| | - Phani Kumar Gumma
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi, India
| | - Soumya Jyoti Chowdhury
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi, India
| | - Vijay Kumar Karra
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi, India
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Lv H, Dong W, Qian G, Wang J, Li X, Cao Z, Lv Q, Wang C, Guo K, Zhang Y. uS10, a novel Npro-interacting protein, inhibits classical swine fever virus replication. J Gen Virol 2017; 98:1679-1692. [PMID: 28721853 DOI: 10.1099/jgv.0.000867] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Classical swine fever (CSF) is a severe, febrile and highly contagious disease caused by classical swine fever virus (CSFV) that has resulted in huge economic losses in the pig industry worldwide. CSFV Npro has been actively studied but remains incompletely understood. Few studies have investigated the cellular proteins that interact with Npro and their participation in viral replication. Here, the yeast two-hybrid (Y2H) system was employed to screen Npro-interacting proteins from a porcine alveolar macrophage (PAM) cDNA library, and a blast search of the NCBI database revealed that 15 cellular proteins interact with Npro. The interaction of Npro with ribosomal protein S20, also known as universal S10 (uS10), was further confirmed by co-immunoprecipitation and glutathione S-transferase pull-down assays. Furthermore, uS10 overexpression inhibited CSFV replication, whereas the knockdown of uS10 promoted CSFV replication in PAMs. In addition, Npro or CSFV reduced uS10 expression in PAMs in a proteasome-dependent manner, indicating that Npro-uS10 interaction might contribute to persistent CSFV replication. Our previous research showed that CSFV decreases Toll-like receptor 3 (TLR3) expression. The results showed that uS10 knockdown reduced TLR3 expression, and that uS10 overexpression increased TLR3 expression. Notably, uS10 knockdown did not promote CSFV replication following TLR3 overexpression. Conversely, uS10 overexpression did not inhibit CSFV replication following TLR3 knockdown. These results revealed that uS10 inhibits CSFV replication by modulating TLR3 expression. This work addresses a novel aspect of the regulation of the innate antiviral immune response during CSFV infection.
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Affiliation(s)
- Huifang Lv
- College of Veterinary Medicine, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, Shaanxi, PR China
| | - Wang Dong
- College of Veterinary Medicine, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, Shaanxi, PR China
| | - Gui Qian
- College of Veterinary Medicine, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, Shaanxi, PR China
| | - Jie Wang
- College of Veterinary Medicine, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, Shaanxi, PR China
| | - Xiaomeng Li
- College of Veterinary Medicine, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, Shaanxi, PR China
| | - Zhi Cao
- Qingdao Yebio Biological Engineering Co. Ltd. (Yebio), No. 21 Aodongnan Road, Qingdao 266114, Shandong, PR China
| | - Qizhuang Lv
- College of Biology and Pharmacy, Yulin Normal University, No. 1303 Jiaoyu East Road, Yulin 537000, Guangxi, PR China
| | - Chengbao Wang
- College of Veterinary Medicine, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, Shaanxi, PR China
| | - Kangkang Guo
- College of Veterinary Medicine, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, Shaanxi, PR China
| | - Yanming Zhang
- College of Veterinary Medicine, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, Shaanxi, PR China
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Feng N, Zhou Z, Li Y, Zhao L, Xue Z, Lu R, Jia K. Enterovirus 71-induced has-miR-21 contributes to evasion of host immune system by targeting MyD88 and IRAK1. Virus Res 2017; 237:27-36. [PMID: 28506791 DOI: 10.1016/j.virusres.2017.05.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 05/06/2017] [Accepted: 05/09/2017] [Indexed: 01/23/2023]
Abstract
Enterovirus71(EV71), the etiological agent of hand-foot-and-mouth disease, has increasingly become a public health challenge around the world. Type I interferons (IFNs) are an important family of cytokines that regulate innate and adaptive immune responses to pathogens.These pathways are tightly regulated by the host to prevent an inappropriate cellular response, but viruses can modulate these pathways to proliferate and spread. In this study, we demonstrated that EV71 evades the immune surveillance system to proliferate by activating microRNA-21. We demonstrated that EV71 infection upregulates miR-21, which in turn suppresses EV71-triggered type I IFN production, thus promoting EV71 replication. Furthermore, we demonstrated that miR-21 targets the myeloid differentiation factor 88(MyD88) and interleukin-1 receptor-associated kinase 1(IRAK1), which are involved in EV71-induced type I IFN production.
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Affiliation(s)
- Na Feng
- Department of Pediatrics, Affiliated Hospital of Yanan University, China
| | - Zhizhao Zhou
- Neonatology Department, Yangling Demonstration Zone Hospital, China
| | - Yuanxia Li
- Department of Pediatrics, Affiliated Hospital of Yanan University, China
| | - Lifang Zhao
- Department of Pediatrics, Affiliated Hospital of Yanan University, China
| | - Zhengfeng Xue
- Department of Pediatrics, Affiliated Hospital of Yanan University, China
| | - Rong Lu
- Department of Pediatrics, Affiliated Hospital of Yanan University, China
| | - Kunpeng Jia
- Department of Pediatrics, Affiliated Hospital of Yanan University, China.
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Liver immunology: How to reconcile tolerance with autoimmunity. Clin Res Hepatol Gastroenterol 2017; 41:6-16. [PMID: 27526967 DOI: 10.1016/j.clinre.2016.06.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Accepted: 06/01/2016] [Indexed: 02/04/2023]
Abstract
There are several examples of liver tolerance: the relative ease by which liver allografts are accepted and the exploitation of the hepatic microenvironment by the malarial parasite and hepatotrophic viruses are notable examples. The vasculature of the liver supports a unique population of antigen presenting cells specialised to maintain immunological tolerance despite continuous exposure to gut-derived antigens. Liver sinusoidal endothelial cells and Kupffer cells appear to be key to the maintenance of immune tolerance, by promoting T cell anergy or deletion and the generation of regulatory cell subsets. Despite this, there are three liver diseases with likely autoimmune involvement: primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis. How can we reconcile this with the inherent tolerogenicity of the liver? Genetic studies have uncovered several associations with genes involved in the activation of the innate and adaptive immune systems. There is also evidence pointing to pathogenic and xenobiotic triggers of autoimmune liver disease. Coupled to this, impaired immunoregulatory mechanisms potentially play a permissive role, allowing the autoimmune response to proceed.
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Tsutsumi T, Okushin K, Enooku K, Fujinaga H, Moriya K, Yotsuyanagi H, Aizaki H, Suzuki T, Matsuura Y, Koike K. Nonstructural 5A Protein of Hepatitis C Virus Interferes with Toll-Like Receptor Signaling and Suppresses the Interferon Response in Mouse Liver. PLoS One 2017; 12:e0170461. [PMID: 28107512 PMCID: PMC5249188 DOI: 10.1371/journal.pone.0170461] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2016] [Accepted: 01/05/2017] [Indexed: 02/06/2023] Open
Abstract
The hepatitis C virus nonstructural protein NS5A is involved in resistance to the host immune response, as well as the viral lifecycle such as replication and maturation. Here, we established transgenic mice expressing NS5A protein in the liver and examined innate immune responses against lipopolysaccharide (LPS) in vivo. Intrahepatic gene expression levels of cytokines such as interleukin-6, tumor necrosis factor-α, and interferon-γ were significantly suppressed after LPS injection in the transgenic mouse liver. Induction of the C-C motif chemokine ligand 2, 4, and 5 was also suppressed. Phosphorylation of the signal transducer and activator of transcription 3, which is activated by cytokines, was also reduced, and expression levels of interferon-stimulated genes, 2’-5’ oligoadenylate synthase, interferon-inducible double-stranded RNA-activated protein kinase, and myxovirus resistance 1 were similarly suppressed. Since LPS binds to toll-like receptor 4 and stimulates the downstream pathway leading to induction of these genes, we examined the extracellular signal-regulated kinase and IκB-α. The phosphorylation levels of these molecules were reduced in transgenic mouse liver, indicating that the pathway upstream of the molecules was disrupted by NS5A. Further analyses revealed that the interaction between interleukin-1 receptor-associated kinase-1 and tumor necrosis factor receptor associated factor-6 was dispersed in transgenic mice, suggesting that NS5A may interfere with this interaction via myeloid differentiation primary response gene 88, which was shown to interact with NS5A. Since the gut microbiota, a source of LPS, is known to be associated with pathological conditions in liver diseases, our results suggest the involvement of NS5A in the pathogenesis of HCV infected-liver via the suppression of innate immunity.
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Affiliation(s)
- Takeya Tsutsumi
- Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- * E-mail:
| | - Kazuya Okushin
- Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kenichiro Enooku
- Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hidetaka Fujinaga
- Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kyoji Moriya
- Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Yotsuyanagi
- Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hideki Aizaki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Tetsuro Suzuki
- Department of Infectious Diseases, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yoshiharu Matsuura
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Kazuhiko Koike
- Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Sise ME, Wisocky J, Rosales IA, Chute D, Holmes JA, Corapi KM, Babitt JL, Tangren JS, Hashemi N, Lundquist AL, Williams WW, Mount DB, Andersson KL, Rennke HG, Smith RN, Colvin R, Thadhani RI, Chung RT. Lupus-like Immune Complex-mediated Glomerulonephritis in Patients with Hepatitis C Virus Infection Treated with Oral, Interferon-free, Direct-acting Antiviral Therapy. Kidney Int Rep 2016; 1:135-143. [PMID: 27990496 PMCID: PMC5155703 DOI: 10.1016/j.ekir.2016.06.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Affiliation(s)
- Meghan E Sise
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Jessica Wisocky
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Ivy A Rosales
- Department of Pathology, Massachusetts General Hospital, Boston, MA
| | - Donald Chute
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Jacinta A Holmes
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Kristin M Corapi
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Jodie L Babitt
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Jessica S Tangren
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Nikroo Hashemi
- Department of Gastroenterology and Hepatology, Brigham and Women's Hospital, Boston, MA
| | - Andrew L Lundquist
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Winfred W Williams
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - David B Mount
- Renal Unit, Brigham and Women's Hospital, Boston, MA
| | - Karin L Andersson
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Helmut G Rennke
- Department of Pathology, Brigham and Women's Hospital, Boston, MA
| | - R Neal Smith
- Department of Pathology, Massachusetts General Hospital, Boston, MA
| | - Robert Colvin
- Department of Pathology, Massachusetts General Hospital, Boston, MA
| | - Ravi I Thadhani
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Raymond T Chung
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA
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Lee CM, Hu TH, Lu SN, Wang JH, Hung CH, Chen CH, Yen YH. Peripheral blood toll-like receptor 4 correlates with rapid virological response to pegylated-interferon and ribavirin therapy in hepatitis C genotype 1 patients. BMC Gastroenterol 2016; 16:73. [PMID: 27457659 PMCID: PMC4960680 DOI: 10.1186/s12876-016-0492-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 07/14/2016] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Toll-like receptors (TLRs) are effectors of the innate immune system that are able to recognize hepatitis C virus (HCV) and give rise to an immune response. Failure of interferon (IFN)-α-based treatment is related to host immunity. Therefore, we sought to study the clinical importance of TLRs in HCV genotype 1 patients who received pegylated IFN (PEG-IFN) plus ribavirin (RBV) therapy. METHODS We enrolled 79 treatment-naïve patients with HCV genotype 1. Patients completed a 24- to 48-week course of response-guided therapy. Peripheral blood monocyte (PBMC) expression of mRNA for TLRs 2, 3, 4, 7, and 9 was quantified by real-time PCR before therapy. TLR mRNA expression is shown as a log ratio relative to GAPDH mRNA (log 2 (-(∆Ct))). RESULTS Forty-five patients (57.0 %) showed a rapid virological response (RVR). Univariate analysis revealed that TLR 2, 3, 4, 7, and 9 were significantly lower in the RVR group than in the non-RVR group (P = 0.001, 0.014, < 0.001, 0.008, and 0.001, respectively). Multivariate analysis revealed that TLR 4 < -2 log (OR: 7.17, 95 % CI: 1.70-30.34, P = 0.007) was an independent predictor for RVR. In addition, levels of TLR 2, 3, 4, 7, and 9 were positively correlated with HCV viral load (P = 0.009, 0.013, < 0.001, 0.007, and 0.001, respectively). CONCLUSIONS A low level of TLR 4 mRNA in PMBCs was correlated with RVR, which indicates that TLR4 may play a critical role in HCV recognition and activation of innate immunity. TLR expression levels were correlated with HCV viral load, indicating that TLR activation upon exposure to HCV may subsequently limit HCV replication.
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Affiliation(s)
- Chuan-Mo Lee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung City, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung City, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung City, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung City, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung City, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung City, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Hao Yen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung City, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Saeed U, Piracha ZZ. Bridging the importance of Toll like receptors in human viral infections. ASIAN PACIFIC JOURNAL OF TROPICAL DISEASE 2016. [DOI: 10.1016/s2222-1808(16)61089-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Innate immunity against hepatitis C virus. Curr Opin Immunol 2016; 42:98-104. [PMID: 27366996 DOI: 10.1016/j.coi.2016.06.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 06/09/2016] [Accepted: 06/15/2016] [Indexed: 12/24/2022]
Abstract
Hepatitis C virus (HCV) infection tends persistent and causes chronic liver diseases, including inflammation, cirrhosis and hepatocellular carcinoma. Innate immune responses triggered by HCV infection, particularly the production of interferons and pro-inflammatory cytokines, shape the early host antiviral defense, and orchestrate subsequent HCV-specific adaptive immunity. Host has evolved multifaceted means to sense HCV infection to induce innate immune responses, whereas HCV has also developed elaborate strategies to evade immune attack. Recent studies in the field have provided many new insights into the interplay of HCV and innate immunity. In this review, we summarized these recent advances, focusing on pathogen recognition by innate sensors, newly discovered anti-HCV innate effectors and new viral strategies to evade innate immunity.
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HIV-1 Tat Protein Activates both the MyD88 and TRIF Pathways To Induce Tumor Necrosis Factor Alpha and Interleukin-10 in Human Monocytes. J Virol 2016; 90:5886-5898. [PMID: 27053552 DOI: 10.1128/jvi.00262-16] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 03/26/2016] [Indexed: 01/26/2023] Open
Abstract
UNLABELLED In this study, we show that the HIV-1 Tat protein interacts with rapid kinetics to engage the Toll-like receptor 4 (TLR4) pathway, leading to the production of proinflammatory and anti-inflammatory cytokines. The pretreatment of human monocytes with Tat protein for 10 to 30 min suffices to irreversibly engage the activation of the TLR4 pathway, leading to the production of tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10), two cytokines strongly implicated in the chronic activation and dysregulation of the immune system during HIV-1 infection. Therefore, this study analyzed whether the HIV-1 Tat protein is able to activate these two pathways separately or simultaneously. Using three complementary approaches, including mice deficient in the MyD88, TIRAP/MAL, or TRIF adaptor, biochemical analysis, and the use of specific small interfering RNAs (siRNAs), we demonstrated (i) that Tat was able to activate both the MyD88 and TRIF pathways, (ii) the capacity of Tat to induce TIRAP/MAL degradation, (iii) the crucial role of the MyD88 pathway in the production of Tat-induced TNF-α and IL-10, (iv) a reduction but not abrogation of IL-10 and TNF-α by Tat-stimulated macrophages from mice deficient in TIRAP/MAL, and (v) the crucial role of the TRIF pathway in Tat-induced IL-10 production. Further, we showed that downstream of the MyD88 and TRIF pathways, the Tat protein activated the protein kinase C (PKC) βII isoform, the mitogen-activated protein (MAP) kinases p38 and extracellular signal-regulated kinase 1/2 (ERK1/2), and NF-κB in a TLR4-dependent manner. Collectively, our data show that by recruiting the TLR4 pathway with rapid kinetics, the HIV-1 Tat protein leads to the engagement of both the MyD88 and TRIF pathways and to the activation of PKC, MAP kinase, and NF-κB signaling to induce the production of TNF-α and IL-10. IMPORTANCE In this study, we demonstrate that by recruiting the TLR4 pathway with rapid kinetics, the HIV-1 Tat protein leads to the engagement of both the MyD88 and TRIF pathways and to the activation of PKC-βII, MAP kinase, and NF-κB signaling to induce the production of TNF-α and IL-10, two cytokines strongly implicated in the chronic activation and dysregulation of the immune system during HIV-1 infection. Thus, it may be interesting to target Tat as a pathogenic factor early after HIV-1 infection. This could be achieved either by vaccination approaches including Tat as an immunogen in potential candidate vaccines or by developing molecules capable of neutralizing the effect of the Tat protein.
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Bang BR, Elmasry S, Saito T. Organ system view of the hepatic innate immunity in HCV infection. J Med Virol 2016; 88:2025-2037. [PMID: 27153233 DOI: 10.1002/jmv.24569] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/04/2016] [Indexed: 12/12/2022]
Abstract
An orchestration of innate and adaptive immunity determines the infection outcome and whether the host achieves clearance or allows the pathogen to establish persistent infection. The robust activation of the innate immune response plays the most critical role in both limiting viral replication and halting the spread of the pathogen immediately after infection. The magnitude of innate immune activation is coupled with the efficient mounting of the adaptive immunity. Although immunity against HCV infection is known to be inadequate as most cases transitions to chronicity, approximately 25% of acute infection cases result in spontaneous clearance. The exact immune mechanisms that govern the infection outcome remain largely unknown; recent discoveries suggest that the innate immune system facilitates this event. Both infected hepatocytes and local innate immune cells trigger the front line defense program of the liver as well as the recruitment of diverse adaptive immune cells to the site of infection. Although hepatocyte is the target of HCV infection, nearly all cell types that exist in the liver are involved in the innate defense and contribute to the pathophysiology of hepatic inflammation. The main focus of this comprehensive review is to discuss the current knowledge on how each hepatic cell type contributes to the organ system level innate immunity against HCV infection as well as interplays with the viral evasion program. Furthermore, this review article also aims to synchronize the observations from both molecular biological studies and clinical studies with the ultimate goal of improving our understanding of HCV mediated hepatitis. J. Med. Virol. 88:2025-2037, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Bo-Ram Bang
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, USC Research Center for Liver Diseases, University of Southern California, Keck School of Medicine, Los Angeles, California
| | - Sandra Elmasry
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, USC Research Center for Liver Diseases, University of Southern California, Keck School of Medicine, Los Angeles, California
| | - Takeshi Saito
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, USC Research Center for Liver Diseases, University of Southern California, Keck School of Medicine, Los Angeles, California. .,Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, California. .,Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles, California.
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Honda T. Links between Human LINE-1 Retrotransposons and Hepatitis Virus-Related Hepatocellular Carcinoma. Front Chem 2016; 4:21. [PMID: 27242996 PMCID: PMC4863659 DOI: 10.3389/fchem.2016.00021] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 04/22/2016] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for approximately 80% of liver cancers, the third most frequent cause of cancer mortality. The most prevalent risk factors for HCC are infections by hepatitis B or hepatitis C virus. Findings suggest that hepatitis virus-related HCC might be a cancer in which LINE-1 retrotransposon, often termed L1, activity plays a potential role. Firstly, hepatitis viruses can suppress host defense factors that also control L1 mobilization. Secondly, many recent studies also have indicated that hypomethylation of L1 affects the prognosis of HCC patients. Thirdly, endogenous L1 retrotransposition was demonstrated to activate oncogenic pathways in HCC. Fourthly, several L1 chimeric transcripts with host or viral genes are found in hepatitis virus-related HCC. Such lines of evidence suggest a linkage between L1 retrotransposons and hepatitis virus-related HCC. Here, I briefly summarize current understandings of the association between hepatitis virus-related HCC and L1. Then, I discuss potential mechanisms of how hepatitis viruses drive the development of HCC via L1 retrotransposons. An increased understanding of the contribution of L1 to hepatitis virus-related HCC may provide unique insights related to the development of novel therapeutics for this disease.
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Affiliation(s)
- Tomoyuki Honda
- Department of Viral Oncology, Institute for Virus Research, Kyoto UniversityKyoto, Japan; Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of MedicineSuita, Japan
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Shah M, Anwar MA, Kim JH, Choi S. Advances in Antiviral Therapies Targeting Toll-like Receptors. Expert Opin Investig Drugs 2016; 25:437-53. [DOI: 10.1517/13543784.2016.1154040] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Cao X. Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat Rev Immunol 2015; 16:35-50. [DOI: 10.1038/nri.2015.8] [Citation(s) in RCA: 364] [Impact Index Per Article: 36.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Xue XX, Gong JM, Tang SD, Gao CF, Wang JJ, Cai L, Wang J, Yu RB, Peng ZH, Fan NJ, Wang CJ, Zhu J, Zhang Y. Single nucleotide polymorphisms of toll-like receptor 7 in hepatitis C virus infection patients from a high-risk chinese population. Inflammation 2015; 38:142-51. [PMID: 25218653 DOI: 10.1007/s10753-014-0016-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Hepatitis C virus (HCV) infection varies in the outcomes depending on both viral and host factors. This study aims to investigate the associations of three single nucleotide polymorphisms (SNPs) of Toll-like receptor 7 (TLR7), rs179016, rs5743733, and rs1634323, with susceptibility to HCV infection and clearance. The three SNPs were genotyped in a high-risk Chinese population, including 444 HCV spontaneous clearance cases, 732 persistent infection cases, and 1107 healthy controls. The G allele of rs1634323 was related to the protection from persistent infection among females (dominant model: odds ratio (OR) = 0.558, 95 % confidence interval (CI) = 0.348-0.894, P = 0.015). This protective effect was more evident in blood donation and HCV non-1 genotype-infected subgroups (all P < 0.05). The carriage of rs179016 C allele was more prone to develop persistent infection (OR = 1.444, 95 % CI = 1.096-1.903, P = 0.009) in males, and the risk effect remained significant among older (>50 years), hemodialysis (HD), and HCV-1 and HCV non-1 genotypes-infected subjects (all P < 0.05). Haplotype analyses showed that CCA haplotype among females was correlated with the elevated risk of HCV susceptibility while the carriage of GGA was more prone to be infected with HCV and CCA was more likely to develop persistent infection (all P < 0.05) among males. Our results first demonstrated that the carriage of rs179016 C allele had a negative effect on spontaneous clearance of HCV among males while rs1634323 G allele conferred a protective effect against persistent infection among female subjects.
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Affiliation(s)
- Xing-Xin Xue
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, No. 140 Hanzhong Road, Nanjing, 210029, Jiangsu, China
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Martínez-Esparza M, Tristán-Manzano M, Ruiz-Alcaraz AJ, García-Peñarrubia P. Inflammatory status in human hepatic cirrhosis. World J Gastroenterol 2015; 21:11522-11541. [PMID: 26556984 PMCID: PMC4631958 DOI: 10.3748/wjg.v21.i41.11522] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 07/31/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
This review focuses on new findings about the inflammatory status involved in the development of human liver cirrhosis induced by the two main causes, hepatitis C virus (HCV) infection and chronic alcohol abuse, avoiding results obtained from animal models. When liver is faced to a persistent and/or intense local damage the maintained inflammatory response gives rise to a progressive replacement of normal hepatic tissue by non-functional fibrotic scar. The imbalance between tissue regeneration and fibrosis will determine the outcome toward health recovery or hepatic cirrhosis. In all cases progression toward liver cirrhosis is caused by a dysregulation of mechanisms that govern the balance between activation/homeostasis of the immune system. Detecting differences between the inflammatory status in HCV-induced vs alcohol-induced cirrhosis could be useful to identify specific targets for preventive and therapeutic intervention in each case. Thus, although survival of patients with alcoholic cirrhosis seems to be similar to that of patients with HCV-related cirrhosis (HCV-C), there are important differences in the altered cellular and molecular mechanisms implicated in the progression toward human liver cirrhosis. The predominant features of HCV-C are more related with those that allow viral evasion of the immune defenses, especially although not exclusively, inhibition of interferons secretion, natural killer cells activation and T cell-mediated cytotoxicity. On the contrary, the inflammatory status of alcohol-induced cirrhosis is determined by the combined effect of direct hepatotoxicity of ethanol metabolites and increases of the intestinal permeability, allowing bacteria and bacterial products translocation, into the portal circulation, mesenteric lymph nodes and peritoneal cavity. This phenomenon generates a stronger pro-inflammatory response compared with HCV-related cirrhosis. Hence, therapeutic intervention in HCV-related cirrhosis must be mainly focused to counteract HCV-immune system evasion, while in the case of alcohol-induced cirrhosis it must try to break the inflammatory loop established at the gut-mesenteric lymph nodes-peritoneal-systemic axis.
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Sachdeva M, Chawla YK, Arora SK. Dendritic cells: The warriors upfront-turned defunct in chronic hepatitis C infection. World J Hepatol 2015; 7:2202-2208. [PMID: 26380045 PMCID: PMC4561774 DOI: 10.4254/wjh.v7.i19.2202] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 08/14/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection causes tremendous morbidity and mortality with over 170 million people infected worldwide. HCV gives rise to a sustained, chronic disease in the majority of infected individuals owing to a failure of the host immune system to clear the virus. In general, an adequate immune response is elicited by an efficient antigen presentation by dendritic cells (DCs), the cells that connect innate and adaptive immune system to generate a specific immune response against a pathogen. However, HCV seems to dysregulate the activity of DCs, making them less proficient antigen presenting cells for the optimal stimulation of virus-specific T cells, hence interfering with an optimal anti-viral immune response. There are discordant reports on the functional status of DCs in chronic HCV infection (CHC), from no phenotypic or functional defects to abnormal functions of DCs. Furthermore, the molecular mechanisms behind the impairment of DC function are even so not completely elucidated during CHC. Understanding the mechanisms of immune dysfunction would help in devising strategies for better management of the disease at the immunological level and help to predict the prognosis of the disease in the patients receiving antiviral therapy. In this review, we have discussed the outcomes of the interaction of DCs with HCV and the mechanisms of DC impairment during HCV infection with its adverse effects on the immune response in the infected host.
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Cao Z, Liang W, Guo K, Lin Z, Zhang Y, Li H, Zheng M, Zhang C, Ning P, Kang K. A comparison of the impact of Shimen and C strains of classical swine fever virus on Toll-like receptor expression. J Gen Virol 2015; 96:1732-45. [DOI: 10.1099/vir.0.000129] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Schaut RG, McGill JL, Neill JD, Ridpath JF, Sacco RE. Bovine viral diarrhea virus type 2 in vivo infection modulates TLR4 responsiveness in differentiated myeloid cells which is associated with decreased MyD88 expression. Virus Res 2015; 208:44-55. [PMID: 26043978 DOI: 10.1016/j.virusres.2015.05.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 05/18/2015] [Accepted: 05/22/2015] [Indexed: 02/06/2023]
Abstract
Symptoms of bovine viral diarrhea virus (BVDV) infection range from subclinical to severe, depending on strain virulence. Several in vitro studies showed BVDV infection impaired leukocyte function. Fewer studies have examined the effects of in vivo BVDV infection on monocyte/macrophage function, especially with strains of differing virulence. We characterized cytokine production by bovine myeloid cells isolated early or late in high (HV) or low virulence (LV) BVDV2 infection. Given BVDV infection may enhance susceptibility to secondary bacterial infection, LPS responses were examined as well. Monocytes from HV and LV infected calves produced higher levels of cytokines compared to cells from controls. In contrast, monocyte-derived macrophage cytokine levels were generally reduced. Modulated cytokine expression in HV BVDV2 macrophages was associated with decreased MyD88 expression, likely due to its interaction with viral NS5A. These data and those of others, suggest that certain Flaviviridae may have evolved strategies for subverting receptor signaling pathways involving MyD88.
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Affiliation(s)
- Robert G Schaut
- Immunobiology Interdepartmental Graduate Program, Iowa State University, 2018 Molecular Biology Building, Ames, IA 50011, USA; Ruminant Diseases and Immunology Research Unit, National Animal Disease Center, ARS, USDA, 1920 Dayton Avenue, Ames, IA 50010, USA
| | - Jodi L McGill
- Ruminant Diseases and Immunology Research Unit, National Animal Disease Center, ARS, USDA, 1920 Dayton Avenue, Ames, IA 50010, USA
| | - John D Neill
- Ruminant Diseases and Immunology Research Unit, National Animal Disease Center, ARS, USDA, 1920 Dayton Avenue, Ames, IA 50010, USA
| | - Julia F Ridpath
- Ruminant Diseases and Immunology Research Unit, National Animal Disease Center, ARS, USDA, 1920 Dayton Avenue, Ames, IA 50010, USA
| | - Randy E Sacco
- Immunobiology Interdepartmental Graduate Program, Iowa State University, 2018 Molecular Biology Building, Ames, IA 50011, USA; Ruminant Diseases and Immunology Research Unit, National Animal Disease Center, ARS, USDA, 1920 Dayton Avenue, Ames, IA 50010, USA.
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