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1
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Woo Y, Ma M, Okawa M, Saito T. Hepatocyte Intrinsic Innate Antiviral Immunity against Hepatitis Delta Virus Infection: The Voices of Bona Fide Human Hepatocytes. Viruses 2024; 16:740. [PMID: 38793622 PMCID: PMC11126147 DOI: 10.3390/v16050740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 04/24/2024] [Accepted: 05/05/2024] [Indexed: 05/26/2024] Open
Abstract
The pathogenesis of viral infection is attributed to two folds: intrinsic cell death pathway activation due to the viral cytopathic effect, and immune-mediated extrinsic cellular injuries. The immune system, encompassing both innate and adaptive immunity, therefore acts as a double-edged sword in viral infection. Insufficient potency permits pathogens to establish lifelong persistent infection and its consequences, while excessive activation leads to organ damage beyond its mission to control viral pathogens. The innate immune response serves as the front line of defense against viral infection, which is triggered through the recognition of viral products, referred to as pathogen-associated molecular patterns (PAMPs), by host cell pattern recognition receptors (PRRs). The PRRs-PAMPs interaction results in the induction of interferon-stimulated genes (ISGs) in infected cells, as well as the secretion of interferons (IFNs), to establish a tissue-wide antiviral state in an autocrine and paracrine manner. Cumulative evidence suggests significant variability in the expression patterns of PRRs, the induction potency of ISGs and IFNs, and the IFN response across different cell types and species. Hence, in our understanding of viral hepatitis pathogenesis, insights gained through hepatoma cell lines or murine-based experimental systems are uncertain in precisely recapitulating the innate antiviral response of genuine human hepatocytes. Accordingly, this review article aims to extract and summarize evidence made possible with bona fide human hepatocytes-based study tools, along with their clinical relevance and implications, as well as to identify the remaining gaps in knowledge for future investigations.
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Affiliation(s)
- Yein Woo
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Muyuan Ma
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Masashi Okawa
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- R&D Department, PhoenixBio USA Corporation, New York, NY 10006, USA
| | - Takeshi Saito
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- USC Research Center for Liver Diseases, Los Angeles, CA 90033, USA
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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2
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Yoneyama M, Kato H, Fujita T. Physiological functions of RIG-I-like receptors. Immunity 2024; 57:731-751. [PMID: 38599168 DOI: 10.1016/j.immuni.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 02/19/2024] [Accepted: 03/04/2024] [Indexed: 04/12/2024]
Abstract
RIG-I-like receptors (RLRs) are crucial for pathogen detection and triggering immune responses and have immense physiological importance. In this review, we first summarize the interferon system and innate immunity, which constitute primary and secondary responses. Next, the molecular structure of RLRs and the mechanism of sensing non-self RNA are described. Usually, self RNA is refractory to the RLR; however, there are underlying host mechanisms that prevent immune reactions. Studies have revealed that the regulatory mechanisms of RLRs involve covalent molecular modifications, association with regulatory factors, and subcellular localization. Viruses have evolved to acquire antagonistic RLR functions to escape the host immune reactions. Finally, the pathologies caused by the malfunction of RLR signaling are described.
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Affiliation(s)
- Mitsutoshi Yoneyama
- Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba, Japan; Division of Pandemic and Post-disaster Infectious Diseases, Research Institute of Disaster Medicine, Chiba University, Chiba, Japan
| | - Hiroki Kato
- Institute of Cardiovascular Immunology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Takashi Fujita
- Institute of Cardiovascular Immunology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany; Laboratory of Regulatory Information, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
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3
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Ding K, Li H, Tai F, Duan J, Wang Q, Zhai R, Fu H, Ge C, Zheng X. Unraveling the Role of RNase L Knockout in Alleviating Immune Response Activation in Mice Bone Marrow after Irradiation. Int J Mol Sci 2024; 25:2722. [PMID: 38473966 PMCID: PMC10932110 DOI: 10.3390/ijms25052722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/09/2024] [Accepted: 02/21/2024] [Indexed: 03/14/2024] Open
Abstract
Ionizing radiation (IR) induces severe hematopoietic injury by causing DNA and RNA damage as well as activating the immune responses, necessitating the development of effective therapeutic strategies. Ribonuclease L (RNase L) as an innate immune response pathway is triggered by exogenous and endogenous abnormal dsRNA under viral infection and dyshomeostasis, thereby activating the immune responses. Thus, we investigated the effect of RNase L on irradiation-induced bone marrow damage using RNase L knockout (RNase L-/-) mice. Phenotypic analysis revealed that RNase L knockout mitigates irradiation-induced injury in the bone marrow. Further investigation into the mechanism of RNase L by RNA-seq, qRT-PCR, and CBA analysis demonstrated that RNase L deficiency counteracts the upregulation of genes related to immune responses induced by irradiation, including cytokines and interferon-stimulated genes. Moreover, RNase L deficiency inhibits the increased levels of immunoglobulins in serum induced by irradiation. These findings indicate that RNase L plays a role in the immune response induced by irradiation in the bone marrow. This study further enhances our understanding of the biological functions of RNase L in the immune response induced by irradiation and offers a novel approach for managing irradiation-induced bone marrow injury through the regulation of RNase L activation.
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Affiliation(s)
| | | | | | | | | | | | | | - Changhui Ge
- Beijing Key Laboratory for Radiobiology, Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Beijing 100850, China; (K.D.); (H.L.); (F.T.); (J.D.); (Q.W.); (R.Z.); (H.F.)
| | - Xiaofei Zheng
- Beijing Key Laboratory for Radiobiology, Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Beijing 100850, China; (K.D.); (H.L.); (F.T.); (J.D.); (Q.W.); (R.Z.); (H.F.)
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4
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Mohd Jaafar F, Belhouchet M, Monsion B, Bell-Sakyi L, Mertens PPC, Attoui H. Orbivirus NS4 Proteins Play Multiple Roles to Dampen Cellular Responses. Viruses 2023; 15:1908. [PMID: 37766314 PMCID: PMC10535134 DOI: 10.3390/v15091908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Non-structural protein 4 (NS4) of insect-borne and tick-borne orbiviruses is encoded by genome segment 9, from a secondary open reading frame. Though a protein dispensable for bluetongue virus (BTV) replication, it has been shown to counter the interferon response in cells infected with BTV or African horse sickness virus. We further explored the functional role(s) of NS4 proteins of BTV and the tick-borne Great Island virus (GIV). We show that NS4 of BTV or GIV helps an E3L deletion mutant of vaccinia virus to replicate efficiently in interferon-treated cells, further confirming the role of NS4 as an interferon antagonist. Our results indicate that ectopically expressed NS4 of BTV localised with caspase 3 within the nucleus and was found in a protein complex with active caspase 3 in a pull-down assay. Previous studies have shown that pro-apoptotic caspases (including caspase 3) suppress type I interferon response by cleaving mediators involved in interferon signalling. Our data suggest that orbivirus NS4 plays a role in modulating the apoptotic process and/or regulating the interferon response in mammalian cells, thus acting as a virulence factor in pathogenesis.
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Affiliation(s)
- Fauziah Mohd Jaafar
- UMR1161 VIROLOGIE, INRAE, Ecole Nationale Vétérinaire d’Alfort, ANSES, Université Paris-Est, 94700 Maisons-Alfort, France;
| | - Mourad Belhouchet
- Division of Structural Biology, Henry Wellcome Building for Genomic Medicine, Oxford OX3 7BN, UK;
| | - Baptiste Monsion
- UMR1161 VIROLOGIE, INRAE, Ecole Nationale Vétérinaire d’Alfort, ANSES, Université Paris-Est, 94700 Maisons-Alfort, France;
| | - Lesley Bell-Sakyi
- Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, 146 Brownlow Hill, Liverpool L3 5RF, UK;
| | - Peter P. C. Mertens
- One Virology, The Wolfson Centre for Global Virus Research, School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus, Loughborough, Leicestershire LE12 5RD, UK;
| | - Houssam Attoui
- UMR1161 VIROLOGIE, INRAE, Ecole Nationale Vétérinaire d’Alfort, ANSES, Université Paris-Est, 94700 Maisons-Alfort, France;
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5
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Ke PY. Crosstalk between Autophagy and RLR Signaling. Cells 2023; 12:cells12060956. [PMID: 36980296 PMCID: PMC10047499 DOI: 10.3390/cells12060956] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/17/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Autophagy plays a homeostatic role in regulating cellular metabolism by degrading unwanted intracellular materials and acts as a host defense mechanism by eliminating infecting pathogens, such as viruses. Upon viral infection, host cells often activate retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling to induce the transcription of type I interferons, thus establishing the first line of the innate antiviral response. In recent years, numerous studies have shown that virus-mediated autophagy activation may benefit viral replication through different actions on host cellular processes, including the modulation of RLR-mediated innate immunity. Here, an overview of the functional molecules and regulatory mechanism of the RLR antiviral immune response as well as autophagy is presented. Moreover, a summary of the current knowledge on the biological role of autophagy in regulating RLR antiviral signaling is provided. The molecular mechanisms underlying the crosstalk between autophagy and RLR innate immunity are also discussed.
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Affiliation(s)
- Po-Yuan Ke
- Department of Biochemistry & Molecular Biology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
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6
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Li N, Rana TM. Regulation of antiviral innate immunity by chemical modification of viral RNA. WILEY INTERDISCIPLINARY REVIEWS. RNA 2022; 13:e1720. [PMID: 35150188 PMCID: PMC9786758 DOI: 10.1002/wrna.1720] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 01/08/2022] [Accepted: 01/11/2022] [Indexed: 12/30/2022]
Abstract
More than 100 chemical modifications of RNA, termed the epitranscriptome, have been described, most of which occur in prokaryotic and eukaryotic ribosomal, transfer, and noncoding RNA and eukaryotic messenger RNA. DNA and RNA viruses can modify their RNA either directly via genome-encoded enzymes or by hijacking the host enzymatic machinery. Among the many RNA modifications described to date, four play particularly important roles in promoting viral infection by facilitating viral gene expression and replication and by enabling escape from the host innate immune response. Here, we discuss our current understanding of the mechanisms by which the RNA modifications such as N6 -methyladenosine (m6A), N6 ,2'-O-dimethyladenosine (m6Am), 5-methylcytidine (m5C), N4-acetylcytidine (ac4C), and 2'-O-methylation (Nm) promote viral replication and/or suppress recognition by innate sensors and downstream activation of the host antiviral response. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution.
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Affiliation(s)
- Na Li
- Division of Genetics, Department of Pediatrics, Program in ImmunologyInstitute for Genomic MedicineLa JollaCaliforniaUSA
| | - Tariq M. Rana
- Division of Genetics, Department of Pediatrics, Program in ImmunologyInstitute for Genomic MedicineLa JollaCaliforniaUSA
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7
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Phenotypic and Transcriptional Changes of Pulmonary Immune Responses in Dogs Following Canine Distemper Virus Infection. Int J Mol Sci 2022; 23:ijms231710019. [PMID: 36077417 PMCID: PMC9456005 DOI: 10.3390/ijms231710019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 11/25/2022] Open
Abstract
Canine distemper virus (CDV), a morbillivirus within the family Paramyxoviridae, is a highly contagious infectious agent causing a multisystemic, devastating disease in a broad range of host species, characterized by severe immunosuppression, encephalitis and pneumonia. The present study aimed at investigating pulmonary immune responses of CDV-infected dogs in situ using immunohistochemistry and whole transcriptome analyses by bulk RNA sequencing. Spatiotemporal analysis of phenotypic changes revealed pulmonary immune responses primarily driven by MHC-II+, Iba-1+ and CD204+ innate immune cells during acute and subacute infection phases, which paralleled pathologic lesion development and coincided with high viral loads in CDV-infected lungs. CD20+ B cell numbers initially declined, followed by lymphoid repopulation in the advanced disease phase. Transcriptome analysis demonstrated an increased expression of transcripts related to innate immunity, antiviral defense mechanisms, type I interferon responses and regulation of cell death in the lung of CDV-infected dogs. Molecular analyses also revealed disturbed cytokine responses with a pro-inflammatory M1 macrophage polarization and impaired mucociliary defense in CDV-infected lungs. The exploratory study provides detailed data on CDV-related pulmonary immune responses, expanding the list of immunologic parameters potentially leading to viral elimination and virus-induced pulmonary immunopathology in canine distemper.
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8
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Koliński M, Kałużna E, Piwecka M. RNA–protein interactomes as invaluable resources to study RNA viruses: Insights from SARS CoV‐2 studies. WIRES RNA 2022; 13:e1727. [PMID: 35343064 PMCID: PMC9111084 DOI: 10.1002/wrna.1727] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 03/03/2022] [Accepted: 03/07/2022] [Indexed: 12/27/2022]
Abstract
Understanding the molecular mechanisms of severe respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection is essential for the successful development of therapeutic strategies against the COVID‐19 pandemic. Numerous studies have focused on the identification of host factors and cellular pathways involved in the viral replication cycle. The speed and magnitude of hijacking the translation machinery of host mRNA, and shutting down host transcription are still not well understood. Since SARS‐CoV‐2 relies on host RNA‐binding proteins for the infection progression, several efforts have been made to define the SARS‐CoV‐2 RNA‐bound proteomes (RNA–protein interactomes). Methodologies that enable the systemic capture of protein interactors of given RNA in vivo have been adapted for the identification of the SARS‐CoV‐2 RNA interactome. The obtained proteomic data aided by genome‐wide and targeted CRISPR perturbation screens, revealed host factors with either pro‐ or anti‐viral activity and highlighted cellular processes and factors involved in host response. We focus here on the recent studies on SARS‐CoV‐2 RNA–protein interactomes, with regard to both the technological aspects of RNA interactome capture methods and the obtained results. We also summarize several related studies, which were used in the interpretation of the SARS‐CoV‐2 RNA–protein interactomes. These studies provided the selection of host factors that are potentially suitable candidates for antiviral therapy. Finally, we underscore the importance of RNA–protein interactome studies in regard to the effective development of antiviral strategies against current and future threats. This article is categorized under:
RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease RNA Methods > RNA Analyses in Cells
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Affiliation(s)
- Marcin Koliński
- Department of Non‐Coding RNAs Institute of Bioorganic Chemistry, Polish Academy of Sciences Poznan Poland
| | - Ewelina Kałużna
- Department of Non‐Coding RNAs Institute of Bioorganic Chemistry, Polish Academy of Sciences Poznan Poland
| | - Monika Piwecka
- Department of Non‐Coding RNAs Institute of Bioorganic Chemistry, Polish Academy of Sciences Poznan Poland
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9
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Alem F, Olanrewaju AA, Omole S, Hobbs HE, Ahsan N, Matulis G, Brantner CA, Zhou W, Petricoin EF, Liotta LA, Caputi M, Bavari S, Wu Y, Kashanchi F, Hakami RM. Exosomes originating from infection with the cytoplasmic single-stranded RNA virus Rift Valley fever virus (RVFV) protect recipient cells by inducing RIG-I mediated IFN-B response that leads to activation of autophagy. Cell Biosci 2021; 11:220. [PMID: 34953502 PMCID: PMC8710069 DOI: 10.1186/s13578-021-00732-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 12/12/2021] [Indexed: 12/12/2022] Open
Abstract
Background Although multiple studies have demonstrated a role for exosomes during virus infections, our understanding of the mechanisms by which exosome exchange regulates immune response during viral infections and affects viral pathogenesis is still in its infancy. In particular, very little is known for cytoplasmic single-stranded RNA viruses such as SARS-CoV-2 and Rift Valley fever virus (RVFV). We have used RVFV infection as a model for cytoplasmic single-stranded RNA viruses to address this gap in knowledge. RVFV is a highly pathogenic agent that causes RVF, a zoonotic disease for which no effective therapeutic or approved human vaccine exist. Results We show here that exosomes released from cells infected with RVFV (designated as EXi-RVFV) serve a protective role for the host and provide a mechanistic model for these effects. Our results show that treatment of both naïve immune cells (U937 monocytes) and naïve non-immune cells (HSAECs) with EXi-RVFV induces a strong RIG-I dependent activation of IFN-B. We also demonstrate that this strong anti-viral response leads to activation of autophagy in treated cells and correlates with resistance to subsequent viral infection. Since we have shown that viral RNA genome is associated with EXi-RVFV, RIG-I activation might be mediated by the presence of packaged viral RNA sequences. Conclusions Using RVFV infection as a model for cytoplasmic single-stranded RNA viruses, our results show a novel mechanism of host protection by exosomes released from infected cells (EXi) whereby the EXi activate RIG-I to induce IFN-dependent activation of autophagy in naïve recipient cells including monocytes. Because monocytes serve as reservoirs for RVFV replication, this EXi-RVFV-induced activation of autophagy in monocytes may work to slow down or halt viral dissemination in the infected organism. These findings offer novel mechanistic insights that may aid in future development of effective vaccines or therapeutics, and that may be applicable for a better molecular understanding of how exosome release regulates innate immune response to other cytoplasmic single-stranded RNA viruses. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-021-00732-z.
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Affiliation(s)
- Farhang Alem
- School of Systems Biology, George Mason University, Manassas, VA, USA.,Center for Infectious Disease Research (Formerly, National Center for Biodefense and Infectious Diseases), George Mason University, Manassas, VA, USA
| | - Adeyemi A Olanrewaju
- School of Systems Biology, George Mason University, Manassas, VA, USA.,Center for Infectious Disease Research (Formerly, National Center for Biodefense and Infectious Diseases), George Mason University, Manassas, VA, USA
| | - Samson Omole
- School of Systems Biology, George Mason University, Manassas, VA, USA.,Center for Infectious Disease Research (Formerly, National Center for Biodefense and Infectious Diseases), George Mason University, Manassas, VA, USA
| | - Heather E Hobbs
- School of Systems Biology, George Mason University, Manassas, VA, USA.,Center for Infectious Disease Research (Formerly, National Center for Biodefense and Infectious Diseases), George Mason University, Manassas, VA, USA
| | - Noor Ahsan
- School of Systems Biology, George Mason University, Manassas, VA, USA.,Center for Infectious Disease Research (Formerly, National Center for Biodefense and Infectious Diseases), George Mason University, Manassas, VA, USA.,Lentigen Technology, Inc., Gaithersburg, MD, USA
| | - Graham Matulis
- School of Systems Biology, George Mason University, Manassas, VA, USA.,Center for Infectious Disease Research (Formerly, National Center for Biodefense and Infectious Diseases), George Mason University, Manassas, VA, USA
| | - Christine A Brantner
- Nanofabrication and Imaging Center, George Washington University, Washington, DC, USA
| | - Weidong Zhou
- School of Systems Biology, George Mason University, Manassas, VA, USA.,Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA
| | - Emanuel F Petricoin
- School of Systems Biology, George Mason University, Manassas, VA, USA.,Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA
| | - Lance A Liotta
- School of Systems Biology, George Mason University, Manassas, VA, USA.,Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA
| | - Massimo Caputi
- Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA
| | | | - Yuntao Wu
- School of Systems Biology, George Mason University, Manassas, VA, USA.,Center for Infectious Disease Research (Formerly, National Center for Biodefense and Infectious Diseases), George Mason University, Manassas, VA, USA
| | - Fatah Kashanchi
- School of Systems Biology, George Mason University, Manassas, VA, USA
| | - Ramin M Hakami
- School of Systems Biology, George Mason University, Manassas, VA, USA. .,Center for Infectious Disease Research (Formerly, National Center for Biodefense and Infectious Diseases), George Mason University, Manassas, VA, USA.
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10
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Cao X, Cordova AF, Li L. Therapeutic Interventions Targeting Innate Immune Receptors: A Balancing Act. Chem Rev 2021; 122:3414-3458. [PMID: 34870969 DOI: 10.1021/acs.chemrev.1c00716] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The innate immune system is an organism's first line of defense against an onslaught of internal and external threats. The downstream adaptive immune system has been a popular target for therapeutic intervention, while there is a relative paucity of therapeutics targeting the innate immune system. However, the innate immune system plays a critical role in many human diseases, such as microbial infection, cancer, and autoimmunity, highlighting the need for ongoing therapeutic research. In this review, we discuss the major innate immune pathways and detail the molecular strategies underpinning successful therapeutics targeting each pathway as well as previous and ongoing efforts. We will also discuss any recent discoveries that could inform the development of novel therapeutic strategies. As our understanding of the innate immune system continues to develop, we envision that therapies harnessing the power of the innate immune system will become the mainstay of treatment for a wide variety of human diseases.
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11
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Li J, Boix E. Host Defence RNases as Antiviral Agents against Enveloped Single Stranded RNA Viruses. Virulence 2021; 12:444-469. [PMID: 33660566 PMCID: PMC7939569 DOI: 10.1080/21505594.2021.1871823] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 12/26/2020] [Accepted: 12/30/2020] [Indexed: 02/06/2023] Open
Abstract
Owing to the recent outbreak of Coronavirus Disease of 2019 (COVID-19), it is urgent to develop effective and safe drugs to treat the present pandemic and prevent other viral infections that might come in the future. Proteins from our own innate immune system can serve as ideal sources of novel drug candidates thanks to their safety and immune regulation versatility. Some host defense RNases equipped with antiviral activity have been reported over time. Here, we try to summarize the currently available information on human RNases that can target viral pathogens, with special focus on enveloped single-stranded RNA (ssRNA) viruses. Overall, host RNases can fight viruses by a combined multifaceted strategy, including the enzymatic target of the viral genome, recognition of virus unique patterns, immune modulation, control of stress granule formation, and induction of autophagy/apoptosis pathways. The review also includes a detailed description of representative enveloped ssRNA viruses and their strategies to interact with the host and evade immune recognition. For comparative purposes, we also provide an exhaustive revision of the currently approved or experimental antiviral drugs. Finally, we sum up the current perspectives of drug development to achieve successful eradication of viral infections.
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Affiliation(s)
- Jiarui Li
- Dpt. Of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma De Barcelona, Spain
| | - Ester Boix
- Dpt. Of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma De Barcelona, Spain
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12
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Steinberg J, Wadenpohl T, Jung S. The Endogenous RIG-I Ligand Is Generated in Influenza A-Virus Infected Cells. Viruses 2021; 13:1564. [PMID: 34452429 PMCID: PMC8402674 DOI: 10.3390/v13081564] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/03/2021] [Accepted: 08/06/2021] [Indexed: 12/16/2022] Open
Abstract
As a result of a viral infection, viral genomes are not only recognized by RIG-I, but also lead to the activation of RNase L, which cleaves cellular RNA to generate the endogenous RIG-I ligand (eRL). The eRL was previously identified as a specific sequence derived from the internal transcribed spacer region 2, which bears a 2'3' cyclic phosphate instead of the common 5' triphosphate. By now, the generation of the eRL and its immunostimulatory effect were shown both in vitro and in reporter systems. In this work, we aimed to elucidate whether the eRL is also generated in Influenza A (IAV) and vesicular stomatitis virus (VSV) infected cells. RNA was extracted from virus-infected cells and used for immunostimulations as well as specific PCR-strategies to detect eRL cleavage. We show that the eRL is generated in IAV infected HEK293 cells, but we could not detect specific eRL fragments in VSV infected cells. Further, RIG-I mediated IFN-response depends not only on viral genomes but also on the eRL, as immunostimulatory properties remain present under 5'triphosphate degrading conditions. In summary, we prove the IAV infection induced eRL generation in HEK293 cells, amplifying the innate immune response.
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Affiliation(s)
| | | | - Stephanie Jung
- Institute of Cardiovascular Immunology, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany; (J.S.); (T.W.)
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13
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Wubben R, Efstathiou C, Stevenson NJ. The interplay between the immune system and viruses. VITAMINS AND HORMONES 2021; 117:1-15. [PMID: 34420576 DOI: 10.1016/bs.vh.2021.06.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The human immune response can be divided into two arms: innate and adaptive immunity. The innate immune system consists of "hard-wired" responses encoded by host germline genes. In contrast, the adaptive response consists of gene elements that are somatically rearranged to assemble antigen-binding molecules with specificity for individual foreign structures. In contrast to the adaptive immune system, which depends upon T and B lymphocytes, innate immune protection is a task performed by cells of both hematopoietic and non-hematopoietic origin. Hematopoietic cells involved in innate immune responses include macrophages, dendritic cells, mast cell, neutrophils, eosinophils, natural killer (NK) cells and natural killer T cells. The induction of an adaptive immune response begins when a pathogen is ingested by an Antigen Presenting Cell (APC), such as the Dendritic cell (DC), in the infected tissue. DCs bridge the gap between first line innate responses and powerful adaptive immune responses, by internalizing, processing and presenting antigens on Major Histocompatibility Complex (MHC) and MHC-like molecules to the adaptive immune cells In addition to DCs, macrophages and B cells are deemed antigen presenting cells (Llewelyn & Cohen, 2002).
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Affiliation(s)
- R Wubben
- Trinity College Dublin, Dublin, Ireland
| | | | - N J Stevenson
- Royal College of Surgeons in Ireland-Medical University of Bahrain, Busaiteen, Kingdom of Bahrain; Trinity College Dublin, Dublin, Ireland.
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14
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Markiewicz L, Drazkowska K, Sikorski PJ. Tricks and threats of RNA viruses - towards understanding the fate of viral RNA. RNA Biol 2021; 18:669-687. [PMID: 33618611 PMCID: PMC8078519 DOI: 10.1080/15476286.2021.1875680] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 12/22/2020] [Accepted: 01/09/2021] [Indexed: 12/24/2022] Open
Abstract
Human innate cellular defence pathways have evolved to sense and eliminate pathogens, of which, viruses are considered one of the most dangerous. Their relatively simple structure makes the identification of viral invasion a difficult task for cells. In the course of evolution, viral nucleic acids have become one of the strongest and most reliable early identifiers of infection. When considering RNA virus recognition, RNA sensing is the central mechanism in human innate immunity, and effectiveness of this sensing is crucial for triggering an appropriate antiviral response. Although human cells are armed with a variety of highly specialized receptors designed to respond only to pathogenic viral RNA, RNA viruses have developed an array of mechanisms to avoid being recognized by human interferon-mediated cellular defence systems. The repertoire of viral evasion strategies is extremely wide, ranging from masking pathogenic RNA through end modification, to utilizing sophisticated techniques to deceive host cellular RNA degrading enzymes, and hijacking the most basic metabolic pathways in host cells. In this review, we aim to dissect human RNA sensing mechanisms crucial for antiviral immune defences, as well as the strategies adopted by RNA viruses to avoid detection and degradation by host cells. We believe that understanding the fate of viral RNA upon infection, and detailing the molecular mechanisms behind virus-host interactions, may be helpful for developing more effective antiviral strategies; which are urgently needed to prevent the far-reaching consequences of widespread, highly pathogenic viral infections.
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15
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McKellar J, Rebendenne A, Wencker M, Moncorgé O, Goujon C. Mammalian and Avian Host Cell Influenza A Restriction Factors. Viruses 2021; 13:522. [PMID: 33810083 PMCID: PMC8005160 DOI: 10.3390/v13030522] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/12/2021] [Accepted: 03/15/2021] [Indexed: 12/27/2022] Open
Abstract
The threat of a new influenza pandemic is real. With past pandemics claiming millions of lives, finding new ways to combat this virus is essential. Host cells have developed a multi-modular system to detect incoming pathogens, a phenomenon called sensing. The signaling cascade triggered by sensing subsequently induces protection for themselves and their surrounding neighbors, termed interferon (IFN) response. This response induces the upregulation of hundreds of interferon-stimulated genes (ISGs), including antiviral effectors, establishing an antiviral state. As well as the antiviral proteins induced through the IFN system, cells also possess a so-called intrinsic immunity, constituted of antiviral proteins that are constitutively expressed, creating a first barrier preceding the induction of the interferon system. All these combined antiviral effectors inhibit the virus at various stages of the viral lifecycle, using a wide array of mechanisms. Here, we provide a review of mammalian and avian influenza A restriction factors, detailing their mechanism of action and in vivo relevance, when known. Understanding their mode of action might help pave the way for the development of new influenza treatments, which are absolutely required if we want to be prepared to face a new pandemic.
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Affiliation(s)
- Joe McKellar
- Institut de Recherche en Infectiologie de Montpellier, CNRS, Université de Montpellier, CEDEX 5, 34293 Montpellier, France; (J.M.); (A.R.)
| | - Antoine Rebendenne
- Institut de Recherche en Infectiologie de Montpellier, CNRS, Université de Montpellier, CEDEX 5, 34293 Montpellier, France; (J.M.); (A.R.)
| | - Mélanie Wencker
- Centre International de Recherche en Infectiologie, INSERM/CNRS/UCBL1/ENS de Lyon, 69007 Lyon, France;
| | - Olivier Moncorgé
- Institut de Recherche en Infectiologie de Montpellier, CNRS, Université de Montpellier, CEDEX 5, 34293 Montpellier, France; (J.M.); (A.R.)
| | - Caroline Goujon
- Institut de Recherche en Infectiologie de Montpellier, CNRS, Université de Montpellier, CEDEX 5, 34293 Montpellier, France; (J.M.); (A.R.)
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16
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Girardi E, Pfeffer S, Baumert TF, Majzoub K. Roadblocks and fast tracks: How RNA binding proteins affect the viral RNA journey in the cell. Semin Cell Dev Biol 2021; 111:86-100. [PMID: 32847707 PMCID: PMC7443355 DOI: 10.1016/j.semcdb.2020.08.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 08/14/2020] [Accepted: 08/14/2020] [Indexed: 12/12/2022]
Abstract
As obligate intracellular parasites with limited coding capacity, RNA viruses rely on host cells to complete their multiplication cycle. Viral RNAs (vRNAs) are central to infection. They carry all the necessary information for a virus to synthesize its proteins, replicate and spread and could also play essential non-coding roles. Regardless of its origin or tropism, vRNA has by definition evolved in the presence of host RNA Binding Proteins (RBPs), which resulted in intricate and complicated interactions with these factors. While on one hand some host RBPs recognize vRNA as non-self and mobilize host antiviral defenses, vRNA must also co-opt other host RBPs to promote viral infection. Focusing on pathogenic RNA viruses, we will review important scenarios of RBP-vRNA interactions during which host RBPs recognize, modify or degrade vRNAs. We will then focus on how vRNA hijacks the largest ribonucleoprotein complex (RNP) in the cell, the ribosome, to selectively promote the synthesis of its proteins. We will finally reflect on how novel technologies are helping in deepening our understanding of vRNA-host RBPs interactions, which can be ultimately leveraged to combat everlasting viral threats.
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Affiliation(s)
- Erika Girardi
- Architecture et Réactivité de l'ARN, Université de Strasbourg, Institut de Biologie Moléculaire et Cellulaire du CNRS, Strasbourg, France
| | - Sebastien Pfeffer
- Architecture et Réactivité de l'ARN, Université de Strasbourg, Institut de Biologie Moléculaire et Cellulaire du CNRS, Strasbourg, France
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, 67000, Strasbourg, France; Pole Hépatodigestif, Institut Hopitalo-universitaire, Hopitaux Universitaires de Strasbourg, 67000 Strasbourg, France
| | - Karim Majzoub
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, 67000, Strasbourg, France.
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17
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Onomoto K, Onoguchi K, Yoneyama M. Regulation of RIG-I-like receptor-mediated signaling: interaction between host and viral factors. Cell Mol Immunol 2021; 18:539-555. [PMID: 33462384 PMCID: PMC7812568 DOI: 10.1038/s41423-020-00602-7] [Citation(s) in RCA: 227] [Impact Index Per Article: 56.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 11/17/2020] [Indexed: 01/31/2023] Open
Abstract
Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are RNA sensor molecules that play essential roles in innate antiviral immunity. Among the three RLRs encoded by the human genome, RIG-I and melanoma differentiation-associated gene 5, which contain N-terminal caspase recruitment domains, are activated upon the detection of viral RNAs in the cytoplasm of virus-infected cells. Activated RLRs induce downstream signaling via their interactions with mitochondrial antiviral signaling proteins and activate the production of type I and III interferons and inflammatory cytokines. Recent studies have shown that RLR-mediated signaling is regulated by interactions with endogenous RNAs and host proteins, such as those involved in stress responses and posttranslational modifications. Since RLR-mediated cytokine production is also involved in the regulation of acquired immunity, the deregulation of RLR-mediated signaling is associated with autoimmune and autoinflammatory disorders. Moreover, RLR-mediated signaling might be involved in the aberrant cytokine production observed in coronavirus disease 2019. Since the discovery of RLRs in 2004, significant progress has been made in understanding the mechanisms underlying the activation and regulation of RLR-mediated signaling pathways. Here, we review the recent advances in the understanding of regulated RNA recognition and signal activation by RLRs, focusing on the interactions between various host and viral factors.
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Affiliation(s)
- Koji Onomoto
- Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8673, Japan
| | - Kazuhide Onoguchi
- Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8673, Japan
| | - Mitsutoshi Yoneyama
- Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8673, Japan.
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18
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Huijser E, Versnel MA. Making Sense of Intracellular Nucleic Acid Sensing in Type I Interferon Activation in Sjögren's Syndrome. J Clin Med 2021; 10:532. [PMID: 33540529 PMCID: PMC7867173 DOI: 10.3390/jcm10030532] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/26/2021] [Accepted: 01/29/2021] [Indexed: 12/13/2022] Open
Abstract
Primary Sjögren's syndrome (pSS) is a systemic autoimmune rheumatic disease characterized by dryness of the eyes and mucous membranes, which can be accompanied by various extraglandular autoimmune manifestations. The majority of patients exhibit persistent systemic activation of the type I interferon (IFN) system, a feature that is shared with other systemic autoimmune diseases. Type I IFNs are integral to anti-viral immunity and are produced in response to stimulation of pattern recognition receptors, among which nucleic acid (NA) receptors. Dysregulated detection of endogenous NAs has been widely implicated in the pathogenesis of systemic autoimmune diseases. Stimulation of endosomal Toll-like receptors by NA-containing immune complexes are considered to contribute to the systemic type I IFN activation. Accumulating evidence suggest additional roles for cytosolic NA-sensing pathways in the pathogenesis of systemic autoimmune rheumatic diseases. In this review, we will provide an overview of the functions and signaling of intracellular RNA- and DNA-sensing receptors and summarize the evidence for a potential role of these receptors in the pathogenesis of pSS and the sustained systemic type I IFN activation.
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Affiliation(s)
| | - Marjan A. Versnel
- Department of Immunology, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands;
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19
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Kim H, Kim AY, Choi J, Park SY, Park SH, Kim JS, Lee SI, Park JH, Park CK, Ko YJ. Foot-and-Mouth Disease Virus Evades Innate Immune Response by 3C-Targeting of MDA5. Cells 2021; 10:271. [PMID: 33572945 PMCID: PMC7912020 DOI: 10.3390/cells10020271] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/18/2021] [Accepted: 01/26/2021] [Indexed: 12/13/2022] Open
Abstract
Foot-and-mouth disease (FMD) is a highly contagious disease caused by FMD virus (FMDV) in cloven-hoofed animals. Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are representative receptors in the cytoplasm for the detection of viral RNA and trigger antiviral responses, leading to the production of type I interferon. Although MDA5 is a crucial receptor for sensing picornavirus RNA, the interplay between MDA5 and FMDV is relatively unknown compared to the interplay between RIG-I and FMDV. Here, we observed that the FMDV infection inhibits MDA5 protein expression. Of the non-structural proteins, the Lb and 3C proteinases (Lbpro and 3Cpro) were identified to be primarily responsible for this inhibition. However, the inhibition by 3Cpro was independent of proteasome, lysosome and caspase-dependent pathway and was by 3C protease activity. A direct interaction between 3Cpro and MDA5 protein was observed. In conclusion, this is the first report that 3Cpro inhibits MDA5 protein expression as a mechanism to evade the innate immune response during FMDV infection. These results elucidate the pathogenesis of FMDV and provide fundamental insights for the development of a novel vaccine or therapeutic agent.
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Affiliation(s)
- Hyejin Kim
- Animal and Plant Quarantine Agency, Gimcheon-si 39660, Korea; (H.K.); (A.-Y.K.); (J.C.); (S.Y.P.); (S.H.P.); (J.-S.K.); (S.-I.L.); (J.-H.P.)
- College of Veterinary Medicine, Animal Disease Intervention Center, Kyungpook National University, Daegu 41566, Korea
| | - Ah-Young Kim
- Animal and Plant Quarantine Agency, Gimcheon-si 39660, Korea; (H.K.); (A.-Y.K.); (J.C.); (S.Y.P.); (S.H.P.); (J.-S.K.); (S.-I.L.); (J.-H.P.)
| | - Jieun Choi
- Animal and Plant Quarantine Agency, Gimcheon-si 39660, Korea; (H.K.); (A.-Y.K.); (J.C.); (S.Y.P.); (S.H.P.); (J.-S.K.); (S.-I.L.); (J.-H.P.)
| | - Sun Young Park
- Animal and Plant Quarantine Agency, Gimcheon-si 39660, Korea; (H.K.); (A.-Y.K.); (J.C.); (S.Y.P.); (S.H.P.); (J.-S.K.); (S.-I.L.); (J.-H.P.)
- College of Veterinary Medicine, Animal Disease Intervention Center, Kyungpook National University, Daegu 41566, Korea
| | - Sang Hyun Park
- Animal and Plant Quarantine Agency, Gimcheon-si 39660, Korea; (H.K.); (A.-Y.K.); (J.C.); (S.Y.P.); (S.H.P.); (J.-S.K.); (S.-I.L.); (J.-H.P.)
| | - Jae-Seok Kim
- Animal and Plant Quarantine Agency, Gimcheon-si 39660, Korea; (H.K.); (A.-Y.K.); (J.C.); (S.Y.P.); (S.H.P.); (J.-S.K.); (S.-I.L.); (J.-H.P.)
| | - Sim-In Lee
- Animal and Plant Quarantine Agency, Gimcheon-si 39660, Korea; (H.K.); (A.-Y.K.); (J.C.); (S.Y.P.); (S.H.P.); (J.-S.K.); (S.-I.L.); (J.-H.P.)
| | - Jong-Hyeon Park
- Animal and Plant Quarantine Agency, Gimcheon-si 39660, Korea; (H.K.); (A.-Y.K.); (J.C.); (S.Y.P.); (S.H.P.); (J.-S.K.); (S.-I.L.); (J.-H.P.)
| | - Choi-Kyu Park
- College of Veterinary Medicine, Animal Disease Intervention Center, Kyungpook National University, Daegu 41566, Korea
| | - Young-Joon Ko
- Animal and Plant Quarantine Agency, Gimcheon-si 39660, Korea; (H.K.); (A.-Y.K.); (J.C.); (S.Y.P.); (S.H.P.); (J.-S.K.); (S.-I.L.); (J.-H.P.)
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20
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Abstract
The development of safe and effective vaccines against viruses is central to disease control. With advancements in DNA synthesis technology, the production of synthetic viral genomes has fueled many research efforts that aim to generate attenuated viruses by introducing synonymous mutations. Elucidation of the mechanisms underlying virus attenuation through synonymous mutagenesis is revealing interesting new biology that can be exploited for vaccine development. Here, we review recent advancements in this field of synthetic virology and focus on the molecular mechanisms of attenuation by genetic recoding of viruses. We highlight the action of the zinc finger antiviral protein (ZAP) and RNase L, two proteins involved in the inhibition of viruses enriched for CpG and UpA dinucleotides, that are often the products of virus recoding algorithms. Additionally, we discuss current challenges in the field as well as studies that may illuminate how other host functions, such as translation, are potentially involved in the attenuation of recoded viruses.
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21
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New RNA Structural Elements Identified in the Coding Region of the Coxsackie B3 Virus Genome. Viruses 2020; 12:v12111232. [PMID: 33143071 PMCID: PMC7692623 DOI: 10.3390/v12111232] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 10/27/2020] [Accepted: 10/28/2020] [Indexed: 01/25/2023] Open
Abstract
Here we present a set of new structural elements formed within the open reading frame of the virus, which are highly probable, evolutionarily conserved and may interact with host proteins. This work focused on the coding regions of the CVB3 genome (particularly the V4-, V1-, 2C-, and 3D-coding regions), which, with the exception of the cis-acting replication element (CRE), have not yet been subjected to experimental analysis of their structures. The SHAPE technique, chemical modification with DMS and RNA cleavage with Pb2+, were performed in order to characterize the RNA structure. The experimental results were used to improve the computer prediction of the structural models, whereas a phylogenetic analysis was performed to check universality of the newly identified structural elements for twenty CVB3 genomes and 11 other enteroviruses. Some of the RNA motifs turned out to be conserved among different enteroviruses. We also observed that the 3'-terminal region of the genome tends to dimerize in a magnesium concentration-dependent manner. RNA affinity chromatography was used to confirm RNA-protein interactions hypothesized by database searches, leading to the discovery of several interactions, which may be important for virus propagation.
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22
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Schwartz SL, Park EN, Vachon VK, Danzy S, Lowen AC, Conn GL. Human OAS1 activation is highly dependent on both RNA sequence and context of activating RNA motifs. Nucleic Acids Res 2020; 48:7520-7531. [PMID: 32678884 PMCID: PMC7367156 DOI: 10.1093/nar/gkaa513] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 06/01/2020] [Accepted: 06/04/2020] [Indexed: 12/18/2022] Open
Abstract
2′-5′-Oligoadenylate synthetases (OAS) are innate immune sensors of cytosolic double-stranded RNA (dsRNA) and play a critical role in limiting viral infection. dsRNA binding induces allosteric structural changes in OAS1 that reorganize its catalytic center to promote synthesis of 2′-5′-oligoadenylate and thus activation of endoribonuclease L. Specific RNA sequences and structural motifs can also enhance activation of OAS1 through currently undefined mechanisms. To better understand these drivers of OAS activation, we tested the impact of defined sequence changes within a short dsRNA that strongly activates OAS1. Both in vitro and in human A549 cells, appending a 3′-end single-stranded pyrimidine (3′-ssPy) can strongly enhance OAS1 activation or have no effect depending on its location, suggesting that other dsRNA features are necessary for correct presentation of the motif to OAS1. Consistent with this idea, we also find that the dsRNA binding position is dictated by an established consensus sequence (WWN9WG). Unexpectedly, however, not all sequences fitting this consensus activate OAS1 equivalently, with strong dependence on the identity of both partially conserved (W) and non-conserved (N9) residues. A picture thus emerges in which both specific RNA features and the context in which they are presented dictate the ability of short dsRNAs to activate OAS1.
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Affiliation(s)
- Samantha L Schwartz
- Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, GA 30322, USA.,Graduate Program in Biochemistry, Cell and Developmental Biology, Graduate Division of Biological and Biomedical Sciences, Emory University, USA
| | - Esther N Park
- Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, GA 30322, USA
| | - Virginia K Vachon
- Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, GA 30322, USA.,Graduate Program in Microbiology and Molecular Genetics, Graduate Division of Biological and Biomedical Sciences, Emory University, USA
| | - Shamika Danzy
- Department of Microbiology and Immunology, Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, GA 30322, USA
| | - Anice C Lowen
- Graduate Program in Microbiology and Molecular Genetics, Graduate Division of Biological and Biomedical Sciences, Emory University, USA.,Department of Microbiology and Immunology, Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, GA 30322, USA
| | - Graeme L Conn
- Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, GA 30322, USA.,Graduate Program in Biochemistry, Cell and Developmental Biology, Graduate Division of Biological and Biomedical Sciences, Emory University, USA.,Graduate Program in Microbiology and Molecular Genetics, Graduate Division of Biological and Biomedical Sciences, Emory University, USA
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23
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Eiermann N, Haneke K, Sun Z, Stoecklin G, Ruggieri A. Dance with the Devil: Stress Granules and Signaling in Antiviral Responses. Viruses 2020; 12:v12090984. [PMID: 32899736 PMCID: PMC7552005 DOI: 10.3390/v12090984] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 08/31/2020] [Accepted: 08/31/2020] [Indexed: 02/07/2023] Open
Abstract
Cells have evolved highly specialized sentinels that detect viral infection and elicit an antiviral response. Among these, the stress-sensing protein kinase R, which is activated by double-stranded RNA, mediates suppression of the host translation machinery as a strategy to limit viral replication. Non-translating mRNAs rapidly condensate by phase separation into cytosolic stress granules, together with numerous RNA-binding proteins and components of signal transduction pathways. Growing evidence suggests that the integrated stress response, and stress granules in particular, contribute to antiviral defense. This review summarizes the current understanding of how stress and innate immune signaling act in concert to mount an effective response against virus infection, with a particular focus on the potential role of stress granules in the coordination of antiviral signaling cascades.
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Affiliation(s)
- Nina Eiermann
- Division of Biochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (N.E.); (K.H.); (G.S.)
| | - Katharina Haneke
- Division of Biochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (N.E.); (K.H.); (G.S.)
| | - Zhaozhi Sun
- Department of Infectious Diseases, Molecular Virology, Center for Integrative Infectious Disease Research (CIID), University of Heidelberg, 69120 Heidelberg, Germany;
| | - Georg Stoecklin
- Division of Biochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (N.E.); (K.H.); (G.S.)
| | - Alessia Ruggieri
- Department of Infectious Diseases, Molecular Virology, Center for Integrative Infectious Disease Research (CIID), University of Heidelberg, 69120 Heidelberg, Germany;
- Correspondence:
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24
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Wu L, Xu Y, Zhao H, Li Y. RNase T2 in Inflammation and Cancer: Immunological and Biological Views. Front Immunol 2020; 11:1554. [PMID: 32903619 PMCID: PMC7438567 DOI: 10.3389/fimmu.2020.01554] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 06/12/2020] [Indexed: 01/13/2023] Open
Abstract
The RNase T2 family consists of evolutionarily conserved endonucleases that express in many different species, including animals, plants, protozoans, bacteria, and viruses. The main biological roles of these ribonucleases are cleaving or degrading RNA substrates. They preferentially cleave single-stranded RNA molecules between purine and uridine residues to generate two nucleotide fragments with 2'3'-cyclic phosphate adenosine/guanosine terminus and uridine residue, respectively. Accumulating studies have revealed that RNase T2 is critical for the pathophysiology of inflammation and cancer. In this review, we introduce the distribution, structure, and functions of RNase T2, its differential roles in inflammation and cancer, and the perspective for its research and related applications in medicine.
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Affiliation(s)
- Lei Wu
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China.,Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yanquan Xu
- Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Huakan Zhao
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China.,Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yongsheng Li
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China.,Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, China
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25
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Bartok E, Hartmann G. Immune Sensing Mechanisms that Discriminate Self from Altered Self and Foreign Nucleic Acids. Immunity 2020; 53:54-77. [PMID: 32668228 PMCID: PMC7359798 DOI: 10.1016/j.immuni.2020.06.014] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/15/2020] [Accepted: 06/16/2020] [Indexed: 12/19/2022]
Abstract
All lifeforms have developed highly sophisticated systems equipped to detect altered self and non-self nucleic acids (NA). In vertebrates, NA-sensing receptors safeguard the integrity of the organism by detecting pathogens, dyshomeostasis and damage, and inducing appropriate responses to eliminate pathogens and reconstitute homeostasis. Effector mechanisms include i) immune signaling, ii) restriction of NA functions such as inhibition of mRNA translation, and iii) cell death pathways. An appropriate effector response is necessary for host defense, but dysregulated NA-sensing can lead to devastating autoimmune and autoinflammatory disease. Their inherent biochemical similarity renders the reliable distinction between self NA under homeostatic conditions and altered or exogenous NA particularly challenging. In this review, we provide an overview of recent progress in our understanding of the closely coordinated and regulated network of innate immune receptors, restriction factors, and nucleases to effectively respond to pathogens and maintain host integrity.
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Affiliation(s)
- Eva Bartok
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
| | - Gunther Hartmann
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.
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26
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RNase L Amplifies Interferon Signaling by Inducing Protein Kinase R-Mediated Antiviral Stress Granules. J Virol 2020; 94:JVI.00205-20. [PMID: 32295917 PMCID: PMC7307175 DOI: 10.1128/jvi.00205-20] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 04/08/2020] [Indexed: 02/07/2023] Open
Abstract
Double-stranded RNAs produced during viral infections serve as pathogen-associated molecular patterns (PAMPs) and bind pattern recognition receptors to stimulate IFN production. RNase L is an IFN-regulated endoribonuclease that is activated in virus-infected cells and cleaves single-stranded viral and cellular RNAs. The RNase L-cleaved dsRNAs signal to Rig-like helicases to amplify IFN production. This study identifies a novel role of antiviral stress granules induced by RNase L as an antiviral signaling hub to coordinate the RNA ligands with cognate receptors to mount an effective host response during viral infections. Virus infection leads to activation of the interferon (IFN)-induced endoribonuclease RNase L, which results in degradation of viral and cellular RNAs. Both cellular and viral RNA cleavage products of RNase L bind pattern recognition receptors (PRRs), like retinoic acid-inducible I (Rig-I) and melanoma differentiation-associated protein 5 (MDA5), to further amplify IFN production and antiviral response. Although much is known about the mechanics of ligand binding and PRR activation, how cells coordinate RNA sensing with signaling response and interferon production remains unclear. We show that RNA cleavage products of RNase L activity induce the formation of antiviral stress granules (avSGs) by regulating activation of double-stranded RNA (dsRNA)-dependent protein kinase R (PKR) and recruit the antiviral proteins Rig-I, PKR, OAS, and RNase L to avSGs. Biochemical analysis of purified avSGs showed interaction of a key stress granule protein, G3BP1, with only PKR and Rig-I and not with OAS or RNase L. AvSG assembly during RNase L activation is required for IRF3-mediated IFN production, but not IFN signaling or proinflammatory cytokine induction. Consequently, cells lacking avSG formation or RNase L signaling produced less IFN and showed higher susceptibility during Sendai virus infection, demonstrating the importance of avSGs in RNase L-mediated host defense. We propose a role during viral infection for RNase L-cleaved RNAs in inducing avSGs containing antiviral proteins to provide a platform for efficient interaction of RNA ligands with pattern recognition receptors to enhance IFN production to mount an effective antiviral response. IMPORTANCE Double-stranded RNAs produced during viral infections serve as pathogen-associated molecular patterns (PAMPs) and bind pattern recognition receptors to stimulate IFN production. RNase L is an IFN-regulated endoribonuclease that is activated in virus-infected cells and cleaves single-stranded viral and cellular RNAs. The RNase L-cleaved dsRNAs signal to Rig-like helicases to amplify IFN production. This study identifies a novel role of antiviral stress granules induced by RNase L as an antiviral signaling hub to coordinate the RNA ligands with cognate receptors to mount an effective host response during viral infections.
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Matsumoto M, Takeda Y, Seya T. Targeting Toll-like receptor 3 in dendritic cells for cancer immunotherapy. Expert Opin Biol Ther 2020; 20:937-946. [PMID: 32223572 DOI: 10.1080/14712598.2020.1749260] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Activation of innate immune system is a key step to develop anti-tumor immunity. Antigen-presenting dendritic cells (DCs) cross-present tumor-associated antigens to cytotoxic CD8+ T cells (CTLs). Signaling from pattern-recognition receptors (PRRs) in DCs is required to induce tumor-specific CTLs. AREAS COVERED This review summarizes the properties of PRRs expressed by antigen-presenting DCs, especially TLR3, and provides the recent knowledge of their function in anti-tumor immunity. We also summarize the characteristics of newly-developed TLR3-specific agonist, ARNAX, which efficiently primes DCs to induce anti-tumor immunity without systemic inflammation in mice. EXPERT OPINION In cancer immunotherapy, the induction of tumor-specific CTLs is significant for tumor regression and to augment the efficacy of PD-1/PD-L1 blockade. Non-inflammatory TLR3 adjuvant ARNAX that can induce tumor-specific CTLs without inducing inflammation benefits cancer immunotherapy. Development of appropriate protocols for ARNAX vaccine therapy would be useful to overcome the PD-1/PD-L1 blockade resistance.
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Affiliation(s)
- Misako Matsumoto
- Department of Vaccine Immunology, Graduate School of Medicine, Hokkaido University , Sapporo, Japan.,Nebuta Research Institute for Life Sciences, Aomori University , Aomori, Japan
| | - Yohei Takeda
- Department of Vaccine Immunology, Graduate School of Medicine, Hokkaido University , Sapporo, Japan
| | - Tsukasa Seya
- Department of Vaccine Immunology, Graduate School of Medicine, Hokkaido University , Sapporo, Japan.,Nebuta Research Institute for Life Sciences, Aomori University , Aomori, Japan
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The Cellular Localization of the p42 and p46 Oligoadenylate Synthetase 1 Isoforms and Their Impact on Mitochondrial Respiration. Viruses 2019; 11:v11121122. [PMID: 31817188 PMCID: PMC6950736 DOI: 10.3390/v11121122] [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: 10/15/2019] [Revised: 11/28/2019] [Accepted: 12/02/2019] [Indexed: 12/12/2022] Open
Abstract
The importance of the IFN-induced oligoadenylate synthetase (OAS) proteins and the OAS/RNase L pathway in the innate response against viral pathogens is well-established, however the observed differences in anti-viral activity between the human OAS1 p46 and p42 isoforms are not fully understood. The protein expression of these isoforms is determined by the SNP rs10774671, either being an A or a G allele resulting in expression of either the p42 or the p46 isoform. Using fluorescence microscopy and immunoblot analysis of fractionated cell samples, we show here that the CaaX motif is of key importance to the cellular localization. The OAS1 p42 isoform is mainly located in the cytosol, whereas the p46 isoform with a C-terminal CaaX motif is translocated to membranous organelles, like the mitochondria. We furthermore observed differences between p42 and p46 in their effect on mitochondrial physiology using high resolution respirometry and fluorometry. Overexpression of OAS1 p42 and IFN-β treatment of HeLa cells (AA genotype) resulted in significantly increased respiration, which was not seen with p46 overexpression. The difference in subcellular localization and mitochondrial effect of these two OAS1 isoforms might help to explain the anti-viral mechanisms that differentiate these proteins.
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Brisse M, Ly H. Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5. Front Immunol 2019; 10:1586. [PMID: 31379819 PMCID: PMC6652118 DOI: 10.3389/fimmu.2019.01586] [Citation(s) in RCA: 238] [Impact Index Per Article: 39.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 06/25/2019] [Indexed: 12/12/2022] Open
Abstract
RIG-I (Retinoic acid-inducible gene I) and MDA5 (Melanoma Differentiation-Associated protein 5), collectively known as the RIG-I-like receptors (RLRs), are key protein sensors of the pathogen-associated molecular patterns (PAMPs) in the form of viral double-stranded RNA (dsRNA) motifs to induce expression of type 1 interferons (IFN1) (IFNα and IFNβ) and other pro-inflammatory cytokines during the early stage of viral infection. While RIG-I and MDA5 share many genetic, structural and functional similarities, there is increasing evidence that they can have significantly different strategies to recognize different pathogens, PAMPs, and in different host species. This review article discusses the similarities and differences between RIG-I and MDA5 from multiple perspectives, including their structures, evolution and functional relationships with other cellular proteins, their differential mechanisms of distinguishing between host and viral dsRNAs and interactions with host and viral protein factors, and their immunogenic signaling. A comprehensive comparative analysis can help inform future studies of RIG-I and MDA5 in order to fully understand their functions in order to optimize potential therapeutic approaches targeting them.
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Affiliation(s)
- Morgan Brisse
- Biochemistry, Molecular Biology, and Biophysics Graduate Program, University of Minnesota, Twin Cities, St. Paul, MN, United States
- Department of Veterinary & Biomedical Sciences, University of Minnesota, Twin Cities, St. Paul, MN, United States
| | - Hinh Ly
- Department of Veterinary & Biomedical Sciences, University of Minnesota, Twin Cities, St. Paul, MN, United States
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Schwartz SL, Conn GL. RNA regulation of the antiviral protein 2'-5'-oligoadenylate synthetase. WILEY INTERDISCIPLINARY REVIEWS-RNA 2019; 10:e1534. [PMID: 30989826 DOI: 10.1002/wrna.1534] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/12/2019] [Accepted: 03/14/2019] [Indexed: 12/25/2022]
Abstract
The innate immune system is a broad collection of critical intra- and extra-cellular processes that limit the infectivity of diverse pathogens. The 2'-5'-oligoadenylate synthetase (OAS) family of enzymes are important sensors of cytosolic double-stranded RNA (dsRNA) that play a critical role in limiting viral infection by activating the latent ribonuclease (RNase L) to halt viral replication and establish an antiviral state. Attesting to the importance of the OAS/RNase L pathway, diverse viruses have developed numerous distinct strategies to evade the effects of OAS activation. How OAS proteins are regulated by viral or cellular RNAs is not fully understood but several recent studies have provided important new insights into the molecular mechanisms of OAS activation by dsRNA. Other studies have revealed unanticipated features of RNA sequence and structure that strongly enhance activation of at least one OAS family member. While these discoveries represent important advances, they also underscore the fact that much remains to be learned about RNA-mediated regulation of the OAS/RNase L pathway. In particular, defining the full complement of RNA molecular signatures that activate OAS is essential to our understanding of how these proteins maximize their protective role against pathogens while still accurately discriminating host molecules to avoid inadvertent activation by cellular RNAs. A more complete knowledge of OAS regulation may also serve as a foundation for the development of novel antiviral therapeutic strategies and lead the way to a deeper understanding of currently unappreciated cellular functions of the OAS/RNase L pathway in the absence of infection. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications Translation > Translation Regulation.
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Affiliation(s)
- Samantha L Schwartz
- Department of Biochemistry, Emory University School of Medicine and Graduate Program in Biochemistry, Cell and Developmental Biology (BCDB), Atlanta, Georgia
| | - Graeme L Conn
- Department of Biochemistry, Emory University School of Medicine and Graduate Program in Biochemistry, Cell and Developmental Biology (BCDB), Atlanta, Georgia
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Abstract
Detection of double-stranded RNAs (dsRNAs) is a central mechanism of innate immune defense in many organisms. We here discuss several families of dsRNA-binding proteins involved in mammalian antiviral innate immunity. These include RIG-I-like receptors, protein kinase R, oligoadenylate synthases, adenosine deaminases acting on RNA, RNA interference systems, and other proteins containing dsRNA-binding domains and helicase domains. Studies suggest that their functions are highly interdependent and that their interdependence could offer keys to understanding the complex regulatory mechanisms for cellular dsRNA homeostasis and antiviral immunity. This review aims to highlight their interconnectivity, as well as their commonalities and differences in their dsRNA recognition mechanisms.
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Affiliation(s)
- Sun Hur
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA; .,Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, USA
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Intracellular RNA Sensing in Mammalian Cells: Role in Stress Response and Cancer Therapies. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2019; 344:31-89. [DOI: 10.1016/bs.ircmb.2018.08.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Tatematsu M, Funami K, Seya T, Matsumoto M. Extracellular RNA Sensing by Pattern Recognition Receptors. J Innate Immun 2018; 10:398-406. [PMID: 30404092 PMCID: PMC6784046 DOI: 10.1159/000494034] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 09/25/2018] [Accepted: 09/25/2018] [Indexed: 12/11/2022] Open
Abstract
RNA works as a genome and messenger in RNA viruses, and it sends messages in most of the creatures of the Earth, including viruses, bacteria, fungi, plants, and animals. The human innate immune system has evolved to detect single- and double-stranded RNA molecules from microbes by pattern recognition receptors and induce defense reactions against infections such as the production of type I interferons and inflammatory cytokines. To avoid cytokine toxicity causing chronic inflammation or autoimmunity by sensing self-RNA, the activation of RNA sensors is strictly regulated. All of the Toll-like receptors that recognize RNA are localized to endosomes/lysosomes, which require internalization of RNA for sensing through an endocytic pathway. RIG-I-like receptors sense RNA in cytosol. These receptors are expressed in a cell type-specific fashion, enabling sensing of RNA for a wide range of microbial invasions. At the same time, both endosomal and cytoplasmic receptors have strategies to respond only to RNA of pathogenic microorganisms or dying cells. RNA are potential vaccine adjuvants for immune enhancement against cancer and provide a benefit for vaccinations. Understanding the detailed molecular mechanisms of the RNA-sensing system will help us to broaden the clinical utility of RNA adjuvants for patients with incurable diseases.
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Affiliation(s)
- Megumi Tatematsu
- Department of Vaccine Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
- Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Munich, Germany
| | - Kenji Funami
- Department of Vaccine Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Tsukasa Seya
- Department of Vaccine Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Misako Matsumoto
- Department of Vaccine Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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Cao X, Xue YJ, Du JL, Xu Q, Yang XC, Zeng Y, Wang BB, Wang HZ, Liu J, Cai KZ, Ma ZR. Induction and Suppression of Innate Antiviral Responses by Hepatitis A Virus. Front Microbiol 2018; 9:1865. [PMID: 30174659 PMCID: PMC6107850 DOI: 10.3389/fmicb.2018.01865] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Accepted: 07/25/2018] [Indexed: 12/25/2022] Open
Abstract
Hepatitis A virus (HAV) belongs to the family Picornaviridae. It is the pathogen of acute viral hepatitis caused by fecal-oral transmission. RNA viruses are sensed by pathogen-associated pattern recognition receptors (PRRs) such as Toll-like receptor 3 (TLR3), retinoic acid-inducible gene I (RIG-I), and melanoma differentiation-associated gene 5 (MDA5). PRR activation leads to production of type 1 interferon (IFN-α/β), serving as the first line of defense against viruses. However, HAV has developed various strategies to compromise the innate immune system and promote viral propagation within the host cells. The long coevolution of HAV in hosts has prompted the development of effective immune antagonism strategies that actively fight against host antiviral responses. Proteases encoded by HAV can cleave the mitochondrial antiviral signaling protein (MAVS, also known as IPS-1, VISA, or Cardif), TIR domain- containing adaptor inducing IFN-β (TRIF, also known as TICAM-1) and nuclear factor-κB (NF-κB) essential modulator (NEMO), which are key adaptor proteins in RIG-I-like receptor (RLR), TLR3 and NF-κB signaling, respectively. In this mini-review, we summarize all the recent progress on the interaction between HAV and the host, especially focusing on how HAV abrogates the antiviral effects of the innate immune system.
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Affiliation(s)
- Xin Cao
- College of Life Science and Engineering, Northwest Minzu University, Engineering & Technology Research Center for Animal Cell, Lanzhou, China
- Key Laboratory of Bioengineering & Biotechnology of State Ethnic Affairs Commission, Lanzhou, China
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Yu-jia Xue
- College of Life Science and Engineering, Northwest Minzu University, Engineering & Technology Research Center for Animal Cell, Lanzhou, China
- Key Laboratory of Bioengineering & Biotechnology of State Ethnic Affairs Commission, Lanzhou, China
| | - Jiang-long Du
- College of Life Science and Engineering, Northwest Minzu University, Engineering & Technology Research Center for Animal Cell, Lanzhou, China
- Key Laboratory of Bioengineering & Biotechnology of State Ethnic Affairs Commission, Lanzhou, China
| | - Qiang Xu
- College of Life Science and Engineering, Northwest Minzu University, Engineering & Technology Research Center for Animal Cell, Lanzhou, China
- Key Laboratory of Bioengineering & Biotechnology of State Ethnic Affairs Commission, Lanzhou, China
| | - Xue-cai Yang
- College of Life Science and Engineering, Northwest Minzu University, Engineering & Technology Research Center for Animal Cell, Lanzhou, China
- Key Laboratory of Bioengineering & Biotechnology of State Ethnic Affairs Commission, Lanzhou, China
| | - Yan Zeng
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Bo-bo Wang
- College of Life Science and Engineering, Northwest Minzu University, Engineering & Technology Research Center for Animal Cell, Lanzhou, China
- Key Laboratory of Bioengineering & Biotechnology of State Ethnic Affairs Commission, Lanzhou, China
| | - Hai-zhen Wang
- Hebi Precision Medical Research Institute, People's Hospital of Hebi, Hebi, China
| | - Jing Liu
- Department of Medical OncologyPeople's Hospital of Hebi, Hebi, China
| | - Kui-zheng Cai
- College of Life Science and Engineering, Northwest Minzu University, Engineering & Technology Research Center for Animal Cell, Lanzhou, China
- Key Laboratory of Bioengineering & Biotechnology of State Ethnic Affairs Commission, Lanzhou, China
| | - Zhong-ren Ma
- College of Life Science and Engineering, Northwest Minzu University, Engineering & Technology Research Center for Animal Cell, Lanzhou, China
- Key Laboratory of Bioengineering & Biotechnology of State Ethnic Affairs Commission, Lanzhou, China
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Zhang Y, Dittmer DP, Mieczkowski PA, Host KM, Fusco WG, Duncan JA, Damania B. RIG-I Detects Kaposi's Sarcoma-Associated Herpesvirus Transcripts in a RNA Polymerase III-Independent Manner. mBio 2018; 9:e00823-18. [PMID: 29970461 PMCID: PMC6030556 DOI: 10.1128/mbio.00823-18] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 06/04/2018] [Indexed: 12/24/2022] Open
Abstract
Retinoic acid-inducible gene I (RIG-I) is a cytosolic pathogen recognition receptor that initiates the innate immune response against many RNA viruses. We previously showed that RIG-I restricts Kaposi's sarcoma-associated herpesvirus (KSHV) reactivation (J. A. West et al., J Virol 88:5778-5787, 2014, https://doi.org/10.1128/JVI.03226-13). In this study, we report that KSHV stimulates the RIG-I signaling pathway in a RNA polymerase (Pol) III-independent manner and subsequently induces type I interferon (IFN) responses. Knockdown or inhibition of RNA Pol III had no effect on beta interferon (IFN-β) induction by KSHV. By using high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP) approach, we identified multiple KSHV regions that give rise to RNA fragments binding to RIG-I, such as ORF810420-10496, Repeat region (LIR1)119059-119204, and ORF2543561-43650 The sequence dissimilarity between these fragments suggests that RIG-I detects a particular structure rather than a specific sequence motif. Synthesized ORF810420-10496 RNA stimulated RIG-I-dependent but RNA Pol III-independent IFN-β signaling. In summary, several KSHV RNAs are sensed by RIG-I in a RNA Pol III-independent manner.IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Innate immune responses against viral infections, especially the induction of type I interferon, are critical for limiting the replication of viruses. Retinoic acid-inducible gene I (RIG-I), a cytosolic RNA helicase sensor, plays a significant role in the induction of type I interferon responses following viral infection. Here, we identified multiple RNA regions in KSHV as potential virus ligands that bind to RIG-I and stimulate RIG-I-dependent but RNA Pol III-independent IFN-β signaling. Our results expand the role of RIG-I by providing an example of a DNA virus activating a canonical RNA-sensing pathway.
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Affiliation(s)
- Yugen Zhang
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Dirk P Dittmer
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Piotr A Mieczkowski
- High Throughput Sequencing Facility, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Kurtis M Host
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - William G Fusco
- Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Joseph A Duncan
- Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Blossom Damania
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Abstract
Pattern recognition receptors (PRRs) survey intra- and extracellular spaces for pathogen-associated molecular patterns (PAMPs) within microbial products of infection. Recognition and binding to cognate PAMP ligand by specific PRRs initiates signaling cascades that culminate in a coordinated intracellular innate immune response designed to control infection. In particular, our immune system has evolved specialized PRRs to discriminate viral nucleic acid from host. These are critical sensors of viral RNA to trigger innate immunity in the vertebrate host. Different families of PRRs of virus infection have been defined and reveal a diversity of PAMP specificity for wide viral pathogen coverage to recognize and extinguish virus infection. In this review, we discuss recent insights in pathogen recognition by the RIG-I-like receptors, related RNA helicases, Toll-like receptors, and other RNA sensor PRRs, to present emerging themes in innate immune signaling during virus infection.
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Affiliation(s)
- Kwan T Chow
- Center for Innate Immunity and Immune Disease and Department of Immunology, University of Washington, Seattle, Washington 98109, USA; , ,
| | - Michael Gale
- Center for Innate Immunity and Immune Disease and Department of Immunology, University of Washington, Seattle, Washington 98109, USA; , ,
| | - Yueh-Ming Loo
- Center for Innate Immunity and Immune Disease and Department of Immunology, University of Washington, Seattle, Washington 98109, USA; , ,
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Gebhardt A, Laudenbach BT, Pichlmair A. Discrimination of Self and Non-Self Ribonucleic Acids. J Interferon Cytokine Res 2018; 37:184-197. [PMID: 28475460 DOI: 10.1089/jir.2016.0092] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Most virus infections are controlled through the innate and adaptive immune system. A surprisingly limited number of so-called pattern recognition receptors (PRRs) have the ability to sense a large variety of virus infections. The reason for the broad activity of PRRs lies in the ability to recognize viral nucleic acids. These nucleic acids lack signatures that are present in cytoplasmic cellular nucleic acids and thereby marking them as pathogen-derived. Accumulating evidence suggests that these signatures, which are predominantly sensed by a class of PRRs called retinoic acid-inducible gene I (RIG-I)-like receptors and other proteins, are not unique to viruses but rather resemble immature forms of cellular ribonucleic acids generated by cellular polymerases. RIG-I-like receptors, and other cellular antiviral proteins, may therefore have mainly evolved to sense nonprocessed nucleic acids typically generated by primitive organisms and pathogens. This capability has not only implications on induction of antiviral immunity but also on the function of cellular proteins to handle self-derived RNA with stimulatory potential.
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Affiliation(s)
- Anna Gebhardt
- Innate Immunity Laboratory, Max-Planck Institute of Biochemistry , Munich, Germany
| | | | - Andreas Pichlmair
- Innate Immunity Laboratory, Max-Planck Institute of Biochemistry , Munich, Germany
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Molecular requirements for sensing of intracellular microbial nucleic acids by the innate immune system. Cytokine 2017; 98:4-14. [DOI: 10.1016/j.cyto.2016.10.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 10/11/2016] [Indexed: 12/24/2022]
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Fros JJ, Dietrich I, Alshaikhahmed K, Passchier TC, Evans DJ, Simmonds P. CpG and UpA dinucleotides in both coding and non-coding regions of echovirus 7 inhibit replication initiation post-entry. eLife 2017; 6:e29112. [PMID: 28960178 PMCID: PMC5659819 DOI: 10.7554/elife.29112] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 09/28/2017] [Indexed: 12/23/2022] Open
Abstract
Most vertebrate and plant RNA and small DNA viruses suppress genomic CpG and UpA dinucleotide frequencies, apparently mimicking host mRNA composition. Artificially increasing CpG/UpA dinucleotides attenuates viruses through an entirely unknown mechanism. Using the echovirus 7 (E7) model in several cell types, we show that the restriction in E7 replication in mutants with increased CpG/UpA dinucleotides occurred immediately after viral entry, with incoming virions failing to form replication complexes. Sequences of CpG/UpA-high virus stocks showed no evidence of increased mutational errors that would render them replication defective, these viral RNAs were not differentially sequestered in cytoplasmic stress granules nor did they induce a systemic antiviral state. Importantly, restriction was not mediated through effects on translation efficiency since replicons with high CpG/UpA sequences inserted into a non-coding region were similarly replication defective. Host-cells thus possess intrinsic defence pathways that prevent replication of viruses with increased CpG/UpA frequencies independently of codon usage.
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Affiliation(s)
- Jelke Jan Fros
- Peter Medawar Building for Pathogen Research, Nuffield Department of MedicineUniversity of OxfordOxfordUnited Kingdom
| | - Isabelle Dietrich
- Peter Medawar Building for Pathogen Research, Nuffield Department of MedicineUniversity of OxfordOxfordUnited Kingdom
| | - Kinda Alshaikhahmed
- Peter Medawar Building for Pathogen Research, Nuffield Department of MedicineUniversity of OxfordOxfordUnited Kingdom
| | - Tim Casper Passchier
- Peter Medawar Building for Pathogen Research, Nuffield Department of MedicineUniversity of OxfordOxfordUnited Kingdom
| | - David John Evans
- Biomedical Sciences Research ComplexUniversity of St AndrewsSt AndrewsUnited Kingdom
| | - Peter Simmonds
- Peter Medawar Building for Pathogen Research, Nuffield Department of MedicineUniversity of OxfordOxfordUnited Kingdom
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40
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Abstract
RIG-I-like receptors (RLRs) are cytosolic innate immune sensors that detect pathogenic RNA and induce a systemic antiviral response. During the last decade, many studies focused on their molecular characterization and the identification of RNA agonists. Therefore, it became more and more clear that RLR activation needs to be carefully regulated, because constitutive signaling or detection of endogenous RNA through loss of specificity is detrimental. Here, we review the current understanding of RLR activation and selectivity. We specifically focus upon recent findings on the function of the helicase domain in discriminating between different RNAs, and whose malfunctioning causes serious autoimmune diseases.
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Affiliation(s)
- Charlotte Lässig
- From the Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, 81377 Munich and
| | - Karl-Peter Hopfner
- From the Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, 81377 Munich and
- the Center for Integrated Protein Sciences, 81377 Munich, Germany
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Ireton RC, Wilkins C, Gale M. RNA PAMPs as Molecular Tools for Evaluating RIG-I Function in Innate Immunity. Methods Mol Biol 2017; 1656:119-129. [PMID: 28808965 DOI: 10.1007/978-1-4939-7237-1_6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Pathogen recognition receptors (PRR)s and their cognate pathogen-associated molecular pattern (PAMP) represent the basis of innate immune activation and immune response induction driven by the host-pathogen interaction that occurs during microbial infection in humans and other animals. For RNA virus infection such as hepatitis C virus (HCV) and others, specific motifs within viral RNA mark it as nonself and visible to the host as a PAMP through interaction with RIG-I-like receptors including retinoic inducible gene-I (RIG-I). Here, we present methods for producing and using HCV PAMP RNA as a molecular tool to study RIG-I and its signaling pathway, both in vitro and in vivo, in innate immune regulation.
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Affiliation(s)
- Renee C Ireton
- Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington School of Medicine, E383, 750 Republican Street, Seattle, WA, 98109, USA
| | - Courtney Wilkins
- Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington School of Medicine, E383, 750 Republican Street, Seattle, WA, 98109, USA
| | - Michael Gale
- Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington School of Medicine, E383, 750 Republican Street, Seattle, WA, 98109, USA.
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Du X, Pan T, Xu J, Zhang Y, Song W, Yi Z, Yuan Z. Hepatitis C virus replicative double-stranded RNA is a potent interferon inducer that triggers interferon production through MDA5. J Gen Virol 2016; 97:2868-2882. [PMID: 27655134 DOI: 10.1099/jgv.0.000607] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
The cytoplasmic RNA sensors, retinoic acid-inducible gene I and melanoma differentiation-associated gene 5, play crucial roles in innate sensing of hepatitis C virus (HCV). However, the exact identity of the IFN inducer generated during HCV infection is poorly understood. To identify the IFN inducer, we extracted the RNAs from HCV-replicating cells and introduced these into IFN signalling-competent cells to examine IFN production. RNAs isolated from HCV-replicating cells triggered robust IFN-β and IFN-λ production in Huh7 cells in a viral replication-dependent manner, preferentially through the melanoma differentiation-associated gene 5 but not through the retinoic acid-inducible gene I-mediated pathway. The IFN-inducing capacity of HCV RNA survived after calf intestinal alkaline phosphatase and ssRNA-specific S1 nuclease treatment, but was completely eliminated by dsRNA-specific RNase III digestion, suggesting that viral replicative dsRNA is an IFN inducer. Furthermore, HCV viral RNA extracted from replicating cells was sensitive to 5'-monophosphate-dependent 5'→3' exonuclease (TER) digestion, suggesting that the HCV genome lacks a 5'-triphosphate or -diphosphate. In semi-permeabilized cells, the HCV IFN inducer primarily resided in an enclosed membranous structure that protects the IFN inducer from RNase digestion. Taken together, we identified HCV replicative dsRNA as a viral IFN inducer enclosed within the viral replication factory.
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Affiliation(s)
- Xiaoting Du
- Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, PR China
| | - Tingting Pan
- Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, PR China
| | - Jun Xu
- Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, PR China
| | - Yang Zhang
- Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, PR China
| | - Wuhui Song
- Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, PR China
| | - Zhigang Yi
- Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, PR China
| | - Zhenghong Yuan
- Institute of Biomedical Sciences, Fudan University, Shanghai, PR China.,Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, PR China.,Institute of Medical Microbiology, Fudan University, Shanghai, PR China
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Abstract
Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) are the most severe coronavirus (CoV)-associated diseases in humans. The causative agents, SARS-CoV and MERS-CoV, are of zoonotic origin but may be transmitted to humans, causing severe and often fatal respiratory disease in their new host. The two coronaviruses are thought to encode an unusually large number of factors that allow them to thrive and replicate in the presence of efficient host defense mechanisms, especially the antiviral interferon system. Here, we review the recent progress in our understanding of the strategies that highly pathogenic coronaviruses employ to escape, dampen, or block the antiviral interferon response in human cells.
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Affiliation(s)
- E Kindler
- University of Bern, Bern, Switzerland; Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
| | - V Thiel
- University of Bern, Bern, Switzerland; Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
| | - F Weber
- Institute of Virology, Faculty of Veterinary Medicine, Justus Liebig University Giessen, Giessen, Germany.
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Gusho E, Baskar D, Banerjee S. New advances in our understanding of the "unique" RNase L in host pathogen interaction and immune signaling. Cytokine 2016; 133:153847. [PMID: 27595182 PMCID: PMC7128181 DOI: 10.1016/j.cyto.2016.08.009] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2016] [Revised: 08/08/2016] [Accepted: 08/08/2016] [Indexed: 12/22/2022]
Abstract
Ever since the discovery of the existence of an interferon (IFN)-regulated ribonuclease, significant advances have been made in understanding the mechanism and associated regulatory effects of its action. What had been studied initially as a "unique" endoribonuclease is currently known as ribonuclease L (RNase L where "L" stands for latent). Some of the key developments include discovery of the RNase L signaling pathway, its structural characterization, and its molecular cloning. RNase L has been implicated in antiviral and antibacterial defense, as well as in hereditary prostate cancer. RNase L is activated by 2'-5' linked oligoadenylates (2-5A), which are synthesized by the oligoadenylate synthetases (OASs), a family of IFN-regulated pathogen recognition receptors that sense double-stranded RNAs. Activated RNase L cleaves single stranded RNAs, including viral RNAs and cellular RNAs. The catalytic activity of RNase L has been found to lead into the activation of several cellular signaling pathways, including those involved in autophagy, apoptosis, IFN-β production, NLRP3 inflammasome activation leading to IL-1β secretion, inhibition of cell migration, and cell adhesion. In this review, we will highlight the newest advances in our understanding of the catalytic role of RNase L in the context of different cellular pathways and extend the scope of these findings to discussion of potential therapeutic targets for antimicrobial drug development.
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Affiliation(s)
- Elona Gusho
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue Cleveland, OH 44195, USA
| | - Danika Baskar
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue Cleveland, OH 44195, USA; Pediatrics Division Office, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA(1)
| | - Shuvojit Banerjee
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue Cleveland, OH 44195, USA.
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Valadão ALC, Aguiar RS, de Arruda LB. Interplay between Inflammation and Cellular Stress Triggered by Flaviviridae Viruses. Front Microbiol 2016; 7:1233. [PMID: 27610098 PMCID: PMC4996823 DOI: 10.3389/fmicb.2016.01233] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 07/25/2016] [Indexed: 12/15/2022] Open
Abstract
The Flaviviridae family comprises several human pathogens, including Dengue, Zika, Yellow Fever, West Nile, Japanese Encephalitis viruses, and Hepatitis C Virus. Those are enveloped, single-stranded positive sense RNA viruses, which replicate mostly in intracellular compartments associated to endoplasmic reticulum (ER) and Golgi complex. Virus replication results in abundant viral RNAs and proteins, which are recognized by cellular mechanisms evolved to prevent virus infection, resulting in inflammation and stress responses. Virus RNA molecules are sensed by Toll-like receptors (TLRs), RIG-I-like receptors (RIG-I and MDA5) and RNA-dependent protein kinases (PKR), inducing the production of inflammatory mediators and interferons. Simultaneously, the synthesis of virus RNA and proteins are distinguished in different compartments such as mitochondria, ER and cytoplasmic granules, triggering intracellular stress pathways, including oxidative stress, unfolded protein response pathway, and stress granules assembly. Here, we review the new findings that connect the inflammatory pathways to cellular stress sensors and the strategies of Flaviviridae members to counteract these cellular mechanisms and escape immune response.
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Affiliation(s)
- Ana L C Valadão
- Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil
| | - Renato S Aguiar
- Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil
| | - Luciana B de Arruda
- Departamento de Virologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil
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Banerjee S. RNase L and the NLRP3-inflammasome: An old merchant in a new trade. Cytokine Growth Factor Rev 2016; 29:63-70. [PMID: 26987611 DOI: 10.1016/j.cytogfr.2016.02.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 02/27/2016] [Indexed: 12/12/2022]
Abstract
The type I/III interferon (IFN)-inducible 2'-5'- oligoadenylate synthetase (OAS)/endoribonuclease L (RNase L) is a classical innate immune pathway that has been implicated in antiviral and antibacterial defense and also in hereditary prostate cancer. The OAS/RNase L pathway is activated when OAS senses double-stranded RNA and catalyzes the synthesis of 2'-5' linked oligodenylates (2-5A) from ATP. 2-5A then binds and activates RNase L, resulting cleavage of single-stranded RNAs. RNase L cleavage products are capable of activating RIG-like receptors such as RIG-I and MDA5 that leads to IFN-β expression during viral infection. Our recent findings suggest that beside the RLR pathway, RNase L cleavage products can also activate the NLRP3-inflammasome pathway, which requires DHX33 (DExD/H-box helicase) and the mitochondrial adaptor protein MAVS. Here we discuss this newly identified role of OAS-RNase L pathway in regulation of inflammasome signaling as an alternative antimicrobial mechanism that has potential as a target for development of new broad-spectrum antimicrobial and anti-inflammatory therapies.
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Affiliation(s)
- Shuvojit Banerjee
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
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47
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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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Aguiar ERGR, Olmo RP, Marques JT. Virus-derived small RNAs: molecular footprints of host-pathogen interactions. WILEY INTERDISCIPLINARY REVIEWS-RNA 2016; 7:824-837. [PMID: 27170499 PMCID: PMC7169819 DOI: 10.1002/wrna.1361] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 04/06/2016] [Accepted: 04/07/2016] [Indexed: 01/21/2023]
Abstract
Viruses are obligatory intracellular parasites that require the host machinery to replicate. During their replication cycle, viral RNA intermediates can be recognized and degraded by different antiviral mechanisms that include RNA decay, RNA interference, and RNase L pathways. As a consequence of viral RNA degradation, infected cells can accumulate virus‐derived small RNAs at high levels compared to cellular molecules. These small RNAs are imprinted with molecular characteristics that reflect their origin. First, small RNAs can be used to reconstruct viral sequences and identify the virus from which they originated. Second, other molecular features of small RNAs such as size, polarity, and base preferences depend on the type of viral substrate and host mechanism of degradation. Thus, the pattern of small RNAs generated in infected cells can be used as a molecular footprint to identify and characterize viruses independent on sequence homology searches against known references. Hence, sequencing of small RNAs obtained from infected cells enables virus discovery and characterization using both sequence‐dependent strategies and novel pattern‐based approaches. Recent studies are helping unlock the full application of small RNA sequencing for virus discovery and characterization. WIREs RNA 2016, 7:824–837. doi: 10.1002/wrna.1361 This article is categorized under:
RNA Processing > Processing of Small RNAs RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Methods > RNA Analyses In Vitro and In Silico
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Affiliation(s)
| | - Roenick Proveti Olmo
- Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - João Trindade Marques
- Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
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Sanchez David RY, Combredet C, Sismeiro O, Dillies MA, Jagla B, Coppée JY, Mura M, Guerbois Galla M, Despres P, Tangy F, Komarova AV. Comparative analysis of viral RNA signatures on different RIG-I-like receptors. eLife 2016; 5:e11275. [PMID: 27011352 PMCID: PMC4841775 DOI: 10.7554/elife.11275] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 03/24/2016] [Indexed: 12/17/2022] Open
Abstract
The RIG-I-like receptors (RLRs) play a major role in sensing RNA virus infection to initiate and modulate antiviral immunity. They interact with particular viral RNAs, most of them being still unknown. To decipher the viral RNA signature on RLRs during viral infection, we tagged RLRs (RIG-I, MDA5, LGP2) and applied tagged protein affinity purification followed by next-generation sequencing (NGS) of associated RNA molecules. Two viruses with negative- and positive-sense RNA genome were used: measles (MV) and chikungunya (CHIKV). NGS analysis revealed that distinct regions of MV genome were specifically recognized by distinct RLRs: RIG-I recognized defective interfering genomes, whereas MDA5 and LGP2 specifically bound MV nucleoprotein-coding region. During CHIKV infection, RIG-I associated specifically to the 3' untranslated region of viral genome. This study provides the first comparative view of the viral RNA ligands for RIG-I, MDA5 and LGP2 in the presence of infection.
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Affiliation(s)
- Raul Y Sanchez David
- Unité de Génomique Virale et Vaccination, Institut Pasteur, CNRS UMR-3569, Paris, France
- Ecole doctorale, Biochimie, Biothérapies, Biologie Moléculaire et Infectiologie (B3MI), Université Paris Diderot - Paris 7, Paris, France
| | - Chantal Combredet
- Unité de Génomique Virale et Vaccination, Institut Pasteur, CNRS UMR-3569, Paris, France
| | - Odile Sismeiro
- Transcriptome and Epigenome, BioMics Pole, Center for Innovation and Technological Research, Institut Pasteur, Paris, France
| | - Marie-Agnès Dillies
- Transcriptome and Epigenome, BioMics Pole, Center for Innovation and Technological Research, Institut Pasteur, Paris, France
| | - Bernd Jagla
- Transcriptome and Epigenome, BioMics Pole, Center for Innovation and Technological Research, Institut Pasteur, Paris, France
| | - Jean-Yves Coppée
- Transcriptome and Epigenome, BioMics Pole, Center for Innovation and Technological Research, Institut Pasteur, Paris, France
| | - Marie Mura
- Unité de Génomique Virale et Vaccination, Institut Pasteur, CNRS UMR-3569, Paris, France
- Unité Interactions Hôte-Agents Pathogens, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France
| | | | - Philippe Despres
- Technology Platform CYROI, University of Reunion Island, Saint-Clotilde, France
| | - Frédéric Tangy
- Unité de Génomique Virale et Vaccination, Institut Pasteur, CNRS UMR-3569, Paris, France
| | - Anastassia V Komarova
- Unité de Génomique Virale et Vaccination, Institut Pasteur, CNRS UMR-3569, Paris, France
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50
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Sensing of latent EBV infection through exosomal transfer of 5'pppRNA. Proc Natl Acad Sci U S A 2016; 113:E587-96. [PMID: 26768848 DOI: 10.1073/pnas.1518130113] [Citation(s) in RCA: 129] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Complex interactions between DNA herpesviruses and host factors determine the establishment of a life-long asymptomatic latent infection. The lymphotropic Epstein-Barr virus (EBV) seems to avoid recognition by innate sensors despite massive transcription of immunostimulatory small RNAs (EBV-EBERs). Here we demonstrate that in latently infected B cells, EBER1 transcripts interact with the lupus antigen (La) ribonucleoprotein, avoiding cytoplasmic RNA sensors. However, in coculture experiments we observed that latent-infected cells trigger antiviral immunity in dendritic cells (DCs) through selective release and transfer of RNA via exosomes. In ex vivo tonsillar cultures, we observed that EBER1-loaded exosomes are preferentially captured and internalized by human plasmacytoid DCs (pDCs) that express the TIM1 phosphatidylserine receptor, a known viral- and exosomal target. Using an EBER-deficient EBV strain, enzymatic removal of 5'ppp, in vitro transcripts, and coculture experiments, we established that 5'pppEBER1 transfer via exosomes drives antiviral immunity in nonpermissive DCs. Lupus erythematosus patients suffer from elevated EBV load and activated antiviral immunity, in particular in skin lesions that are infiltrated with pDCs. We detected high levels of EBER1 RNA in such skin lesions, as well as EBV-microRNAs, but no intact EBV-DNA, linking non-cell-autonomous EBER1 presence with skin inflammation in predisposed individuals. Collectively, our studies indicate that virus-modified exosomes have a physiological role in the host-pathogen stand-off and may promote inflammatory disease.
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