1
|
Yu M, Zhang L, Wang Y, Wang S, Liu Y, Liu P, Chen Y, Guo R, Meng L, Zhang T, Fan W, Qi X, Duan Y, Zhang Y, Cui H, Gao Y. N6-methyladenosine modification of the subgroup J avian leukosis viral RNAs attenuates host innate immunity via MDA5 signaling. PLoS Pathog 2025; 21:e1013064. [PMID: 40198675 PMCID: PMC12043233 DOI: 10.1371/journal.ppat.1013064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 04/30/2025] [Accepted: 03/21/2025] [Indexed: 04/10/2025] Open
Abstract
Subgroup J avian leukosis virus (ALV-J), a retrovirus, elicits immunosuppression and persistent infections in chickens. Although it is widely acknowledged that ALV-J can evade the host's innate immune defenses, the mechanisms behind this immune evasion remain elusive. N6-methyladenosine (m6A), the most prevalent internal RNA modification, plays a role in innate immune evasion. Our research identified ALV-J as an inefficient stimulator of innate immunity in vitro and in vivo, with its genomic RNA featuring m6A modifications predominantly in the envelope protein (Env) region and 3' untranslated region (3'UTR). To elucidate the functional consequences of m6A modification, we subsequently generated m6A-deficient ALV-J through its culturing in the DF-1 overexpressing fat mass and obesity-associated protein (FTO) cells. The m6A-deficient ALV-J virus, or its RNAs significantly enhanced IFN-β production compared to the wild-type (wt) ALV-J, suggesting a pivotal regulatory function of m6A modifications in modulating innate immune response. Mechanistically, the m6A modification of the ALV-J genomic RNA directly impacted its recognition by MDA5, weakening its binding and ubiquitination and attenuating IFN-β activation. Moreover, m6A-deficient ALV-J, created by inducing mutations in m6A sites within Env and 3'UTR, exhibited reduced replication capacity and elevated IFN-β expression in host cells. Importantly, this phenomenon was abolished in MDA5-knockout DF-1 cells, further demonstrating the core role of MDA5. These data demonstrate that m6A modification of ALV-J genomic RNA dampens the host's innate immune response through MDA5 signaling pathway.
Collapse
Affiliation(s)
- Mengmeng Yu
- Avian Immunosuppressive Diseases Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, PR China
| | - Li Zhang
- Avian Immunosuppressive Diseases Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, PR China
| | - Ying Wang
- Avian Immunosuppressive Diseases Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, PR China
| | - Suyan Wang
- Avian Immunosuppressive Diseases Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, PR China
| | - Yongzhen Liu
- Avian Immunosuppressive Diseases Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, PR China
| | - Peng Liu
- Avian Immunosuppressive Diseases Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, PR China
| | - Yuntong Chen
- Avian Immunosuppressive Diseases Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, PR China
| | - Ru Guo
- Avian Immunosuppressive Diseases Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, PR China
| | - Lingzhai Meng
- Avian Immunosuppressive Diseases Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, PR China
| | - Tao Zhang
- Avian Immunosuppressive Diseases Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, PR China
| | - Wenrui Fan
- Avian Immunosuppressive Diseases Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, PR China
| | - Xiaole Qi
- Avian Immunosuppressive Diseases Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, PR China
| | - Yulu Duan
- Avian Immunosuppressive Diseases Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, PR China
| | - Yanping Zhang
- Avian Immunosuppressive Diseases Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, PR China
| | - Hongyu Cui
- Avian Immunosuppressive Diseases Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, PR China
| | - Yulong Gao
- Avian Immunosuppressive Diseases Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, PR China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonoses, Yangzhou University, Yangzhou, PR China
- National Poultry Laboratory Animal Resource Center, Harbin, PR China
| |
Collapse
|
2
|
Ribó-Molina P, Groen K, Susma B, van Nieuwkoop S, Funk M, Fouchier RAM, van den Hoogen BG. The role of M2 proteins of pneumoviruses in transcription regulation, prevention of hypermutation, and activation of the type I interferon pathway. J Virol 2025; 99:e0124324. [PMID: 39835813 PMCID: PMC11852930 DOI: 10.1128/jvi.01243-24] [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: 08/12/2024] [Accepted: 12/19/2024] [Indexed: 01/22/2025] Open
Abstract
Human metapneumovirus (HMPV) is an important causative agent of respiratory tract disease. Fundamental knowledge of the interaction between HMPV and the innate immune system could lead to the design of novel antiviral therapies. Previously, we demonstrated that HMPV M2-2 deletion mutants had hypermutated genomes and contained defective interfering particles (DIs), which are potent inducers of the IFN response. Here, we investigated the role of the HMPV M2-2 protein as IFN antagonist using chimeric HMPV expressing M2 proteins of other pneumoviruses: respiratory syncytial virus (RSV) and avian metapneumovirus type C (AMPV/C). Chimeric HMPVs expressing the M2 proteins of RSV or AMPV/C were attenuated in HEp-2 cells but did not activate the IFN response, and their genomes were not hypermutated. In contrast, chimeric HMPVs expressing the M2-2 proteins of RSV and AMPV/C, in combination with HMPV M2-1, did activate the IFN response, and their genomes were hypermutated. Investigation of the role of the pneumovirus M2 proteins in transcription regulation demonstrated that the M2-2 protein, only in concerted action with autologous M2-1 protein, acted as a transcription elongation factor. As a second approach, chimeric RSV in which the IFN antagonists NS1 and NS2 were replaced by the HMPV M2-2 gene failed to suppress an IFN response, indicating that the HMPV M2-2 protein is not a potent IFN antagonist. These data indicate that expression of autologous M2-1 and M2-2 proteins is important for the fidelity of the RNA-dependent RNA polymerase, necessary to prevent the accumulation of mutations, and possibly DIs, thereby preventing activation of the IFN responses.IMPORTANCEThe M2-2 protein of human metapneumovirus is suggested to function as a type I interferon antagonist, a function so far not assigned to the M2 proteins of other pneumoviruses. Although M2-2 deletion mutants of HMPV activate the type I interferon pathway, these mutants have hypermutated genomes and contain defective interfering RNAs, known to activate the interferon pathway. Here, we show that the M2-2 protein, in concerted action with autologous M2-1 protein, acts as a transcription elongation factor, which could explain the accumulation of DIs in M2-2 deletion mutants. Additionally, chimeric RSV in which the IFN antagonists NS1 and NS2 were replaced by the HMPV M2-2 gene failed to suppress an IFN response. These data indicate that expression of autologous M2-1 and M2-2 proteins is required for the fidelity of the RNA-dependent RNA polymerase to prevent genome hypermutation and activation of the type I IFN pathway.
Collapse
Affiliation(s)
- Pau Ribó-Molina
- Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Kevin Groen
- Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands
| | | | | | - Mathis Funk
- Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Ron A. M. Fouchier
- Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands
| | | |
Collapse
|
3
|
Babawale PI, Martínez-Espinoza I, Mitchell AM, Guerrero-Plata A. Preventing RSV Infection in Children: Current Passive Immunizations and Vaccine Development. Pathogens 2025; 14:104. [PMID: 40005481 PMCID: PMC11858734 DOI: 10.3390/pathogens14020104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 01/12/2025] [Accepted: 01/17/2025] [Indexed: 02/27/2025] Open
Abstract
Human respiratory syncytial virus (RSV) is a leading cause of acute respiratory tract infection and lower respiratory tract infection, associated with high morbidity and mortality in young children, the elderly, and immunocompromised individuals. Initial attempts to develop an RSV vaccine in the 1960s were faced with a setback due to the enhanced RSV disease developed by vaccinated children. More recent advancements have led to the generation of RSV vaccines for older adults and pregnant women. However, there are still no commercially available RSV vaccines for infants. This work summarizes the current passive immunizations and the ongoing efforts to develop an RSV vaccine for infants.
Collapse
Affiliation(s)
| | | | | | - Antonieta Guerrero-Plata
- Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA; (P.I.B.); (I.M.-E.); (A.M.M.)
| |
Collapse
|
4
|
da Silva Barcelos L, Ford AK, Frühauf MI, Botton NY, Fischer G, Maggioli MF. Interactions Between Bovine Respiratory Syncytial Virus and Cattle: Aspects of Pathogenesis and Immunity. Viruses 2024; 16:1753. [PMID: 39599867 PMCID: PMC11598946 DOI: 10.3390/v16111753] [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: 10/02/2024] [Revised: 10/25/2024] [Accepted: 11/05/2024] [Indexed: 11/29/2024] Open
Abstract
Bovine respiratory syncytial virus (BRSV) is a major respiratory pathogen in cattle and is relevant to the livestock industry worldwide. BRSV is most severe in young calves and is often associated with stressful management events. The disease is responsible for economic losses due to lower productivity, morbidity, mortality, and prevention and treatment costs. As members of the same genus, bovine and human RSV share a high degree of homology and are similar in terms of their genomes, transmission, clinical signs, and epidemiology. This overlap presents an opportunity for One Health approaches and translational studies, with dual benefits; however, there is still a relative lack of studies focused on BRSV, and the continued search for improved prophylaxis highlights the need for a deeper understanding of its immunological features. BRSV employs different host-immunity-escaping mechanisms that interfere with effective long-term memory responses to current vaccines and natural infections. This review presents an updated description of BRSV's immunity processes, such as the PRRs and signaling pathways involved in BRSV infection, aspects of its pathogeny, and the evading mechanisms developed by the virus to thwart the immune response.
Collapse
Affiliation(s)
- Lariane da Silva Barcelos
- Department of Veterinary Pathobiology, Oklahoma State University, Stillwater, OK 74078, USA; (L.d.S.B.)
- Laboratory of Virology and Immunology, Veterinary College, Universidade Federal de Pelotas, Capão do Leão, Rio Grande do Sul 96010, Brazil; (M.I.F.); (N.Y.B.); (G.F.)
| | - Alexandra K. Ford
- Department of Veterinary Pathobiology, Oklahoma State University, Stillwater, OK 74078, USA; (L.d.S.B.)
| | - Matheus Iuri Frühauf
- Laboratory of Virology and Immunology, Veterinary College, Universidade Federal de Pelotas, Capão do Leão, Rio Grande do Sul 96010, Brazil; (M.I.F.); (N.Y.B.); (G.F.)
| | - Nadalin Yandra Botton
- Laboratory of Virology and Immunology, Veterinary College, Universidade Federal de Pelotas, Capão do Leão, Rio Grande do Sul 96010, Brazil; (M.I.F.); (N.Y.B.); (G.F.)
| | - Geferson Fischer
- Laboratory of Virology and Immunology, Veterinary College, Universidade Federal de Pelotas, Capão do Leão, Rio Grande do Sul 96010, Brazil; (M.I.F.); (N.Y.B.); (G.F.)
| | - Mayara Fernanda Maggioli
- Department of Veterinary Pathobiology, Oklahoma State University, Stillwater, OK 74078, USA; (L.d.S.B.)
| |
Collapse
|
5
|
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.
Collapse
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.
| |
Collapse
|
6
|
Su P, Jiang C, Zhang Y. The implication of infection with respiratory syncytial virus in pediatric recurrent wheezing and asthma: knowledge expanded post-COVID-19 era. Eur J Clin Microbiol Infect Dis 2024; 43:403-416. [PMID: 38153660 DOI: 10.1007/s10096-023-04744-0] [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: 11/05/2023] [Accepted: 12/21/2023] [Indexed: 12/29/2023]
Abstract
BACKGROUND Respiratory syncytial virus (RSV) infection has been identified to serve as the primary cause of acute lower respiratory infectious diseases in children under the age of one and a significant risk factor for the emergence and development of pediatric recurrent wheezing and asthma, though the exact mechanism is still unknown. METHODS AND RESULTS In this study, we discuss the key routes that lead to recurrent wheezing and bronchial asthma following RSV infection. It is interesting to note that following the coronavirus disease 2019 (COVID-19) epidemic, the prevalence of RSV changes significantly. This presents us with a rare opportunity to better understand the associated mechanism for RSV infection, its effects on the respiratory system, and the immunological response to RSV following the COVID-19 epidemic. To better understand the associated mechanisms in the occurrence and progression of pediatric asthma, we thoroughly described how the RSV infection directly destroys the physical barrier of airway epithelial tissue, promotes inflammatory responses, enhances airway hyper-responsiveness, and ultimately causes the airway remodeling. More critically, extensive discussion was also conducted regarding the potential impact of RSV infection on host pulmonary immune response. CONCLUSION In conclusion, this study offers a comprehensive perspective to better understand how the RSV infection interacts in the control of the host's pulmonary immune system, causing recurrent wheezing and the development of asthma, and it sheds fresh light on potential avenues for pharmaceutical therapy in the future.
Collapse
Affiliation(s)
- Peipei Su
- Xi'an Medical University, Xi'an, 710068, Shaanxi, China
- Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, National Regional Children's Medical Centre (Northwest), Xi'an Key Laboratory of Children's Health and Diseases, Shaanxi Institute for Pediatric Diseases, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, 710003, Shaanxi, China
| | - Congshan Jiang
- Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, National Regional Children's Medical Centre (Northwest), Xi'an Key Laboratory of Children's Health and Diseases, Shaanxi Institute for Pediatric Diseases, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, 710003, Shaanxi, China
| | - Yanmin Zhang
- Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, National Regional Children's Medical Centre (Northwest), Xi'an Key Laboratory of Children's Health and Diseases, Shaanxi Institute for Pediatric Diseases, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, 710003, Shaanxi, China.
- Department of Cardiology, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, 710003, Shaanxi, China.
| |
Collapse
|
7
|
Merritt TN, Pei J, Leung DW. Pathogenicity and virulence of human respiratory syncytial virus: Multifunctional nonstructural proteins NS1 and NS2. Virulence 2023:2283897. [PMID: 37964591 DOI: 10.1080/21505594.2023.2283897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 11/09/2023] [Indexed: 11/16/2023] Open
Abstract
Human respiratory syncytial virus (hRSV) is a major cause of acute lower respiratory tract infections in children under the age of two as well as in the elderly and immunocompromised worldwide. Despite its discovery over 60 years ago and the global impact on human health, limited specific and effective prophylactic or therapeutic options have been available for hRSV infections. Part of the lack of treatment options is attributed to the legacy of vaccine failure in the 1960s using a formalin-inactivated RSV (FI-RSV), which led to enhancement of disease post exposure to hRSV infection and hampered subsequent development of vaccine candidates. Recent FDA approval of a vaccine for older adults and impending approval for a maternal vaccine are major advancements but leaves children between 6 months and 5 years of age unprotected. Part of this limitation can be attributed to a lack of complete understanding of the factors that contribute to hRSV pathogenesis. The nonstructural proteins NS1 and NS2 are multifunctional virulence factors that are unique to hRSV and that play critical roles during hRSV infection, including antagonizing interferon (IFN) signalling to modulate host responses to hRSV infection. However, the molecular mechanisms by which the nonstructural proteins mediate their IFN inhibitory functions have not been completely defined. Current progress on the characterization of NS1 and NS2 during infection provides deeper insight into their roles. Furthermore, reverse genetics systems for hRSV provide a viable strategy to generate attenuated viruses by introduction of select mutations while maintaining immunogenicity required to elicit a long-term protective response. Here we will review the current state of knowledge of the nonstructural proteins, their contributions to RSV pathogenesis, and their potential as targets for therapeutic development.
Collapse
Affiliation(s)
- Trudy N Merritt
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Jingjing Pei
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Daisy W Leung
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| |
Collapse
|
8
|
Schoen A, Hölzer M, Müller MA, Wallerang KB, Drosten C, Marz M, Lamp B, Weber F. Functional comparisons of the virus sensor RIG-I from humans, the microbat Myotis daubentonii, and the megabat Rousettus aegyptiacus, and their response to SARS-CoV-2 infection. J Virol 2023; 97:e0020523. [PMID: 37728614 PMCID: PMC10653997 DOI: 10.1128/jvi.00205-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 07/09/2023] [Indexed: 09/21/2023] Open
Abstract
IMPORTANCE A common hypothesis holds that bats (order Chiroptera) are outstanding reservoirs for zoonotic viruses because of a special antiviral interferon (IFN) system. However, functional studies about key components of the bat IFN system are rare. RIG-I is a cellular sensor for viral RNA signatures that activates the antiviral signaling chain to induce IFN. We cloned and functionally characterized RIG-I genes from two species of the suborders Yangochiroptera and Yinpterochiroptera. The bat RIG-Is were conserved in their sequence and domain organization, and similar to human RIG-I in (i) mediating virus- and IFN-activated gene expression, (ii) antiviral signaling, (iii) temperature dependence, and (iv) recognition of RNA ligands. Moreover, RIG-I of Rousettus aegyptiacus (suborder Yinpterochiroptera) and of humans were found to recognize SARS-CoV-2 infection. Thus, members of both bat suborders encode RIG-Is that are comparable to their human counterpart. The ability of bats to harbor zoonotic viruses therefore seems due to other features.
Collapse
Affiliation(s)
- Andreas Schoen
- Institute for Virology, FB10-Veterinary Medicine, Justus-Liebig University, Giessen, Germany
| | - Martin Hölzer
- RNA Bioinformatics and High-Throughput Analysis, Friedrich Schiller University Jena, Jena, Germany
- European Virus Bioinformatics Center, Jena, Germany
| | - Marcel A. Müller
- German Centre for Infection Research (DZIF), Partner Sites Giessen and Charité, Berlin, Germany
- Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Kai B. Wallerang
- Institute for Virology, FB10-Veterinary Medicine, Justus-Liebig University, Giessen, Germany
| | - Christian Drosten
- European Virus Bioinformatics Center, Jena, Germany
- German Centre for Infection Research (DZIF), Partner Sites Giessen and Charité, Berlin, Germany
- Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Manja Marz
- RNA Bioinformatics and High-Throughput Analysis, Friedrich Schiller University Jena, Jena, Germany
- European Virus Bioinformatics Center, Jena, Germany
| | - Benjamin Lamp
- Institute for Virology, FB10-Veterinary Medicine, Justus-Liebig University, Giessen, Germany
| | - Friedemann Weber
- Institute for Virology, FB10-Veterinary Medicine, Justus-Liebig University, Giessen, Germany
- European Virus Bioinformatics Center, Jena, Germany
- German Centre for Infection Research (DZIF), Partner Sites Giessen and Charité, Berlin, Germany
| |
Collapse
|
9
|
Agac A, Kolbe SM, Ludlow M, Osterhaus ADME, Meineke R, Rimmelzwaan GF. Host Responses to Respiratory Syncytial Virus Infection. Viruses 2023; 15:1999. [PMID: 37896776 PMCID: PMC10611157 DOI: 10.3390/v15101999] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 09/22/2023] [Accepted: 09/23/2023] [Indexed: 10/29/2023] Open
Abstract
Respiratory syncytial virus (RSV) infections are a constant public health problem, especially in infants and older adults. Virtually all children will have been infected with RSV by the age of two, and reinfections are common throughout life. Since antigenic variation, which is frequently observed among other respiratory viruses such as SARS-CoV-2 or influenza viruses, can only be observed for RSV to a limited extent, reinfections may result from short-term or incomplete immunity. After decades of research, two RSV vaccines were approved to prevent lower respiratory tract infections in older adults. Recently, the FDA approved a vaccine for active vaccination of pregnant women to prevent severe RSV disease in infants during their first RSV season. This review focuses on the host response to RSV infections mediated by epithelial cells as the first physical barrier, followed by responses of the innate and adaptive immune systems. We address possible RSV-mediated immunomodulatory and pathogenic mechanisms during infections and discuss the current vaccine candidates and alternative treatment options.
Collapse
Affiliation(s)
| | | | | | | | | | - Guus F. Rimmelzwaan
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; (A.A.); (S.M.K.); (M.L.); (A.D.M.E.O.); (R.M.)
| |
Collapse
|
10
|
Bergeron HC, Hansen MR, Tripp RA. Interferons-Implications in the Immune Response to Respiratory Viruses. Microorganisms 2023; 11:2179. [PMID: 37764023 PMCID: PMC10535750 DOI: 10.3390/microorganisms11092179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/15/2023] [Accepted: 08/28/2023] [Indexed: 09/29/2023] Open
Abstract
Interferons (IFN) are an assemblage of signaling proteins made and released by various host cells in response to stimuli, including viruses. Respiratory syncytial virus (RSV), influenza virus, and SARS-CoV-2 are major causes of respiratory disease that induce or antagonize IFN responses depending on various factors. In this review, the role and function of type I, II, and III IFN responses to respiratory virus infections are considered. In addition, the role of the viral proteins in modifying anti-viral immunity is noted, as are the specific IFN responses that underly the correlates of immunity and protection from disease.
Collapse
Affiliation(s)
| | | | - Ralph A. Tripp
- Department of Infectious Diseases, University of Georgia College of Veterinary Medicine, Athens, GA 30605, USA; (H.C.B.); (M.R.H.)
| |
Collapse
|
11
|
Hsu BW, Chen BS. Genetic and Epigenetic Host-Virus Network to Investigate Pathogenesis and Identify Biomarkers for Drug Repurposing of Human Respiratory Syncytial Virus via Real-World Two-Side RNA-Seq Data: Systems Biology and Deep-Learning Approach. Biomedicines 2023; 11:1531. [PMID: 37371627 DOI: 10.3390/biomedicines11061531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/23/2023] [Accepted: 05/23/2023] [Indexed: 06/29/2023] Open
Abstract
Human respiratory syncytial virus (hRSV) affects more than 33 million people each year, but there are currently no effective drugs or vaccines approved. In this study, we first constructed a candidate host-pathogen interspecies genome-wide genetic and epigenetic network (HPI-GWGEN) via big-data mining. Then, we employed reversed dynamic methods via two-side host-pathogen RNA-seq time-profile data to prune false positives in candidate HPI-GWGEN to obtain the real HPI-GWGEN. With the aid of principal-network projection and the annotation of KEGG pathways, we can extract core signaling pathways during hRSV infection to investigate the pathogenic mechanism of hRSV infection and select the corresponding significant biomarkers as drug targets, i.e., TRAF6, STAT3, IRF3, TYK2, and MAVS. Finally, in order to discover potential molecular drugs, we trained a DNN-based DTI model by drug-target interaction databases to predict candidate molecular drugs for these drug targets. After screening these candidate molecular drugs by three drug design specifications simultaneously, i.e., regulation ability, sensitivity, and toxicity. We finally selected acitretin, RS-67333, and phenformin to combine as a potential multimolecule drug for the therapeutic treatment of hRSV infection.
Collapse
Affiliation(s)
- Bo-Wei Hsu
- Laboratory of Automatic Control, Signal Processing and Systems Biology, Department of Electrical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Bor-Sen Chen
- Laboratory of Automatic Control, Signal Processing and Systems Biology, Department of Electrical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan
| |
Collapse
|
12
|
Tovo PA, Garazzino S, Savino F, Daprà V, Pruccoli G, Dini M, Filisetti G, Funiciello E, Galliano I, Bergallo M. Expressions of Type I and III Interferons, Endogenous Retroviruses, TRIM28, and SETDB1 in Children with Respiratory Syncytial Virus Bronchiolitis. Curr Issues Mol Biol 2023; 45:1197-1217. [PMID: 36826024 PMCID: PMC9954910 DOI: 10.3390/cimb45020079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/24/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Interferons (IFNs) and IFN-stimulated genes (ISGs) play essential roles for the control of viral infections. Their expression in infants with respiratory syncytial virus (RSV) bronchiolitis is poorly defined. Human endogenous retroviruses (HERVs) represent 8% of our genome and modulate inflammatory and immune reactions. TRIM28 and SETDB1 participate in the epigenetic regulation of genes involved in the immune response, including IFNs and HERVs. No study has explored the expression of HERVs, TRIM28, and SETDB1 during RSV bronchiolitis. We assessed, through a PCR real-time Taqman amplification assay, the transcription levels of six IFN-I ISGs, four IFNλs, the pol genes of HERV-H, -K, and -W families, the env genes of Syncytin (SYN)1 and SYN2, and of TRIM28/SETDB1 in whole blood from 37 children hospitalized for severe RSV bronchiolitis and in healthy children (HC). The expression of most IFN-I ISGs was significantly higher in RSV+ patients than in age-matched HC, but it was inhibited by steroid therapy. The mRNA concentrations of IFN-λs were comparable between patients and age-matched HC. This lack of RSV-driven IFN-III activation may result in the defective protection of the airway mucosal surface leading to severe bronchiolitis. The expression of IFN-III showed a positive correlation with age in HC, that could account for the high susceptibility of young children to viral respiratory tract infections. The transcription levels of every HERV gene were significantly lower in RSV+ patients than in HC, while the expressions of TRIM28/SETDB1 were overlapping. Given the negative impact of HERVs and the positive effects of TRIM28/SETDB1 on innate and adaptive immune responses, the downregulation of the former and the normal expression of the latter may contribute to preserving immune functions against infection.
Collapse
Affiliation(s)
- Pier-Angelo Tovo
- Department of Pediatric Sciences and Public Health, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
- Correspondence: Correspondence: (P.-A.T.); (M.B.)
| | - Silvia Garazzino
- Department of Pediatric Sciences and Public Health, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
- Infectious Diseases Unit, Department of Pediatrics, Regina Margherita Children’s Hospital, Piazza Polonia 94, 10126 Turin, Italy
| | - Francesco Savino
- Early Infancy Special Care Unit, Department of Pediatric Care, Regina Margherita Children’s Hospital, Piazza Polonia 94, 10126 Turin, Italy
| | - Valentina Daprà
- Department of Pediatric Sciences and Public Health, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
- Pediatric Laboratory, Department of Pediatric Sciences and Public Health, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
| | - Giulia Pruccoli
- Infectious Diseases Unit, Department of Pediatrics, Regina Margherita Children’s Hospital, Piazza Polonia 94, 10126 Turin, Italy
| | - Maddalena Dini
- Department of Pediatric Sciences and Public Health, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
- Pediatric Laboratory, Department of Pediatric Sciences and Public Health, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
| | - Giacomo Filisetti
- Department of Pediatric Sciences and Public Health, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
- Early Infancy Special Care Unit, Department of Pediatric Care, Regina Margherita Children’s Hospital, Piazza Polonia 94, 10126 Turin, Italy
| | - Elisa Funiciello
- Department of Pediatric Sciences and Public Health, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
- Infectious Diseases Unit, Department of Pediatrics, Regina Margherita Children’s Hospital, Piazza Polonia 94, 10126 Turin, Italy
| | - Ilaria Galliano
- Department of Pediatric Sciences and Public Health, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
- Pediatric Laboratory, Department of Pediatric Sciences and Public Health, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
| | - Massimiliano Bergallo
- Department of Pediatric Sciences and Public Health, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
- Pediatric Laboratory, Department of Pediatric Sciences and Public Health, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
- Correspondence: Correspondence: (P.-A.T.); (M.B.)
| |
Collapse
|
13
|
Azeez IA, Awogbindin IO, Olayinka JN, Folarin RO, Adamu AS, Ior LD, Shehu AM, Mukhtar AI, Ajeigbe OF, Emokpae AO, Usende IL, Babatunde BR, Yusha'u Y, Olateju OI, Kamoga R, Benson AIO, Oparaji KC, Owemidu IO, Iliyasu MO, Imam MI, Olopade JO. Neural stem cell research in Africa: current realities and future prospects. Biol Open 2022; 11:280534. [PMID: 36326097 PMCID: PMC9641530 DOI: 10.1242/bio.059574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Neural stem cells (NSCs) are immature progenitor cells that are found in developing and adult brains that have the potential of dividing actively and renewing themselves, with a complex form of gene expression. The generation of new brain cells in adult individuals was initially considered impossible, however, the landmark discovery of human neural stem cells in the hippocampus has been followed by further discoveries in other discreet regions of the brain. Investigation into the current state in Africa of the research and use of NSCs shows relatively limited activities on the continent. Information on the African application of NSCs for modelling disease mechanisms, drug discovery, and therapeutics is still limited. The International Brain Research Organization (IBRO)-African Regional Committee (ARC), with support from the Company of Biologists, and the Movement Disorder Society, sponsored the first African Basic School on NSC in Ibadan, Nigeria, with the vision of bringing together young neuroscientists and physicians across different fields in neuroscience to learn from leaders who have applied NSCs in stem cell research, the pathophysiology of neurodegenerative diseases, neuroanatomy, and neurotherapeutics. Twenty early-career researchers in academic institutions at junior and senior faculty cadres were selected from South Africa, Uganda and Nigeria. The students and organizer of the school, who wrote this review on the state of NSCs research in Africa, recommended the following: (1) other African countries can take a cue from South Africa and Nigeria in probing the phenomena of adult neurogenesis in unique animal species on the continent; (2) Africa should leverage the expertise and facilities of South African scientists and international collaborators in scaling up NSC research into these unique species and (3) Centers of Excellence should be established on the continent to serve as research hubs for training postgraduate students, and facilities for African scientists who trained overseas on NSCs.
Collapse
Affiliation(s)
- Idris A. Azeez
- Department of Veterinary Anatomy, University of Jos 1 , Jos, 930001 Nigeria
| | | | - Juliet N. Olayinka
- Department of Pharmacology and Therapeutics, Afe Babalola University 3 , Ado-Ekiti, 360001 Nigeria
| | - Royhaan O. Folarin
- Department of Anatomy, Olabisi Onabanjo University 4 , Ago-Iwoye, 120107 Nigeria
| | - Abubakar S. Adamu
- Department of Human Anatomy, Ahmadu Bello University 5 , Zaria, 810107 , Nigeria
| | - Lydia D. Ior
- Department of Pharmacology, University of Jos 6 , Jos, 930001 , Nigeria
| | - Asmau M. Shehu
- Department of Human Anatomy, Federal University Dutse 7 , Dutse, 720223 , Nigeria
- School of Anatomical Sciences, University of the Witwatersrand 8 , Johannesburg, Wits 2050 , South Africa
| | - Abubakar I. Mukhtar
- Department of Human Anatomy, Ahmadu Bello University 5 , Zaria, 810107 , Nigeria
| | - Olufunke F. Ajeigbe
- Elizade University, Ilara-Mokin, 340112 9 Department of Physical and Chemical Sciences, Biochemistry Programme , , Nigeria
| | | | - Ifukibot L. Usende
- Department of Veterinary Anatomy, University of Abuja 11 , Abuja, 900105 , Nigeria
| | | | - Yusuf Yusha'u
- Department of Human Physiology, Ahmadu Bello University 12 , Zaria, 810107 , Nigeria
| | - Oladiran I. Olateju
- School of Anatomical Sciences, University of the Witwatersrand 8 , Johannesburg, Wits 2050 , South Africa
| | - Ronald Kamoga
- Department of Pharmacology and Therapeutics, Mbarara University of Science and Technology 13 , Mbarara P.O. Box 1410 , Uganda
| | - Ayoola I. O. Benson
- Department of Human Anatomy, Elizade University, Ilara-Mokin 14 , Abakaliki, 482131 Nigeria
| | - Kenneth C. Oparaji
- Department of Physiology, Alex Ekwueme Federal University Ndufu-Alike 15 , Abakaliki, 482131 , Nigeria
| | - Idowu O. Owemidu
- Department of Physiology, Kogi State University 16 , Anyigba, 272102 , Nigeria
| | - Musa O. Iliyasu
- Department of Anatomy, Kogi State University 17 , Anyigba, 272102 , Nigeria
| | - Maryam I. Imam
- Department of Human Physiology, Ahmadu Bello University 12 , Zaria, 810107 , Nigeria
| | - James O. Olopade
- Department of Veterinary Anatomy, University of Ibadan 18 , Ibadan, 200005 , Nigeria
| |
Collapse
|
14
|
An Unexpected Encounter: Respiratory Syncytial Virus Nonstructural Protein 1 Interacts with Mediator Subunit MED25. J Virol 2022; 96:e0129722. [PMID: 36102648 PMCID: PMC9555202 DOI: 10.1128/jvi.01297-22] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Innate immune responses, including the production of type I and III interferons, play a crucial role in the first line of defense against RSV infection. However, only a poor induction of type I IFNs is observed during RSV infection, suggesting that RSV has evolved mechanisms to prevent type I IFN expression by the infected host cell.
Collapse
|
15
|
Ohta K, Saka N, Nishio M. Hazara Orthonairovirus Nucleoprotein Antagonizes Type I Interferon Production by Inhibition of RIG-I Ubiquitination. Viruses 2022; 14:v14091965. [PMID: 36146771 PMCID: PMC9504875 DOI: 10.3390/v14091965] [Citation(s) in RCA: 3] [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: 08/10/2022] [Revised: 08/31/2022] [Accepted: 09/02/2022] [Indexed: 11/16/2022] Open
Abstract
Viruses have evolved various strategies to evade the host innate immune system. The relationship between nairoviruses and the interferon (IFN) system is poorly understood. We investigated whether and how nairoviruses antagonize host innate immunity using Hazara orthonairovirus (HAZV) as a surrogate model for Crimean-Congo hemorrhagic fever virus. HAZV nucleoprotein (N) was found to interact with the tripartite motif-containing protein 25 (TRIM25). The N-terminal region of N protein and the C-terminal region of TRIM25 are important for their interaction. Overexpression of N protein results in weakened interaction of TRIM25 with retinoic acid-inducible gene I (RIG-I). Furthermore, K63-linked polyubiquitination of RIG-I is inhibited in the presence of N protein. Our data collectively suggest that HAZV N protein interferes with the binding of TRIM25 to RIG-I and subsequent K63-linked polyubiquitination of RIG-I, which leads to inhibition of type I IFN production.
Collapse
|
16
|
Ouyang Y, Liao H, Hu Y, Luo K, Hu S, Zhu H. Innate Immune Evasion by Human Respiratory Syncytial Virus. Front Microbiol 2022; 13:865592. [PMID: 35308390 PMCID: PMC8931408 DOI: 10.3389/fmicb.2022.865592] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 02/17/2022] [Indexed: 01/03/2023] Open
Abstract
Respiratory syncytial virus (RSV) is the leading cause of severe respiratory infection in young children. Nearly all individuals become infected in their early childhood, and reinfections with RSV are common throughout life. Primary infection with RSV is usually involved in the symptom of bronchiolitis and pneumonia in the lower respiratory tract, which accounts for over 3 million hospitalizations and approximately 66,000 deaths annually worldwide. Despite the widespread prevalence and high morbidity and lethality rates of diseases caused by RSV infection, there is currently no licensed RSV vaccine. During RSV infection, innate immunity plays the first line of defense to suppress RSV infection and replication. However, RSV has evolved multiple mechanisms to evade the host’s innate immune responses to gain a window of opportunity for efficient viral replication. This review discusses the comprehensive interaction between RSV infection and the host antiviral innate immunity and updates recent findings on how RSV modulates the host innate immune response for survival, which may provide novel insights to find potent drug targets and vaccines against RSV.
Collapse
Affiliation(s)
- Yan Ouyang
- Neonatal/Pediatric Intensive Care Unit, Children's Medical Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Hongqun Liao
- Neonatal/Pediatric Intensive Care Unit, Children's Medical Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Ganzhou Key Laboratory of Immunotherapeutic Drugs Developing for Childhood Leukemia, Ganzhou, China
| | - Yan Hu
- Department of Gynecology, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Kaiyuan Luo
- Neonatal/Pediatric Intensive Care Unit, Children's Medical Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Shaowen Hu
- Basic Medical College of Gannan Medical University, Ganzhou, China
| | - Huifang Zhu
- Neonatal/Pediatric Intensive Care Unit, Children's Medical Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Ganzhou Key Laboratory of Immunotherapeutic Drugs Developing for Childhood Leukemia, Ganzhou, China
- Basic Medical College of Gannan Medical University, Ganzhou, China
- Institute of Children's Medical, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- *Correspondence: Huifang Zhu,
| |
Collapse
|
17
|
Short-chain fatty acid acetate triggers antiviral response mediated by RIG-I in cells from infants with respiratory syncytial virus bronchiolitis. EBioMedicine 2022; 77:103891. [PMID: 35220042 PMCID: PMC8871125 DOI: 10.1016/j.ebiom.2022.103891] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 01/26/2022] [Accepted: 02/04/2022] [Indexed: 12/31/2022] Open
Abstract
Background Gut microbiota-derived short-chain fatty-acid (SFCA) acetate protects mice against RSV A2 strain infection by increasing interferon-β production and expression of interferon-stimulated genes (ISGs). However, the role of SFCA in RSV infection using strains isolated from patients is unknown. Methods We first used RSV clinical strains isolated from infants hospitalized with RSV bronchiolitis to investigate the effects of in vitro SCFA-acetate treatment of human pulmonary epithelial cells. We next examined whether SCFA-acetate treatment is beneficial in a mouse model of RSV infection using clinical isolates. We sought to investigate the relationship of gut microbiota and fecal acetate with disease severity among infants hospitalized with RSV bronchiolitis, and whether treating their respiratory epithelial cells with SCFA-acetate ex-vivo impacts viral load and ISG expression. We further treated epithelial cells from SARS-CoV-2 infected patients with SCFA-acetate. Findings In vitro pre-treatment of A549 cells with SCFA-acetate reduced RSV infection with clinical isolates and increased the expression of RIG-I and ISG15. Animals treated with SCFA-acetate intranasally recovered significantly faster, with reduction in the RSV clinical isolates viral load, and increased lung expression of IFNB1 and the RIG-I. Experiments in RIG-I knockout A549 cells demonstrated that the protection relies on RIG-I presence. Gut microbial profile was associated with bronchiolitis severity and with acetate in stool. Increased SCFA-acetate levels were associated with increasing oxygen saturation at admission, and shorter duration of fever. Ex-vivo treatment of patients’ respiratory cells with SCFA-acetate reduced RSV load and increased expression of ISGs OAS1 and ISG15, and virus recognition receptors MAVS and RIG-I, but not IFNB1. These SCFA-acetate effects were not found on cells from SARS-CoV-2 infected patients. Interpretation SCFA-acetate reduces the severity of RSV infection and RSV viral load through modulation of RIG-I expression. Funding FAPERGS (FAPERGS/MS/CNPq/SESRS no. 03/2017 - PPSUS 17/2551-0001380-8 and COVID-19 20/2551-0000258-6); CNPq 312504/2017-9; CAPES) - Finance Code 001.
Collapse
|
18
|
Van Royen T, Rossey I, Sedeyn K, Schepens B, Saelens X. How RSV Proteins Join Forces to Overcome the Host Innate Immune Response. Viruses 2022; 14:v14020419. [PMID: 35216012 PMCID: PMC8874859 DOI: 10.3390/v14020419] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/11/2022] [Accepted: 02/14/2022] [Indexed: 12/10/2022] Open
Abstract
Respiratory syncytial virus (RSV) is the leading cause of severe acute lower respiratory tract infections in infants worldwide. Although several pattern recognition receptors (PRRs) can sense RSV-derived pathogen-associated molecular patterns (PAMPs), infection with RSV is typically associated with low to undetectable levels of type I interferons (IFNs). Multiple RSV proteins can hinder the host’s innate immune response. The main players are NS1 and NS2 which suppress type I IFN production and signalling in multiple ways. The recruitment of innate immune cells and the production of several cytokines are reduced by RSV G. Next, RSV N can sequester immunostimulatory proteins to inclusion bodies (IBs). N might also facilitate the assembly of a multiprotein complex that is responsible for the negative regulation of innate immune pathways. Furthermore, RSV M modulates the host’s innate immune response. The nuclear accumulation of RSV M has been linked to an impaired host gene transcription, in particular for nuclear-encoded mitochondrial proteins. In addition, RSV M might also directly target mitochondrial proteins which results in a reduced mitochondrion-mediated innate immune recognition of RSV. Lastly, RSV SH might prolong the viral replication in infected cells and influence cytokine production.
Collapse
Affiliation(s)
- Tessa Van Royen
- VIB-UGent Center for Medical Biotechnology, VIB, 9000 Ghent, Belgium; (T.V.R.); (I.R.); (K.S.); (B.S.)
- Department for Biochemistry and Microbiology, Ghent University, 9000 Ghent, Belgium
| | - Iebe Rossey
- VIB-UGent Center for Medical Biotechnology, VIB, 9000 Ghent, Belgium; (T.V.R.); (I.R.); (K.S.); (B.S.)
- Department for Biochemistry and Microbiology, Ghent University, 9000 Ghent, Belgium
| | - Koen Sedeyn
- VIB-UGent Center for Medical Biotechnology, VIB, 9000 Ghent, Belgium; (T.V.R.); (I.R.); (K.S.); (B.S.)
- Department for Biochemistry and Microbiology, Ghent University, 9000 Ghent, Belgium
| | - Bert Schepens
- VIB-UGent Center for Medical Biotechnology, VIB, 9000 Ghent, Belgium; (T.V.R.); (I.R.); (K.S.); (B.S.)
- Department for Biochemistry and Microbiology, Ghent University, 9000 Ghent, Belgium
| | - Xavier Saelens
- VIB-UGent Center for Medical Biotechnology, VIB, 9000 Ghent, Belgium; (T.V.R.); (I.R.); (K.S.); (B.S.)
- Department for Biochemistry and Microbiology, Ghent University, 9000 Ghent, Belgium
- Correspondence:
| |
Collapse
|
19
|
Martín-Vicente M, Resino S, Martínez I. Early innate immune response triggered by the human respiratory syncytial virus and its regulation by ubiquitination/deubiquitination processes. J Biomed Sci 2022; 29:11. [PMID: 35152905 PMCID: PMC8841119 DOI: 10.1186/s12929-022-00793-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/28/2022] [Indexed: 12/25/2022] Open
Abstract
The human respiratory syncytial virus (HRSV) causes severe lower respiratory tract infections in infants and the elderly. An exuberant inadequate immune response is behind most of the pathology caused by the HRSV. The main targets of HRSV infection are the epithelial cells of the respiratory tract, where the immune response against the virus begins. This early innate immune response consists of the expression of hundreds of pro-inflammatory and anti-viral genes that stimulates subsequent innate and adaptive immunity. The early innate response in infected cells is mediated by intracellular signaling pathways composed of pattern recognition receptors (PRRs), adapters, kinases, and transcriptions factors. These pathways are tightly regulated by complex networks of post-translational modifications, including ubiquitination. Numerous ubiquitinases and deubiquitinases make these modifications reversible and highly dynamic. The intricate nature of the signaling pathways and their regulation offers the opportunity for fine-tuning the innate immune response against HRSV to control virus replication and immunopathology.
Collapse
Affiliation(s)
- María Martín-Vicente
- Unidad de Infección Viral E Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220 Majadahonda, Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain
| | - Salvador Resino
- Unidad de Infección Viral E Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220 Majadahonda, Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain
| | - Isidoro Martínez
- Unidad de Infección Viral E Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220 Majadahonda, Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain
| |
Collapse
|
20
|
Barik S. Mechanisms of Viral Degradation of Cellular Signal Transducer and Activator of Transcription 2. Int J Mol Sci 2022; 23:ijms23010489. [PMID: 35008916 PMCID: PMC8745392 DOI: 10.3390/ijms23010489] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/28/2021] [Accepted: 12/31/2021] [Indexed: 12/31/2022] Open
Abstract
Virus infection of eukaryotes triggers cellular innate immune response, a major arm of which is the type I interferon (IFN) family of cytokines. Binding of IFN to cell surface receptors triggers a signaling cascade in which the signal transducer and activator of transcription 2 (STAT2) plays a key role, ultimately leading to an antiviral state of the cell. In retaliation, many viruses counteract the immune response, often by the destruction and/or inactivation of STAT2, promoted by specific viral proteins that do not possess protease activities of their own. This review offers a summary of viral mechanisms of STAT2 subversion with emphasis on degradation. Some viruses also destroy STAT1, another major member of the STAT family, but most viruses are selective in targeting either STAT2 or STAT1. Interestingly, degradation of STAT2 by a few viruses requires the presence of both STAT proteins. Available evidence suggests a mechanism in which multiple sites and domains of STAT2 are required for engagement and degradation by a multi-subunit degradative complex, comprising viral and cellular proteins, including the ubiquitin–proteasomal system. However, the exact molecular nature of this complex and the alternative degradation mechanisms remain largely unknown, as critically presented here with prospective directions of future study.
Collapse
Affiliation(s)
- Sailen Barik
- EonBio, 3780 Pelham Drive, Mobile, AL 36619, USA
| |
Collapse
|
21
|
Xue M, Zhang Y, Wang H, Kairis EL, Lu M, Ahmad S, Attia Z, Harder O, Zhang Z, Wei J, Chen P, Gao Y, Peeples ME, Sharma A, Boyaka P, He C, Hur S, Niewiesk S, Li J. Viral RNA N6-methyladenosine modification modulates both innate and adaptive immune responses of human respiratory syncytial virus. PLoS Pathog 2021; 17:e1010142. [PMID: 34929018 PMCID: PMC8759664 DOI: 10.1371/journal.ppat.1010142] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 01/14/2022] [Accepted: 11/19/2021] [Indexed: 12/29/2022] Open
Abstract
Human respiratory syncytial virus (RSV) is the leading cause of respiratory tract infections in humans. A well-known challenge in the development of a live attenuated RSV vaccine is that interferon (IFN)-mediated antiviral responses are strongly suppressed by RSV nonstructural proteins which, in turn, dampens the subsequent adaptive immune responses. Here, we discovered a novel strategy to enhance innate and adaptive immunity to RSV infection. Specifically, we found that recombinant RSVs deficient in viral RNA N6-methyladenosine (m6A) and RSV grown in m6A methyltransferase (METTL3)-knockdown cells induce higher expression of RIG-I, bind more efficiently to RIG-I, and enhance RIG-I ubiquitination and IRF3 phosphorylation compared to wild-type virion RNA, leading to enhanced type I IFN production. Importantly, these m6A-deficient RSV mutants also induce a stronger IFN response in vivo, are significantly attenuated, induce higher neutralizing antibody and T cell immune responses in mice and provide complete protection against RSV challenge in cotton rats. Collectively, our results demonstrate that inhibition of RSV RNA m6A methylation enhances innate immune responses which in turn promote adaptive immunity.
Collapse
Affiliation(s)
- Miaoge Xue
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Yuexiu Zhang
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Haitao Wang
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, Massachusetts, United States of America
| | - Elizabeth L. Kairis
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Mijia Lu
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Sadeem Ahmad
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, Massachusetts, United States of America
| | - Zayed Attia
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Olivia Harder
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Zijie Zhang
- Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois, United States of America
| | - Jiangbo Wei
- Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois, United States of America
| | - Phylip Chen
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Youling Gao
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Mark E. Peeples
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, United States of America
| | - Amit Sharma
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Prosper Boyaka
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Chuan He
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, Massachusetts, United States of America
- Howard Hughes Medical Institute, The University of Chicago, Chicago, Illinois, United States of America
| | - Sun Hur
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America
- Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, Massachusetts, United States of America
| | - Stefan Niewiesk
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Jianrong Li
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America
| |
Collapse
|
22
|
Pei J, Beri NR, Zou AJ, Hubel P, Dorando HK, Bergant V, Andrews RD, Pan J, Andrews JM, Sheehan KCF, Pichlmair A, Amarasinghe GK, Brody SL, Payton JE, Leung DW. Nuclear-localized human respiratory syncytial virus NS1 protein modulates host gene transcription. Cell Rep 2021; 37:109803. [PMID: 34644581 PMCID: PMC8609347 DOI: 10.1016/j.celrep.2021.109803] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 04/28/2021] [Accepted: 09/16/2021] [Indexed: 12/13/2022] Open
Abstract
Human respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections in the pediatric, elderly, and immunocompromised individuals. RSV non-structural protein NS1 is a known cytosolic immune antagonist, but how NS1 modulates host responses remains poorly defined. Here, we observe NS1 partitioning into the nucleus of RSV-infected cells, including the human airway epithelium. Nuclear NS1 coimmunoprecipitates with Mediator complex and is chromatin associated. Chromatin-immunoprecipitation demonstrates enrichment of NS1 that overlaps Mediator and transcription factor binding within the promoters and enhancers of differentially expressed genes during RSV infection. Mutation of the NS1 C-terminal helix reduces NS1 impact on host gene expression. These data suggest that nuclear NS1 alters host responses to RSV infection by binding at regulatory elements of immune response genes and modulating host gene transcription. Our study identifies another layer of regulation by virally encoded proteins that shapes host response and impacts immunity to RSV.
Collapse
Affiliation(s)
- Jingjing Pei
- Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Nina R Beri
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Angela J Zou
- Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Philipp Hubel
- Innate Immunity Laboratory, Max-Planck Institute of Biochemistry, Martinsried/Munich 82152, Germany
| | - Hannah K Dorando
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Valter Bergant
- Institute for Virology, Technical University of Munich, School of Medicine, 81675 Munich, Germany
| | - Rebecca D Andrews
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Jiehong Pan
- Department of Medicine, Division of Pulmonary and Critical Care, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Jared M Andrews
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Kathleen C F Sheehan
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Andreas Pichlmair
- Innate Immunity Laboratory, Max-Planck Institute of Biochemistry, Martinsried/Munich 82152, Germany; Institute for Virology, Technical University of Munich, School of Medicine, 81675 Munich, Germany
| | - Gaya K Amarasinghe
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Steven L Brody
- Department of Medicine, Division of Pulmonary and Critical Care, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Jacqueline E Payton
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
| | - Daisy W Leung
- Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
| |
Collapse
|
23
|
Chen Y, Shi Y, Wu J, Qi N. MAVS: A Two-Sided CARD Mediating Antiviral Innate Immune Signaling and Regulating Immune Homeostasis. Front Microbiol 2021; 12:744348. [PMID: 34566944 PMCID: PMC8458965 DOI: 10.3389/fmicb.2021.744348] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 08/11/2021] [Indexed: 12/12/2022] Open
Abstract
Mitochondrial antiviral signaling protein (MAVS) functions as a "switch" in the immune signal transduction against most RNA viruses. Upon viral infection, MAVS forms prion-like aggregates by receiving the cytosolic RNA sensor retinoic acid-inducible gene I-activated signaling and further activates/switches on the type I interferon signaling. While under resting state, MAVS is prevented from spontaneously aggregating to switch off the signal transduction and maintain immune homeostasis. Due to the dual role in antiviral signal transduction and immune homeostasis, MAVS has emerged as the central regulation target by both viruses and hosts. Recently, researchers show increasing interest in viral evasion strategies and immune homeostasis regulations targeting MAVS, especially focusing on the post-translational modifications of MAVS, such as ubiquitination and phosphorylation. This review summarizes the regulations of MAVS in antiviral innate immune signaling transduction and immune homeostasis maintenance.
Collapse
Affiliation(s)
- Yunqiang Chen
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Institue of Engineering Biology and Health, Zhejiang University of Technology, Hangzhou, China
| | - Yuheng Shi
- Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jing Wu
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Institue of Engineering Biology and Health, Zhejiang University of Technology, Hangzhou, China
| | - Nan Qi
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Institue of Engineering Biology and Health, Zhejiang University of Technology, Hangzhou, China
| |
Collapse
|
24
|
Grochowska J, Czerwinska J, Borowski LS, Szczesny RJ. Mitochondrial RNA, a new trigger of the innate immune system. WILEY INTERDISCIPLINARY REVIEWS-RNA 2021; 13:e1690. [PMID: 34498404 DOI: 10.1002/wrna.1690] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 02/06/2023]
Abstract
Mitochondria play a pivotal role in numerous cellular processes. One of them is regulation of the innate immune pathway. In this instance, mitochondria function in two different aspects of regulatory mechanisms. First, mitochondria are part of the antiviral signaling cascade that is triggered in the cytoplasm and transmitted to effector proteins through mitochondria-localized proteins. Second, mitochondria can become an endogenous source of innate immune stimuli. Under some pathophysiological conditions, mitochondria release to the cytoplasm immunogenic factors, such as mitochondrial nucleic acids. Here, we focus on immunogenic mitochondrial double-stranded RNA (mt-dsRNA) and its origin and metabolism. We discuss factors that are responsible for regulating mt-dsRNA and its escape from mitochondria, emphasizing the contribution of polynucleotide phosphorylase (PNPase, PNPT1). Finally, we review current knowledge of the role of PNPase in human health and disease. This article is categorized under: RNA in Disease and Development > RNA in Disease.
Collapse
Affiliation(s)
- Joanna Grochowska
- Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland
| | - Jolanta Czerwinska
- Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland
| | - Lukasz S Borowski
- Faculty of Biology, Institute of Genetics and Biotechnology, University of Warsaw, Warsaw, Poland
| | - Roman J Szczesny
- Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland
| |
Collapse
|
25
|
Saied AA, Metwally AA, Mohamed HMA, Haridy MAM. The contribution of bovines to human health against viral infections. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:46999-47023. [PMID: 34272669 PMCID: PMC8284698 DOI: 10.1007/s11356-021-14941-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 06/12/2021] [Indexed: 04/12/2023]
Abstract
In the last 40 years, novel viruses have evolved at a much faster pace than other pathogens. Viral diseases pose a significant threat to public health around the world. Bovines have a longstanding history of significant contributions to human nutrition, agricultural, industrial purposes, medical research, drug and vaccine development, and livelihood. The life cycle, genomic structures, viral proteins, and pathophysiology of bovine viruses studied in vitro paved the way for understanding the human counterparts. Calf model has been used for testing vaccines against RSV, papillomavirus vaccines and anti-HCV agents were principally developed after using the BPV and BVDV model, respectively. Some bovine viruses-based vaccines (BPIV-3 and bovine rotaviruses) were successfully developed, clinically tried, and commercially produced. Cows, immunized with HIV envelope glycoprotein, produced effective broadly neutralizing antibodies in their serum and colostrum against HIV. Here, we have summarized a few examples of human viral infections for which the use of bovines has contributed to the acquisition of new knowledge to improve human health against viral infections covering the convergence between some human and bovine viruses and using bovines as disease models. Additionally, the production of vaccines and drugs, bovine-based products were covered, and the precautions in dealing with bovines and bovine-based materials.
Collapse
Affiliation(s)
- AbdulRahman A Saied
- Department of Food Establishments Licensing (Aswan Branch), National Food Safety Authority (NFSA), Aswan, 81511, Egypt.
- Touristic Activities and Interior Offices Sector (Aswan Office), Ministry of Tourism and Antiquities, Aswan, 81511, Egypt.
| | - Asmaa A Metwally
- Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Aswan University, Aswan, 81511, Egypt
| | - Hams M A Mohamed
- Department of Microbiology, Faculty of Veterinary Medicine, South Valley University, Qena, 83523, Egypt
| | - Mohie A M Haridy
- Department of Pathology and Clinical Pathology, Faculty of Veterinary Medicine, South Valley University, Qena, 83523, Egypt.
| |
Collapse
|
26
|
Yepsen EN, Harrod KS. Influenza Antiviral Subversion: Now the Host Is in on the Act. Am J Respir Cell Mol Biol 2021; 65:1-3. [PMID: 33848230 PMCID: PMC8320119 DOI: 10.1165/rcmb.2021-0094ed] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Erin N Yepsen
- Department of Anesthesiology and Perioperative Medicine University of Alabama at Birmingham Birmingham, Alabama
| | - Kevin S Harrod
- Department of Anesthesiology and Perioperative Medicine University of Alabama at Birmingham Birmingham, Alabama
| |
Collapse
|
27
|
Thornhill EM, Salpor J, Verhoeven D. Respiratory syntycial virus: Current treatment strategies and vaccine approaches. Antivir Chem Chemother 2021; 28:2040206620947303. [PMID: 32741202 PMCID: PMC7412623 DOI: 10.1177/2040206620947303] [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] [Indexed: 01/09/2023] Open
Abstract
Respiratory Syncytial Virus is a yearly respiratory virus that causes significant frequencies of morbidities, particularly in the young and elderly populations. However, preventive vaccines and/or treatment therapies are generally lacking, although much attention is now being placed on this virus. Moreover, there are now multiple strategies currently being explored in a race to the first licensed vaccine. While vaccines are being developed, multiple treatment strategies are being explored to attenuate the severity of infection and thus reduce hospitalization rates in vulnerable populations. This review outlines current strategies to prevent or treat this virus in the hopes of reducing significant human morbidity and mortality that occurs yearly with this seasonal virus.
Collapse
Affiliation(s)
- Elena Margret Thornhill
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, USA
| | - Jessica Salpor
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, USA
| | - David Verhoeven
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, USA
| |
Collapse
|
28
|
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.
Collapse
|
29
|
Mann M, Brasier AR. Evolution of proteomics technologies for understanding respiratory syncytial virus pathogenesis. Expert Rev Proteomics 2021; 18:379-394. [PMID: 34018899 PMCID: PMC8277732 DOI: 10.1080/14789450.2021.1931130] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 05/14/2021] [Indexed: 10/21/2022]
Abstract
Introduction: Respiratory syncytial virus (RSV) is a major human pathogen associated with long term morbidity. RSV replication occurs primarily in the epithelium, producing a complex cellular response associated with acute inflammation and long-lived changes in pulmonary function and allergic disease. Proteomics approaches provide important insights into post-transcriptional regulatory processes including alterations in cellular complexes regulating the coordinated innate response and epigenome.Areas covered: Peer-reviewed proteomics studies of host responses to RSV infections and proteomics techniques were analyzed. Methodologies identified include 1)." bottom-up" discovery proteomics, 2). Organellar proteomics by LC-gel fractionation; 3). Dynamic changes in protein interaction networks by LC-MS; and 4). selective reaction monitoring MS. We introduce recent developments in single-cell proteomics, top-down mass spectrometry, and photo-cleavable surfactant chemistries that will have impact on understanding how RSV induces extracellular matrix (ECM) composition and airway remodeling.Expert opinion: RSV replication induces global changes in the cellular proteome, dynamic shifts in nuclear proteins, and remodeling of epigenetic regulatory complexes linked to the innate response. Pathways discovered by proteomics technologies have led to deeper mechanistic understanding of the roles of heat shock proteins, redox response, transcriptional elongation complex remodeling and ECM secretion remodeling in host responses to RSV infections and pathological sequelae.
Collapse
Affiliation(s)
- Morgan Mann
- Department of Internal Medicine, University of Wisconsin-Madison School of Medicine and Public Health (SMPH), Madison, WI, USA
| | - Allan R Brasier
- Department of Internal Medicine and Institute for Clinical and Translational Research (ICTR), University of Wisconsin-Madison, Madison, WI, USA
| |
Collapse
|
30
|
Pei J, Wagner ND, Zou AJ, Chatterjee S, Borek D, Cole AR, Kim PJ, Basler CF, Otwinowski Z, Gross ML, Amarasinghe GK, Leung DW. Structural basis for IFN antagonism by human respiratory syncytial virus nonstructural protein 2. Proc Natl Acad Sci U S A 2021; 118:e2020587118. [PMID: 33649232 PMCID: PMC7958447 DOI: 10.1073/pnas.2020587118] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Human respiratory syncytial virus (RSV) nonstructural protein 2 (NS2) inhibits host interferon (IFN) responses stimulated by RSV infection by targeting early steps in the IFN-signaling pathway. But the molecular mechanisms related to how NS2 regulates these processes remain incompletely understood. To address this gap, here we solved the X-ray crystal structure of NS2. This structure revealed a unique fold that is distinct from other known viral IFN antagonists, including RSV NS1. We also show that NS2 directly interacts with an inactive conformation of the RIG-I-like receptors (RLRs) RIG-I and MDA5. NS2 binding prevents RLR ubiquitination, a process critical for prolonged activation of downstream signaling. Structural analysis, including by hydrogen-deuterium exchange coupled to mass spectrometry, revealed that the N terminus of NS2 is essential for binding to the RIG-I caspase activation and recruitment domains. N-terminal mutations significantly diminish RIG-I interactions and result in increased IFNβ messenger RNA levels. Collectively, our studies uncover a previously unappreciated regulatory mechanism by which NS2 further modulates host responses and define an approach for targeting host responses.
Collapse
Affiliation(s)
- Jingjing Pei
- John T. Milliken Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO 63110
| | - Nicole D Wagner
- Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63110
| | - Angela J Zou
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
| | - Srirupa Chatterjee
- John T. Milliken Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO 63110
| | - Dominika Borek
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Aidan R Cole
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
| | - Preston J Kim
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
| | - Christopher F Basler
- Center for Microbial Pathogenesis, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303
| | - Zbyszek Otwinowski
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Michael L Gross
- Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63110
| | - Gaya K Amarasinghe
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
| | - Daisy W Leung
- John T. Milliken Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO 63110;
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
| |
Collapse
|
31
|
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: 230] [Impact Index Per Article: 57.5] [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.
Collapse
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.
| |
Collapse
|
32
|
Malinczak CA, Parolia A, Fonseca W, Morris S, Rasky AJ, Bawa P, Zhang Y, Mire MM, Ziegler SF, Ptaschinski C, Chinnaiyan AM, Lukacs NW. TSLP-Driven Chromatin Remodeling and Trained Systemic Immunity after Neonatal Respiratory Viral Infection. THE JOURNAL OF IMMUNOLOGY 2021; 206:1315-1328. [PMID: 33514510 DOI: 10.4049/jimmunol.2001205] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 01/04/2021] [Indexed: 12/26/2022]
Abstract
Our studies have previously shown a role for persistent TSLP production in the lungs of mice after early-life respiratory syncytial virus (RSV) infection that leads to an altered immune phenotype, including accumulation of "inflammatory" dendritic cells (DC). This study investigates the role of TSLP driving systemic trained immunity in DC in early-life RSV-infected mice. Bone marrow-derived DCs (BMDC) from early-life RSV-infected mice at 4 wk postinfection showed enhanced expression of costimulatory molecules and cytokines, including Tslp, that regulate immune cell function. The adoptive transfer of BMDC grown from early-life RSV-infected mice was sufficient to exacerbate allergic disease development. The addition of recombinant TSLP during differentiation of BMDC from naive mice induced a similar altered phenotype as BMDC grown from early-life RSV-infected mice, suggesting a role for TSLP in the phenotypic changes. To assess the role of TSLP in these changes, global transcriptomic characterization of TSLPR-/- BMDC infected with RSV was performed and showed a higher upregulation of type 1 IFN genes and concomitant downregulation of inflammatory genes. Assay for transposase-accessible chromatin using sequencing analysis demonstrated that TSLPR-/- BMDC had a parallel gain in physical chromatin accessibility near type 1 genes and loss in accessibility near genes related to RSV pathology, with IFN regulatory factor 4 (IRF4) and STAT3 predicted as top transcription factors binding within differentially accessible regions in wild-type. Importantly, these studies show that in the absence of TSLP signaling, BMDC are able to mount an appropriate type 1 IFN-associated antiviral response to RSV. In summary, RSV-induced TSLP alters chromatin structure in DC to drive trained innate immunity and activates pathogenic gene programs in mice.
Collapse
Affiliation(s)
| | - Abhijit Parolia
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109
| | - Wendy Fonseca
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109
| | - Susan Morris
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109
| | - Andrew J Rasky
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109
| | - Pushpinder Bawa
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109
| | - Yuping Zhang
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109
| | - Mohamed M Mire
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109
| | - Steven F Ziegler
- Department of Immunology, Benaroya Research Institute, Seattle, WA 98101
| | - Catherine Ptaschinski
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109.,Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, MI 48109
| | - Arul M Chinnaiyan
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109.,Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109; and.,Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109
| | - Nicholas W Lukacs
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109.,Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, MI 48109
| |
Collapse
|
33
|
Mara K, Dai M, Brice AM, Alexander MR, Tribolet L, Layton DS, Bean AGD. Investigating the Interaction between Negative Strand RNA Viruses and Their Hosts for Enhanced Vaccine Development and Production. Vaccines (Basel) 2021; 9:vaccines9010059. [PMID: 33477334 PMCID: PMC7830660 DOI: 10.3390/vaccines9010059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 01/13/2021] [Indexed: 11/30/2022] Open
Abstract
The current pandemic has highlighted the ever-increasing risk of human to human spread of zoonotic pathogens. A number of medically-relevant zoonotic pathogens are negative-strand RNA viruses (NSVs). NSVs are derived from different virus families. Examples like Ebola are known for causing severe symptoms and high mortality rates. Some, like influenza, are known for their ease of person-to-person transmission and lack of pre-existing immunity, enabling rapid spread across many countries around the globe. Containment of outbreaks of NSVs can be difficult owing to their unpredictability and the absence of effective control measures, such as vaccines and antiviral therapeutics. In addition, there remains a lack of essential knowledge of the host–pathogen response that are induced by NSVs, particularly of the immune responses that provide protection. Vaccines are the most effective method for preventing infectious diseases. In fact, in the event of a pandemic, appropriate vaccine design and speed of vaccine supply is the most critical factor in protecting the population, as vaccination is the only sustainable defense. Vaccines need to be safe, efficient, and cost-effective, which is influenced by our understanding of the host–pathogen interface. Additionally, some of the major challenges of vaccines are the establishment of a long-lasting immunity offering cross protection to emerging strains. Although many NSVs are controlled through immunisations, for some, vaccine design has failed or efficacy has proven unreliable. The key behind designing a successful vaccine is understanding the host–pathogen interaction and the host immune response towards NSVs. In this paper, we review the recent research in vaccine design against NSVs and explore the immune responses induced by these viruses. The generation of a robust and integrated approach to development capability and vaccine manufacture can collaboratively support the management of outbreaking NSV disease health risks.
Collapse
|
34
|
Control of IFN-I responses by the aminopeptidase IRAP in neonatal C57BL/6 alveolar macrophages during RSV infection. Mucosal Immunol 2021; 14:949-962. [PMID: 33846534 PMCID: PMC8221999 DOI: 10.1038/s41385-021-00402-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 03/03/2021] [Accepted: 03/22/2021] [Indexed: 02/04/2023]
Abstract
Respiratory Syncytial Virus (RSV) is the major cause of lower respiratory tract infection in infants, in whom, the sensing of RSV by innate immune receptors and its regulation are still poorly described. However, the severe bronchiolitis following RSV infection in neonates has been associated with a defect in type I interferons (IFN-I) production, a cytokine produced mainly by alveolar macrophages (AMs) upon RSV infection in adults. In the present study, neonatal C57BL/6 AMs mobilized very weakly the IFN-I pathway upon RSV infection in vitro and failed to restrain virus replication. However, IFN-I productions by neonatal AMs were substantially increased by the deletion of Insulin-Responsive AminoPeptidase (IRAP), a protein previously involved in the regulation of IFN-I production by dendritic cells. Moreover, neonatal IRAPKO AMs showed a higher expression of IFN-stimulated genes than their wild-type C57BL/6 counterpart. Interestingly, depletion of IRAP did not affect adult AM responses. Finally, we demonstrated that newborn IRAPKO mice infected with RSV had more IFN-I in their lungs and eliminated the virus more efficiently than WT neonates. Taken together, early-life susceptibility to RSV infection may be related to an original age-dependent suppressive function of IRAP on the IFN-I driven-antiviral responses in neonatal AMs.
Collapse
|
35
|
Asha K, Khanna M, Kumar B. Current Insights into the Host Immune Response to Respiratory Viral Infections. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1313:59-83. [PMID: 34661891 DOI: 10.1007/978-3-030-67452-6_4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Respiratory viral infections often lead to severe illnesses varying from mild or asymptomatic upper respiratory tract infections to severe bronchiolitis and pneumonia or/and chronic obstructive pulmonary disease. Common viral infections, including but not limited to influenza virus, respiratory syncytial virus, rhinovirus and coronavirus, are often the leading cause of morbidity and mortality. Since the lungs are continuously exposed to foreign particles, including respiratory pathogens, it is also well equipped for recognition and antiviral defense utilizing the complex network of innate and adaptive immune cells. Immediately upon infection, a range of proinflammatory cytokines, chemokines and an interferon response is generated, thereby making the immune response a two edged sword, on one hand it is required to eliminate viral pathogens while on other hand it's prolonged response can lead to chronic infection and significant pulmonary damage. Since vaccines to all respiratory viruses are not available, a better understanding of the virus-host interactions, leading to the development of immune response, is critically needed to design effective therapies to limit the severity of inflammatory damage, enhance viral clearance and to compliment the current strategies targeting the virus. In this chapter, we discuss the host responses to common respiratory viral infections, the key players of adaptive and innate immunity and the fine balance that exists between the viral clearance and immune-mediated damage.
Collapse
Affiliation(s)
- Kumari Asha
- Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Madhu Khanna
- Department of Virology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India
| | - Binod Kumar
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL, USA
| |
Collapse
|
36
|
Efstathiou C, Abidi SH, Harker J, Stevenson NJ. Revisiting respiratory syncytial virus's interaction with host immunity, towards novel therapeutics. Cell Mol Life Sci 2020; 77:5045-5058. [PMID: 32556372 PMCID: PMC7298439 DOI: 10.1007/s00018-020-03557-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 05/18/2020] [Accepted: 05/20/2020] [Indexed: 12/24/2022]
Abstract
Every year there are > 33 million cases of Respiratory Syncytial Virus (RSV)-related respiratory infection in children under the age of five, making RSV the leading cause of lower respiratory tract infection (LRTI) in infants. RSV is a global infection, but 99% of related mortality is in low/middle-income countries. Unbelievably, 62 years after its identification, there remains no effective treatment nor vaccine for this deadly virus, leaving infants, elderly and immunocompromised patients at high risk. The success of all pathogens depends on their ability to evade and modulate the host immune response. RSV has a complex and intricate relationship with our immune systems, but a clearer understanding of these interactions is essential in the development of effective medicines. Therefore, in a bid to update and focus our research community's understanding of RSV's interaction with immune defences, this review aims to discuss how our current knowledgebase could be used to combat this global viral threat.
Collapse
Affiliation(s)
- C Efstathiou
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - S H Abidi
- Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan
| | - J Harker
- Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College London, South Kensington, London, UK
| | - N J Stevenson
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
| |
Collapse
|
37
|
Jobe F, Simpson J, Hawes P, Guzman E, Bailey D. Respiratory Syncytial Virus Sequesters NF-κB Subunit p65 to Cytoplasmic Inclusion Bodies To Inhibit Innate Immune Signaling. J Virol 2020; 94:JVI.01380-20. [PMID: 32878896 PMCID: PMC7592213 DOI: 10.1128/jvi.01380-20] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 08/28/2020] [Indexed: 12/20/2022] Open
Abstract
Viruses routinely employ strategies to prevent the activation of innate immune signaling in infected cells. Respiratory syncytial virus (RSV) is no exception, as it encodes two accessory proteins (NS1 and NS2) which are well established to block interferon signaling. However, RSV-encoded mechanisms for inhibiting NF-κB signaling are less well characterized. In this study, we identified RSV-mediated antagonism of this pathway, independent of the NS1 and NS2 proteins and indeed distinct from other known viral mechanisms of NF-κB inhibition. In both human and bovine RSV-infected cells, we demonstrated that the p65 subunit of NF-κB is rerouted to perinuclear puncta in the cytoplasm, which are synonymous with viral inclusion bodies (IBs), the site for viral RNA replication. Captured p65 was unable to translocate to the nucleus or transactivate a NF-κB reporter following tumor necrosis factor alpha (TNF-α) stimulation, confirming the immune-antagonistic nature of this sequestration. Subsequently, we used correlative light electron microscopy (CLEM) to colocalize the RSV N protein and p65 within bovine RSV (bRSV) IBs, which are granular, membraneless regions of cytoplasm with liquid organelle-like properties. Additional characterization of bRSV IBs indicated that although they are likely formed by liquid-liquid phase separation (LLPS), they have a differential sensitivity to hypotonic shock proportional to their size. Together, these data identify a novel mechanism for viral antagonism of innate immune signaling which relies on sequestration of the NF-κB subunit p65 to a biomolecular condensate-a mechanism conserved across the Orthopneumovirus genus and not host-cell specific. More generally, they provide additional evidence that RNA virus IBs are important immunomodulatory complexes within infected cells.IMPORTANCE Many viruses replicate almost entirely in the cytoplasm of infected cells; however, how these pathogens are able to compartmentalize their life cycle to provide favorable conditions for replication and to avoid the litany of antiviral detection mechanisms in the cytoplasm remains relatively uncharacterized. In this manuscript, we show that bovine respiratory syncytial virus (bRSV), which infects cattle, does this by generating inclusion bodies in the cytoplasm of infected cells. We confirm that both bRSV and human RSV viral RNA replication takes place in these inclusion bodies, likely meaning these organelles are a functionally conserved feature of this group of viruses (the orthopneumoviruses). Importantly, we also showed that these organelles are able to capture important innate immune transcription factors (in this case NF-KB), blocking the normal signaling processes that tell the nucleus the cell is infected, which may help us to understand how these viruses cause disease.
Collapse
Affiliation(s)
| | | | - Philippa Hawes
- The Pirbright Institute, Guildford, Surrey, United Kingdom
| | - Efrain Guzman
- The Pirbright Institute, Guildford, Surrey, United Kingdom
| | - Dalan Bailey
- The Pirbright Institute, Guildford, Surrey, United Kingdom
| |
Collapse
|
38
|
Zhang X, Zhu Z, Wang C, Yang F, Cao W, Li P, Du X, Zhao F, Liu X, Zheng H. Foot-and-Mouth Disease Virus 3B Protein Interacts with Pattern Recognition Receptor RIG-I to Block RIG-I-Mediated Immune Signaling and Inhibit Host Antiviral Response. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2020; 205:2207-2221. [PMID: 32917788 PMCID: PMC7533709 DOI: 10.4049/jimmunol.1901333] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 08/10/2020] [Indexed: 12/23/2022]
Abstract
Foot-and-mouth disease is a highly contagious disease of pigs, sheep, goats, bovine, and various wild cloven-hoofed animals caused by foot-and-mouth disease virus (FMDV) that has given rise to significant economic loss to global livestock industry. FMDV 3B protein is an important determinant of virulence of the virus. Modifications in 3B protein of FMDV considerably decrease virus yield. In the current study, we demonstrated the significant role of 3B protein in suppression of type I IFN production and host antiviral response in both human embryonic kidney HEK293T cells and porcine kidney PK-15 cells. We found that 3B protein interacted with the viral RNA sensor RIG-I to block RIG-I-mediated immune signaling. 3B protein did not affect the expression of RIG-I but interacted with RIG-I to block the interaction between RIG-I and the E3 ubiquitin ligase TRIM25, which prevented the TRIM25-mediated, Lys63-linked ubiquitination and activation of RIG-I. This inhibition of RIG-I-mediated immune signaling by 3B protein decreased IFN-β, IFN-stimulated genes, and proinflammatory cytokines expression, which in turn promoted FMDV replication. All of the three nonidentical copies of 3B could inhibit type I IFN production, and the aa 17A in each copy of 3B was involved in suppression of IFN-related antiviral response during FMDV infection in porcine cells. Together, our results indicate the role of 3B in suppression of host innate immune response and reveal a novel antagonistic mechanism of FMDV that is mediated by 3B protein.
Collapse
Affiliation(s)
- Xiangle Zhang
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China
| | - Zixiang Zhu
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China
| | - Congcong Wang
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China
| | - Fan Yang
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China
| | - Weijun Cao
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China
| | - Pengfei Li
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China
| | - Xiaoli Du
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China
| | - Furong Zhao
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China
- Institute of Oceanography, Minjiang University, Fuzhou, Fujian 350108, China; and
| | - Xiangtao Liu
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China
- National Foot and Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China
| | - Haixue Zheng
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China;
| |
Collapse
|
39
|
Andresen AMS, Boudinot P, Gjøen T. Kinetics of transcriptional response against poly (I:C) and infectious salmon anemia virus (ISAV) in Atlantic salmon kidney (ASK) cell line. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2020; 110:103716. [PMID: 32360383 DOI: 10.1016/j.dci.2020.103716] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 04/16/2020] [Accepted: 04/16/2020] [Indexed: 05/03/2023]
Abstract
Vaccine adjuvants induce host innate immune responses improving long-lasting adaptive immunity against vaccine antigens. In vitro models can be used to compare these responses between adjuvants and the infection targeted by the vaccine. We utilized transcriptomic profiling of an Atlantic salmon cell line to compare innate immune responses against ISAV and an experimental viral vaccine adjuvant: poly (I:C). Induction of interferon and interferon induced genes were observed after both treatments, but often with different amplitude and kinetics. Using KEGG ortholog database and available software from Bioconductor we could specify a complete bioinformatic pipeline for analysis of transcriptomic data from Atlantic salmon, a feature not previously available. We have identified important differences in the transcriptional profile of Atlantic salmon cells exposed to viral infection and a viral vaccine adjuvant candidate, poly (I:C). This report increases our knowledge of viral host-pathogen interaction in salmon and to which extent these can be mimicked by adjuvant compounds.
Collapse
Affiliation(s)
| | - Pierre Boudinot
- INRA, Virologie et Immunologie Moléculaires, Jouy-en-Josas, France
| | - Tor Gjøen
- Department of Pharmacy, Section for Pharmacology and Pharmaceutical Biosciences, University of Oslo, Oslo, Norway.
| |
Collapse
|
40
|
Andrade CA, Pacheco GA, Gálvez NMS, Soto JA, Bueno SM, Kalergis AM. Innate Immune Components that Regulate the Pathogenesis and Resolution of hRSV and hMPV Infections. Viruses 2020; 12:E637. [PMID: 32545470 PMCID: PMC7354512 DOI: 10.3390/v12060637] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 06/09/2020] [Accepted: 06/09/2020] [Indexed: 02/06/2023] Open
Abstract
The human respiratory syncytial virus (hRSV) and human Metapneumovirus (hMPV) are two of the leading etiological agents of acute lower respiratory tract infections, which constitute the main cause of mortality in infants. However, there are currently approved vaccines for neither hRSV nor hMPV. Moreover, despite the similarity between the pathology caused by both viruses, the immune response elicited by the host is different in each case. In this review, we discuss how dendritic cells, alveolar macrophages, neutrophils, eosinophils, natural killer cells, innate lymphoid cells, and the complement system regulate both pathogenesis and the resolution of hRSV and hMPV infections. The roles that these cells play during infections by either of these viruses will help us to better understand the illnesses they cause. We also discuss several controversial findings, relative to some of these innate immune components. To better understand the inflammation in the lungs, the role of the respiratory epithelium in the recruitment of innate immune cells is briefly discussed. Finally, we review the main prophylactic strategies and current vaccine candidates against both hRSV and hMPV.
Collapse
Affiliation(s)
- Catalina A. Andrade
- Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile; (C.A.A.); (G.A.P.); (N.M.S.G.); (J.A.S.); (S.M.B.)
| | - Gaspar A. Pacheco
- Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile; (C.A.A.); (G.A.P.); (N.M.S.G.); (J.A.S.); (S.M.B.)
| | - Nicolas M. S. Gálvez
- Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile; (C.A.A.); (G.A.P.); (N.M.S.G.); (J.A.S.); (S.M.B.)
| | - Jorge A. Soto
- Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile; (C.A.A.); (G.A.P.); (N.M.S.G.); (J.A.S.); (S.M.B.)
| | - Susan M. Bueno
- Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile; (C.A.A.); (G.A.P.); (N.M.S.G.); (J.A.S.); (S.M.B.)
| | - Alexis M. Kalergis
- Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile; (C.A.A.); (G.A.P.); (N.M.S.G.); (J.A.S.); (S.M.B.)
- Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile
| |
Collapse
|
41
|
Ren Z, Ding T, Zuo Z, Xu Z, Deng J, Wei Z. Regulation of MAVS Expression and Signaling Function in the Antiviral Innate Immune Response. Front Immunol 2020; 11:1030. [PMID: 32536927 PMCID: PMC7267026 DOI: 10.3389/fimmu.2020.01030] [Citation(s) in RCA: 130] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 04/29/2020] [Indexed: 12/13/2022] Open
Abstract
Viral infection is controlled by host innate immune cells that express specialized receptors for viral components. Engagement of these pattern recognition receptors triggers a series of signaling pathways that culminate in the production of antiviral mediators such as type I interferons. Mitochondrial antiviral-signaling protein (MAVS) acts as a central hub for signal transduction initiated by RIG-I-like receptors, which predominantly recognize viral RNA. MAVS expression and function are regulated by both post-transcriptional and post-translational mechanisms, of which ubiquitination and phosphorylation play the most important roles in modulating MAVS function. Increasing evidence indicates that viruses can escape the host antiviral response by interfering at multiple points in the MAVS signaling pathways, thereby maintaining viral survival and replication. This review summarizes recent studies on the mechanisms by which MAVS expression and signaling are normally regulated and on the various strategies employed by viruses to antagonize MAVS activity, which may provide new insights into the design of novel antiviral agents.
Collapse
Affiliation(s)
- Zhihua Ren
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Ting Ding
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Zhicai Zuo
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Zhiwen Xu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Junliang Deng
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Zhanyong Wei
- The College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, China
| |
Collapse
|
42
|
Thornhill EM, Verhoeven D. Respiratory Syncytial Virus's Non-structural Proteins: Masters of Interference. Front Cell Infect Microbiol 2020; 10:225. [PMID: 32509597 PMCID: PMC7248305 DOI: 10.3389/fcimb.2020.00225] [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: 02/25/2020] [Accepted: 04/22/2020] [Indexed: 01/12/2023] Open
Abstract
Respiratory Syncytial Virus (RSV) is a highly prevalent virus that affects the majority of the population. The virus can cause severe disease in vulnerable populations leading to high hospitalization rates from bronchiolitis or secondary bacterial infections leading to pneumonia. Two early and non-structural proteins (Ns1 and Ns2), strongly over-ride the antiviral innate system but also diminish the adaptive response as well. This review will cover interactions of Ns1 and Ns2 with the host antiviral response with a focus on alterations to signaling pathways, cytokine gene expression, and effects of the Ns proteins on mitochondria.
Collapse
Affiliation(s)
| | - David Verhoeven
- Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA, United States
| |
Collapse
|
43
|
Human Type I Interferon Antiviral Effects in Respiratory and Reemerging Viral Infections. J Immunol Res 2020; 2020:1372494. [PMID: 32455136 PMCID: PMC7231083 DOI: 10.1155/2020/1372494] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 02/17/2020] [Accepted: 04/02/2020] [Indexed: 12/13/2022] Open
Abstract
Type I interferons (IFN-I) are a group of related proteins that help regulate the activity of the immune system and play a key role in host defense against viral infections. Upon infection, the IFN-I are rapidly secreted and induce a wide range of effects that not only act upon innate immune cells but also modulate the adaptive immune system. While IFN-I and many IFN stimulated genes are well-known for their protective antiviral role, recent studies have associated them with potential pathogenic functions. In this review, we summarize the current knowledge regarding the complex effects of human IFN-I responses in respiratory as well as reemerging flavivirus infections of public health significance and the molecular mechanisms by which viral proteins antagonize the establishment of an antiviral host defense. Antiviral effects and immune modulation of IFN-stimulated genes is discussed in resisting and controlling pathogens. Understanding the mechanisms of these processes will be crucial in determining how viral replication can be effectively controlled and in developing safe and effective vaccines and novel therapeutic strategies.
Collapse
|
44
|
Stephens LM, Varga SM. Function and Modulation of Type I Interferons during Respiratory Syncytial Virus Infection. Vaccines (Basel) 2020; 8:vaccines8020177. [PMID: 32290326 PMCID: PMC7349809 DOI: 10.3390/vaccines8020177] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/04/2020] [Accepted: 04/07/2020] [Indexed: 02/07/2023] Open
Abstract
Respiratory syncytial virus (RSV) is the leading cause of lower respiratory infections in infants and young children, accounting for an estimated 3 million hospitalizations annually worldwide. Despite the major health burden, there is currently no licensed RSV vaccine. RSV is recognized by a range of cellular receptors including both toll-like receptors (TLR) and retinoic acid-inducible gene-I-like receptors (RIG-I). This interaction initiates signaling through mitochondrial antiviral signaling (MAVS) and interferon regulatory factor (IRF) proteins, resulting in the induction of type I interferons (IFN). Early viral control is mediated by either IFN-α or IFN-β signaling through the IFN receptor (IFNAR), inducing the production of antiviral interferon-stimulating genes (ISGs). Type I IFNs also initiate the early production of proinflammatory cytokines including interleukin 6 (IL-6), tumor necrosis factor (TNF), and IFN-γ. Type I IFN levels correlate with age, and inadequate production may be a critical factor in facilitating the increased RSV disease severity observed in infants. Here, we review the current literature on the function of type I IFNs in RSV pathogenesis, as well as their involvement in the differential immune responses observed in infants and adults.
Collapse
Affiliation(s)
- Laura M. Stephens
- Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, USA;
| | - Steven M. Varga
- Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, USA;
- Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242, USA
- Department of Pathology, University of Iowa, Iowa City, IA 52242, USA
- Correspondence: ; Tel.: +1-319-335-7784
| |
Collapse
|
45
|
Hu M, Bogoyevitch MA, Jans DA. Impact of Respiratory Syncytial Virus Infection on Host Functions: Implications for Antiviral Strategies. Physiol Rev 2020; 100:1527-1594. [PMID: 32216549 DOI: 10.1152/physrev.00030.2019] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Respiratory syncytial virus (RSV) is one of the leading causes of viral respiratory tract infection in infants, the elderly, and the immunocompromised worldwide, causing more deaths each year than influenza. Years of research into RSV since its discovery over 60 yr ago have elucidated detailed mechanisms of the host-pathogen interface. RSV infection elicits widespread transcriptomic and proteomic changes, which both mediate the host innate and adaptive immune responses to infection, and reflect RSV's ability to circumvent the host stress responses, including stress granule formation, endoplasmic reticulum stress, oxidative stress, and programmed cell death. The combination of these events can severely impact on human lungs, resulting in airway remodeling and pathophysiology. The RSV membrane envelope glycoproteins (fusion F and attachment G), matrix (M) and nonstructural (NS) 1 and 2 proteins play key roles in modulating host cell functions to promote the infectious cycle. This review presents a comprehensive overview of how RSV impacts the host response to infection and how detailed knowledge of the mechanisms thereof can inform the development of new approaches to develop RSV vaccines and therapeutics.
Collapse
Affiliation(s)
- MengJie Hu
- Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia; and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia
| | - Marie A Bogoyevitch
- Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia; and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia
| | - David A Jans
- Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia; and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia
| |
Collapse
|
46
|
Wu W, Choi EJ, Lee I, Lee YS, Bao X. Non-Coding RNAs and Their Role in Respiratory Syncytial Virus (RSV) and Human Metapneumovirus (hMPV) Infections. Viruses 2020; 12:v12030345. [PMID: 32245206 PMCID: PMC7150941 DOI: 10.3390/v12030345] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 03/14/2020] [Accepted: 03/18/2020] [Indexed: 12/17/2022] Open
Abstract
Recent high-throughput sequencing revealed that only 2% of the transcribed human genome codes for proteins, while the majority of transcriptional products are non-coding RNAs (ncRNAs). Herein, we review the current knowledge regarding ncRNAs, both host- and virus-derived, and their role in respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) infections. RSV is known as the most common cause of lower respiratory tract infection (LRTI) in children, while hMPV is also a significant contributor to LRTI in the pediatrics population. Although RSV and hMPV are close members, belonging to the Pneumoviridae family, they induce distinct changes in the ncRNA profile. Several types of host ncRNAs, including long ncRNA (lncRNA), microRNAs (miRNAs), and transfer RNA (tRNA)-derived RNA fragments (tRFs), are involved as playing roles in RSV and/or hMPV infection. Given the importance of ncRNAs in regulating the expression and functions of genes and proteins, comprehensively understanding the roles of ncRNAs in RSV/hMPV infection could shed light upon the disease mechanisms of RSV and hMPV, potentially providing insights into the development of prevention strategies and antiviral therapy. The presence of viral-derived RNAs and the potential of using ncRNAs as diagnostic biomarkers are also discussed in this review.
Collapse
Affiliation(s)
- Wenzhe Wu
- Department of Pediatrics, The University of Texas Medical Branch, Galveston, TX 77555, USA; (W.W.); (E.-J.C.)
| | - Eun-Jin Choi
- Department of Pediatrics, The University of Texas Medical Branch, Galveston, TX 77555, USA; (W.W.); (E.-J.C.)
| | | | - Yong Sun Lee
- Department of Cancer System Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si Gyeonggi-do 10408, Korea;
| | - Xiaoyong Bao
- Department of Pediatrics, The University of Texas Medical Branch, Galveston, TX 77555, USA; (W.W.); (E.-J.C.)
- Sealy Center for Molecular Medicine, The University of Texas Medical Branch, Galveston, TX 77555, USA
- The Institute of Translational Sciences, The University of Texas Medical Branch, Galveston, TX 77555, USA
- The Institute for Human Infections and Immunity, The University of Texas Medical Branch, Galveston, TX 77555, USA
- Correspondence: ; Tel.: +409-772-1777
| |
Collapse
|
47
|
Bergeron HC, Tripp RA. Emerging small and large molecule therapeutics for respiratory syncytial virus. Expert Opin Investig Drugs 2020; 29:285-294. [PMID: 32096420 DOI: 10.1080/13543784.2020.1735349] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Introduction: Respiratory syncytial virus (RSV) causes lower respiratory tract infections and can lead to morbidity and mortality in the infant, elderly and immunocompromised. There is no vaccine and therapeutic interventions are limited. RSV disease research has yielded the development of several prophylactic and therapeutic treatments. Several promising candidates are currently under investigation.Areas covered: Small and large molecule approaches to RSV treatment were examined and categorized by their mechanism of action using data from PubMed, clinicaltrials.gov, and from the sponsoring organizations publicly available pipeline information. These results are prefaced by an overview of RSV to provide the context for rational therapy development.Expert opinion: While small molecule drugs show promise for RSV treatment, we believe that large molecule therapy using anti-RSV G and F protein monoclonal antibodies (mAbs) will most efficaciously and safely ameliorate RSV disease.
Collapse
Affiliation(s)
- Harrison C Bergeron
- Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
| | - Ralph A Tripp
- Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
| |
Collapse
|
48
|
Contribution of Dendritic Cells in Protective Immunity against Respiratory Syncytial Virus Infection. Viruses 2020; 12:v12010102. [PMID: 31952261 PMCID: PMC7020095 DOI: 10.3390/v12010102] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 01/08/2020] [Accepted: 01/13/2020] [Indexed: 02/07/2023] Open
Abstract
Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in infants and the elderly. The socioeconomic burden of RSV infection is substantial because it leads to serious respiratory problems, subsequent hospitalization, and mortality. Despite its clinical significance, a safe and effective vaccine is not yet available to prevent RSV infection. Upon RSV infection, lung dendritic cells (DCs) detecting pathogens migrate to the lymph nodes and activate the adaptive immune response. Therefore, RSV has evolved various immunomodulatory strategies to inhibit DC function. Due to the capacity of RSV to modulate defense mechanisms in hosts, RSV infection results in inappropriate activation of immune responses resulting in immunopathology and frequent reinfection throughout life. This review discusses how DCs recognize invading RSV and induce adaptive immune responses, as well as the regulatory mechanisms mediated by RSV to disrupt DC functions and ultimately avoid host defenses.
Collapse
|
49
|
Respiratory syncytial virus nonstructural proteins 1 and 2: Exceptional disrupters of innate immune responses. PLoS Pathog 2019; 15:e1007984. [PMID: 31622448 PMCID: PMC6797084 DOI: 10.1371/journal.ppat.1007984] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Human respiratory syncytial virus (RSV) is the most important cause of acute lower respiratory tract disease in infants worldwide. As a first line of defense against respiratory infections, innate immune responses, including the production of type I and III interferons (IFNs), play an important role. Upon infection with RSV, multiple pattern recognition receptors (PRRs) can recognize RSV-derived pathogen-associated molecular patterns (PAMPs) and mount innate immune responses. Retinoic-acid-inducible gene-I (RIG-I) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) have been identified as important innate receptors to mount type I IFNs during RSV infection. However, type I IFN levels remain surprisingly low during RSV infection despite strong viral replication. The poor induction of type I IFNs can be attributed to the cooperative activity of 2 unique, nonstructural (NS) proteins of RSV, i.e., NS1 and NS2. These viral proteins have been shown to suppress both the production and signaling of type I and III IFNs by counteracting a plethora of key host innate signaling proteins. Moreover, increasing numbers of IFN-stimulated genes (ISGs) are being identified as targets of the NS proteins in recent years, highlighting an underexplored protein family in the identification of NS target proteins. To understand the diverse effector functions of NS1 and NS2, Goswami and colleagues proposed the hypothesis of the NS degradasome (NSD) complex, a multiprotein complex made up of, at least, NS1 and NS2. Furthermore, the crystal structure of NS1 was resolved recently and, remarkably, identified NS1 as a structural paralogue of the RSV matrix protein. Unfortunately, no structural data on NS2 have been published so far. In this review, we briefly describe the PRRs that mount innate immune responses upon RSV infection and provide an overview of the various effector functions of NS1 and NS2. Furthermore, we discuss the ubiquitination effector functions of NS1 and NS2, which are in line with the hypothesis that the NSD shares features with the canonical 26S proteasome.
Collapse
|
50
|
Barik S. In silico structure analysis of alphaviral RNA genomes shows diversity in the evasion of IFIT1-mediated innate immunity. J Biosci 2019; 44:79. [PMID: 31502557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The IFIT (interferon-induced proteins with tetratricopeptide repeats) family constitutes a major arm of the antiviral function of type I interferon (IFN). Human IFIT1, the earliest discovered member of this family, inhibits several viruses of positivestrand RNA genome. IFIT1 specifically recognizes single-stranded RNAwith canonical 7-methylguanylate cap at the 50 end (Cap0), and inhibits their translation by competing with eIF4E (eukaryotic initiation factor 4E), an essential factor for 50Cap recognition. Recently, a novel viral mechanism of IFIT1 suppression was reported, in which an RNA hairpin in the 50 untranslated region (50UTR) of the viral genome prevented recognition by IFIT1 and enhanced virus growth. Here, I have analyzed the in silico predicted structures in the 50UTR of the genomes of the Alphaviruses, a large group of enveloped RNA virus with positive-sense single-stranded genome. The results uncovered a large ensemble of RNA secondary structures of diverse size and shape in the different viruses, which showed little correspondence to the phylogeny of the viruses. Unexpectedly, the 50UTR of several viral genomes in this family did not fold into any structure, suggesting either their extreme sensitivity to IFIT1 or the existence of alternative viral mechanisms of subverting IFIT1 function.
Collapse
|