Rotavirus VP3 targets MAVS for degradation to inhibit type III interferon expression in intestinal epithelial cells
- Stanford University, United States
- University of Science and Technology of China, China
- Jiangsu Academy of Agricultural Sciences, China
- Yale University, United States
Abstract
Rotaviruses (RVs), a leading cause of severe diarrhea in young children1 and many mammalian species, have evolved multiple strategies to counteract the host innate immunity, specifically interferon (IFN) signaling through RV non-structural protein 1 (NSP1)2. However, whether RV structural components also subvert antiviral response remains under-studied. Here, we found that MAVS, critical for the host RNA sensing pathway upstream of IFN induction3, is degraded by the RV RNA methyl- and guanylyl-transferase (VP3) in a host-range-restricted manner. Mechanistically, VP3 localizes to the mitochondria and mediates the phosphorylation of a previously unidentified SPLTSS motif within the MAVS proline-rich region, leading to its proteasomal degradation and blockade of IFN-λ production in RV-infected intestinal epithelial cells. Importantly, VP3 inhibition of MAVS activity contributes to enhanced RV replication and to viral pathogenesis in vivo. Collectively, our findings establish RV VP3 as a viral antagonist of MAVS function in mammals and uncover a novel pathogen-mediated inhibitory mechanism of MAVS signaling.
Data availability
The data that support the findings of this study are available in the main text, main figures, supplementary figures or attached as Supplementary Tables 1 and 2. Additional information is available in the format of Source Data.
Article and author information
Author details
Funding
National Institute of Allergy and Infectious Diseases (R01 AI125249)
- Harry B Greenberg
National Institute of Allergy and Infectious Diseases (U19 AI116484)
- Harry B Greenberg
Thrasher Research Fund (Early Career Award)
- Siyuan Ding
National Natural Science Foundation of China (81788104)
- Shu Zhu
Howard Hughes Medical Institute
- Richard A Flavell
National Institute of Allergy and Infectious Diseases (K99 AI135031)
- Siyuan Ding
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Age and sex-matched were used in this study. Mice were specific pathogen-free, maintained under a strict 12 hour light cycle, and given a regular chow diet ad libitum. All protocols used in this study were compliant with the Veterinary Medical Unit of Palo Alto VA Health Care System (PAVAHCS) and approved by the IACUC committee.
Copyright
© 2018, Ding et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Rotavirus VP3 targets MAVS for degradation to inhibit type III interferon expression in intestinal epithelial cells
eLife 7:e39494.
https://doi.org/10.7554/eLife.39494
Further reading
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- Epidemiology and Global Health
- Microbiology and Infectious Disease
Background:
In many settings, a large fraction of the population has both been vaccinated against and infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hence, quantifying the protection provided by post-infection vaccination has become critical for policy. We aimed to estimate the protective effect against SARS-CoV-2 reinfection of an additional vaccine dose after an initial Omicron variant infection.
Methods:
We report a retrospective, population-based cohort study performed in Shanghai, China, using electronic databases with information on SARS-CoV-2 infections and vaccination history. We compared reinfection incidence by post-infection vaccination status in individuals initially infected during the April–May 2022 Omicron variant surge in Shanghai and who had been vaccinated before that period. Cox models were fit to estimate adjusted hazard ratios (aHRs).
Results:
275,896 individuals were diagnosed with real-time polymerase chain reaction-confirmed SARS-CoV-2 infection in April–May 2022; 199,312/275,896 were included in analyses on the effect of a post-infection vaccine dose. Post-infection vaccination provided protection against reinfection (aHR 0.82; 95% confidence interval 0.79–0.85). For patients who had received one, two, or three vaccine doses before their first infection, hazard ratios for the post-infection vaccination effect were 0.84 (0.76–0.93), 0.87 (0.83–0.90), and 0.96 (0.74–1.23), respectively. Post-infection vaccination within 30 and 90 days before the second Omicron wave provided different degrees of protection (in aHR): 0.51 (0.44–0.58) and 0.67 (0.61–0.74), respectively. Moreover, for all vaccine types, but to different extents, a post-infection dose given to individuals who were fully vaccinated before first infection was protective.
Conclusions:
In previously vaccinated and infected individuals, an additional vaccine dose provided protection against Omicron variant reinfection. These observations will inform future policy decisions on COVID-19 vaccination in China and other countries.
Funding:
This study was funded the Key Discipline Program of Pudong New Area Health System (PWZxk2022-25), the Development and Application of Intelligent Epidemic Surveillance and AI Analysis System (21002411400), the Shanghai Public Health System Construction (GWVI-11.2-XD08), the Shanghai Health Commission Key Disciplines (GWVI-11.1-02), the Shanghai Health Commission Clinical Research Program (20214Y0020), the Shanghai Natural Science Foundation (22ZR1414600), and the Shanghai Young Health Talents Program (2022YQ076).
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- Microbiology and Infectious Disease
Pathogenic and nonpathogenic mycobacteria secrete extracellular vesicles (EVs) under various conditions. EVs produced by Mycobacterium tuberculosis (Mtb) have raised significant interest for their potential in cell communication, nutrient acquisition, and immune evasion. However, the relevance of vesicle secretion during tuberculosis infection remains unknown due to the limited understanding of mycobacterial vesicle biogenesis. We have previously shown that a transposon mutant in the LCP-related gene virR (virRmut) manifested a strong attenuated phenotype during experimental macrophage and murine infections, concomitant to enhanced vesicle release. In this study, we aimed to understand the role of VirR in the vesicle production process in Mtb. We employ genetic, transcriptional, proteomics, ultrastructural, and biochemical methods to investigate the underlying processes explaining the enhanced vesiculogenesis phenomenon observed in the virRmut. Our results establish that VirR is critical to sustain proper cell permeability via regulation of cell envelope remodeling possibly through the interaction with similar cell envelope proteins, which control the link between peptidoglycan and arabinogalactan. These findings advance our understanding of mycobacterial extracellular vesicle biogenesis and suggest that these set of proteins could be attractive targets for therapeutic intervention.
