Antagonism of stress granules is key to SARS-CoV-2 infection and pathogenesis
9 affiliations
- 1Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas, USA
- 2Human Pathophysiology and Translational Medicine, University of Texas Medical Branch, Galveston, Texas, USA
- 3Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas, USA
- 4Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
- 5Emory Vaccine Center, Emory University, Atlanta, Georgia, USA
- 6World Reference Center of Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, Texas, USA
- 7Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
- 8Center for Biodefense & Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA
- 9Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, Texas, USA
Abstract
Viruses must subvert host responses to facilitate successful infection. While most antiviral responses are associated with interferons, stress granules (SGs) are another barrier to viral infection by inducing translation arrest. To combat SG activity, viruses have evolved mechanisms to disrupt formation and disassemble these complexes. Our prior studies identified residues in SARS-CoV-2 NSP3 (Y138/F145) and nucleocapsid (F17) that independently antagonize SG activity. Disrupting these key residues in NSP3 or nucleocapsid attenuated viral replication, but only modestly impacted in vivo pathogenesis, suggesting overlap in SG antagonism partially compensates for the individual losses. In this study, we evaluated a SARS-CoV-2 mutant (YF/F17A) that combines the NSP3 and N mutations. We find that loss of both SG-antagonizing functions attenuates SARS-CoV-2 replication in vitro. While no changes are seen in type I interferon sensitivity, attenuation corresponds to increased induction of SGs. Importantly, the SARS-CoV-2 YF/F17A mutant attenuates significantly in vivo, with reduced viral replication, less weight loss, and limited immune pathology. Notably, infection with the YF/F17A mutant stimulated less interferon and inflammation. Despite these muted host responses, the YF/F17A mutant stimulated robust protection against subsequent challenge with WT SARS-CoV-2. Overall, the study highlights the importance of SG control for SARS-CoV-2 infection and offers a novel, interferon-independent target for vaccination and therapeutic treatment going forward.
IMPORTANCE: This study demonstrates that SARS-CoV-2 uses multiple mechanisms to block host stress granules during infection. Knocking out both N- and NSP3-mediated antagonism of stress granules attenuates viral replication and disease caused by SARS-CoV-2. Importantly, while most therapeutics target key viral processes or induce interferon pathways, this study shows stress granule activation as a novel approach to attenuate and treat coronavirus infection.
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BibTeX
@article{alvarado2026antagonism,
title = {{Antagonism of stress granules is key to SARS-CoV-2 infection and pathogenesis}},
author = {R. Elias Alvarado and Jennifer Chen and Kumari G. Lokugamage and Yiyang Zhou and Leah K. Estes and Angelica L. Morgan and Yani Ahearn and Xiangxue Deng and Lilin Lai and Arian Moayyed and William Meyers and Jessica A. Plante and Ken S. Plante and David H. Walker and Xuping Xie and Mehul S. Suthar and Bryan A. Johnson and Vineet D. Menachery},
journal = {Journal of Virology},
year = {2026},
month = sep,
doi = {10.1128/jvi.00992-26},
url = {https://doi.org/10.1128/jvi.00992-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Antagonism of stress granules is key to SARS-CoV-2 infection and pathogenesis
AU - R. Elias Alvarado
AU - Jennifer Chen
AU - Kumari G. Lokugamage
AU - Yiyang Zhou
AU - Leah K. Estes
AU - Angelica L. Morgan
AU - Yani Ahearn
AU - Xiangxue Deng
AU - Lilin Lai
AU - Arian Moayyed
AU - William Meyers
AU - Jessica A. Plante
AU - Ken S. Plante
AU - David H. Walker
AU - Xuping Xie
AU - Mehul S. Suthar
AU - Bryan A. Johnson
AU - Vineet D. Menachery
PY - 2026
DA - 2026/09/08
JO - Journal of Virology
DO - 10.1128/jvi.00992-26
UR - https://doi.org/10.1128/jvi.00992-26
AB - Viruses must subvert host responses to facilitate successful infection. While most antiviral responses are associated with interferons, stress granules (SGs) are another barrier to viral infection by inducing translation arrest. To combat SG activity, viruses have evolved mechanisms to disrupt formation and disassemble these complexes. Our prior studies identified residues in SARS-CoV-2 NSP3 (Y138/F145) and nucleocapsid (F17) that independently antagonize SG activity. Disrupting these key residues in NSP3 or nucleocapsid attenuated viral replication, but only modestly impacted in vivo pathogenesis, suggesting overlap in SG antagonism partially compensates for the individual losses. In this study, we evaluated a SARS-CoV-2 mutant (YF/F17A) that combines the NSP3 and N mutations. We find that loss of both SG-antagonizing functions attenuates SARS-CoV-2 replication in vitro. While no changes are seen in type I interferon sensitivity, attenuation corresponds to increased induction of SGs. Importantly, the SARS-CoV-2 YF/F17A mutant attenuates significantly in vivo, with reduced viral replication, less weight loss, and limited immune pathology. Notably, infection with the YF/F17A mutant stimulated less interferon and inflammation. Despite these muted host responses, the YF/F17A mutant stimulated robust protection against subsequent challenge with WT SARS-CoV-2. Overall, the study highlights the importance of SG control for SARS-CoV-2 infection and offers a novel, interferon-independent target for vaccination and therapeutic treatment going forward. IMPORTANCE: This study demonstrates that SARS-CoV-2 uses multiple mechanisms to block host stress granules during infection. Knocking out both N- and NSP3-mediated antagonism of stress granules attenuates viral replication and disease caused by SARS-CoV-2. Importantly, while most therapeutics target key viral processes or induce interferon pathways, this study shows stress granule activation as a novel approach to attenuate and treat coronavirus infection.
SN - 0022-538X
SN - 1098-5514
ER -