{
  "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.\n\nIMPORTANCE: 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas, USA",
    "Human Pathophysiology and Translational Medicine, University of Texas Medical Branch, Galveston, Texas, USA",
    "Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas, USA",
    "Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA",
    "Emory Vaccine Center, Emory University, Atlanta, Georgia, USA",
    "World Reference Center of Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, Texas, USA",
    "Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA",
    "Center for Biodefense & Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA",
    "Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, Texas, USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 18,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "R. Elias Alvarado"
    },
    {
      "affs": [
        0
      ],
      "name": "Jennifer Chen"
    },
    {
      "affs": [
        0,
        3,
        4
      ],
      "name": "Kumari G. Lokugamage"
    },
    {
      "affs": [
        0
      ],
      "name": "Yiyang Zhou",
      "orcid": "0000-0001-8956-3229"
    },
    {
      "affs": [
        0
      ],
      "name": "Leah K. Estes"
    },
    {
      "affs": [
        0,
        3,
        4
      ],
      "name": "Angelica L. Morgan"
    },
    {
      "affs": [
        0
      ],
      "name": "Yani Ahearn"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiangxue Deng"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Lilin Lai"
    },
    {
      "affs": [
        0
      ],
      "name": "Arian Moayyed"
    },
    {
      "affs": [
        0
      ],
      "name": "William Meyers"
    },
    {
      "affs": [
        0,
        5
      ],
      "name": "Jessica A. Plante"
    },
    {
      "affs": [
        0,
        5
      ],
      "name": "Ken S. Plante"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "David H. Walker"
    },
    {
      "affs": [
        0,
        8
      ],
      "name": "Xuping Xie",
      "orcid": "0000-0003-0918-016X"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Mehul S. Suthar",
      "orcid": "0000-0002-2686-8380"
    },
    {
      "affs": [
        0,
        8
      ],
      "name": "Bryan A. Johnson",
      "orcid": "0000-0002-8999-1255"
    },
    {
      "affs": [
        0,
        3,
        4
      ],
      "name": "Vineet D. Menachery",
      "orcid": "0000-0001-8803-7606"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7r9z8gbdxxg63.bib",
  "cited_by": 0,
  "doi": "10.1128/jvi.00992-26",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13712807/",
  "id": "7r9z8gbdxxg63",
  "issns": [
    "0022-538X",
    "1098-5514"
  ],
  "landing_url": "https://doi.org/10.1128/jvi.00992-26",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Virus-Cell Interactions"
    ],
    [
      "openalex",
      "2725|SARS-CoV-2 and COVID-19 Research"
    ]
  ],
  "openalex": "W7211930607",
  "pdf_url": null,
  "pmcid": "PMC13712807",
  "pmid": "42708611",
  "published": "2026-09-08",
  "publisher": "American Society for Microbiology (ASM)",
  "ris": "https://research.draconitic.com/paper/7r9z8gbdxxg63.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:23:19Z",
      "native_id": "PMC13712807",
      "source": "pmc",
      "url": "https://doi.org/10.1128/jvi.00992-26"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2725|SARS-CoV-2 and COVID-19 Research",
      "subfield": "infectious-disease"
    }
  ],
  "title": "Antagonism of stress granules is key to SARS-CoV-2 infection and pathogenesis",
  "title_text": "Antagonism of stress granules is key to SARS-CoV-2 infection and pathogenesis",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:23:19Z",
  "url": "https://research.draconitic.com/paper/7r9z8gbdxxg63",
  "venue": "Journal of Virology",
  "versions": []
}