{
  "abstract": "Cells sense infection through dedicated receptors, yet these surveillance pathways are often subverted by pathogen-encoded virulence factors. Guard immunity provides complementary defense by rapidly killing infected cells in response to infection induced stress. However, the symptoms of infection frequently resemble noninfectious stress, raising the question of how they are distinguished. Using quantitative transcriptomics, proteomics, and global translation measurements during viral infections in vitro and in vivo, we show that infection globally suppresses host gene expression and prevents direct antiviral responses. However, the resulting proteostatic stress does not activate guard immunity unless tumor necrosis factor-α (TNFα) is present. We identify the anti-apoptotic protein c-FLIP as a guard for gene expression integrity: its loss sensitizes cells to TNFα, triggering cell death and limiting viral spread. Modeling demonstrates that TNFα and c-FLIP loss function as a biological AND-gate, providing specificity and speed. These findings show how cells integrate internal stress signals with external inflammatory cues to improve the fidelity of death decisions, and how this circuitry may misfire during noninfectious inflammation.",
  "abstract_shown": true,
  "affiliations": [
    "The Department of Systems Biology, Harvard Medical School, Boston, MA 02115",
    "The Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA 19104",
    "Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115",
    "The Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Matthew Sonnett"
    },
    {
      "affs": [
        0
      ],
      "name": "Sanne Boersma",
      "orcid": "0000-0003-3657-0817"
    },
    {
      "affs": [
        0
      ],
      "name": "Madeline E. Ward",
      "orcid": "0009-0001-6850-8885"
    },
    {
      "affs": [
        1
      ],
      "name": "Laura C. Van Eyndhoven"
    },
    {
      "affs": [
        0
      ],
      "name": "Edoardo Centofanti",
      "orcid": "0000-0001-9416-8856"
    },
    {
      "affs": [
        0
      ],
      "name": "Max Brambach",
      "orcid": "0000-0001-6194-9568"
    },
    {
      "affs": [
        2
      ],
      "name": "Changhong Zhou"
    },
    {
      "affs": [
        2
      ],
      "name": "David M. Knipe",
      "orcid": "0000-0003-1554-6236"
    },
    {
      "affs": [
        1,
        3
      ],
      "name": "Arjun Raj"
    },
    {
      "affs": [
        0
      ],
      "name": "Alon Oyler-Yaniv"
    },
    {
      "affs": [
        0
      ],
      "name": "Jennifer Oyler-Yaniv",
      "orcid": "0000-0001-8937-8592"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3466d15nawjf0.bib",
  "cited_by": 0,
  "doi": "10.1073/pnas.2600336123",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13715744/",
  "id": "3466d15nawjf0",
  "issns": [
    "0027-8424",
    "1091-6490"
  ],
  "landing_url": "https://doi.org/10.1073/pnas.2600336123",
  "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",
      "435"
    ],
    [
      "heading",
      "Biological Sciences"
    ],
    [
      "heading",
      "Systems Biology"
    ],
    [
      "openalex",
      "2403|interferon and immune responses"
    ]
  ],
  "openalex": "W7223249581",
  "pdf_url": null,
  "pmcid": "PMC13715744",
  "pmid": "42911865",
  "published": "2026-10-22",
  "publisher": "National Academy of Sciences",
  "ris": "https://research.draconitic.com/paper/3466d15nawjf0.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T12:22:57Z",
      "native_id": "PMC13715744",
      "source": "pmc",
      "url": "https://doi.org/10.1073/pnas.2600336123"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "heading:Systems Biology",
      "subfield": "systems-synthetic"
    }
  ],
  "title": "c-FLIP loss links arrest of gene expression to TNFα-dependent antiviral guard immunity",
  "title_text": "c-FLIP loss links arrest of gene expression to TNFα-dependent antiviral guard immunity",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:22:57Z",
  "url": "https://research.draconitic.com/paper/3466d15nawjf0",
  "venue": "Proceedings of the National Academy of Sciences of the United States of America",
  "versions": []
}