ArticleProceedings of the National Academy of Sciences of the United States of America2022
Caspase-4/11 exacerbates disease severity in SARS-CoV-2 infection by promoting inflammation and immunothrombosis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 62 citations in OpenAlex.
- Caspase-11-mediated hyperinflammation impairs CD8+ T cell immunity and viral clearance in severe SARS-CoV-2 infection.JCI insight · 2026Article
- Association of bronchoalveolar lavage fluid caspase-4 with inflammatory responses in pediatric acute respiratory distress syndrome.Translational pediatrics · 2026Article
- ERK/Smurf1 regulates non-canonical pyroptosis by prompting Caspase-11 ubiquitination.Cell death and differentiation · 2026Article
- Gasdermin E is dispensable for H1N1 influenza virus pathogenesis in mice.Microbiology spectrum · 2026Article
- IFITM3 deficiency drives SARS-CoV-2 adaptation while preserving variant-specific traits.Nature communications · 2026Article
- Advances of Caspase-11 for veterinary respiratory infections.Frontiers in veterinary science · 2026Review
- SARS-CoV-2 innate immune recognition and implications for respiratory health.Cytokine & growth factor reviews · 2025Review
- Regulation of inflammatory processes by caspases.Nature reviews. Molecular cell biology · 2025Review
- Pyroptosis in Respiratory Virus Infections: A Narrative Review of Mechanisms, Pathophysiology, and Potential Therapeutic Interventions.Microorganisms · 2025Review
- Cardioprotective effects of AMPK activation in H1N1 influenza virus infection.bioRxiv : the preprint server for biology · 2025Article
- New insights into the noncanonical inflammasome point to caspase-4 as a druggable target.Nature reviews. Immunology · 2025Review
- Bruton's tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors driven by BCL10 gain-of-function mutants to venetoclax.Blood cancer journal · 2025Article
- Review
- Cell death in acute lung injury: caspase-regulated apoptosis, pyroptosis, necroptosis, and PANoptosis.Frontiers in pharmacology · 2025Review
- Exploring Pyroptosis-related Signature Genes and Potential Drugs in Ulcerative Colitis by Transcriptome Data and Animal Experimental Validation.Inflammation · 2024Article
- Innate Immunity in Protection and Pathogenesis During Coronavirus Infections and COVID-19.Annual review of immunology · 2024Review
- IFN-λ uniquely promotes CD8 T cell immunity against SARS-CoV-2 relative to type I IFN.JCI insight · 2024Article
- Gasdermin D promotes influenza virus-induced mortality through neutrophil amplification of inflammation.Nature communications · 2024Article
- Bioluminescence imaging reveals enhanced SARS-CoV-2 clearance in mice with combinatorial regimens.iScience · 2024Article
- Dectin-1 aggravates neutrophil inflammation through caspase-11/4-mediated macrophage pyroptosis in asthma.Respiratory research · 2024Article
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Authors and funding
42 authors at 6 institutions in 2 countries.
Funding
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2) is a worldwide health concern, and new treatment strategies are needed. Targeting inflammatory innate immunity pathways holds therapeutic promise, but effective molecular targets remain elusive. Here, we show that human caspase-4 (CASP4) and its mouse homolog, caspase-11 (CASP11), are up-regulated in SARS–CoV-2 infections and that CASP4 expression correlates with severity of SARS–CoV-2 infection in humans. SARS–CoV-2–infected Casp11−/− mice were protected from severe weight loss and lung pathology, including blood vessel damage, compared to wild-type (WT) mice and mice lacking the caspase downstream effector gasdermin-D (Gsdmd−/−). Notably, viral titers were similar regardless of CASP11 knockout. Global transcriptomics of SARS–CoV-2–infected WT, Casp11−/−, and Gsdmd−/− lungs identified restrained expression of inflammatory molecules and altered neutrophil gene signatures in Casp11−/− mice. We confirmed that protein levels of inflammatory mediators interleukin (IL)-1β, IL-6, and CXCL1, as well as neutrophil functions, were reduced in Casp11−/− lungs. Additionally, Casp11−/− lungs accumulated less von Willebrand factor, a marker for endothelial damage, but expressed more Kruppel-Like Factor 2, a transcription factor that maintains vascular integrity. Overall, our results demonstrate that CASP4/11 promotes detrimental SARS–CoV-2–induced inflammation and coagulopathy, largely independently of GSDMD, identifying CASP4/11 as a promising drug target for treatment and prevention of severe COVID-19.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.