{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:33:35Z","timestamp":1792787615188,"version":"4.5.0"},"reference-count":81,"publisher":"American Society for Clinical Investigation","issue":"18","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Allergy and Infectious Diseases","award":["5P01AI175399-02"],"award-info":[{"award-number":["5P01AI175399-02"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,22]]},"abstract":"<jats:p>\n                    Severe SARS-CoV-2 infection is characterized by lung hyperinflammation, impaired IFN responses, and defective T cell activation, yet the molecular drivers of these immune dysregulations remain incompletely understood. Caspase-11 (CASP11), a key effector of the noncanonical inflammasome, has been shown to mediate an innate hyperinflammatory response and cytokine release in a mild SARS-CoV-2 infection model. However, the role played by CASP11 in severe SARS-CoV-2 disease and how it affects adaptive immunity has not been identified. Here, we found that CASP11 exacerbates severe SARS-CoV-2 pathogenesis by amplifying early innate immune responses while concurrently impairing antiviral CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell immunity. Using global KO mice, hematopoietic BM chimeras, and Cx3cr1-expressing mononuclear phagocyte system cell\u2013specific CASP11 deletion models, we show that targeting CASP11 reduces lung inflammation, promotes early NK cell\u2013mediated IFN-\u03b3 production, and enhances robust virus-specific effector CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell responses. This was associated with enhanced viral clearance and improved survival, even under lethal infection conditions. Importantly, CASP11-KO mice also exhibited faster resolution of postviral inflammation. These findings position CASP11 as a promising immunomodulatory target for acute and delayed manifestations of severe SARS-CoV-2 infection.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.199896","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:01:08Z","timestamp":1790013668000},"source":"Crossref","is-referenced-by-count":0,"title":["Caspase-11\u2013mediated hyperinflammation impairs CD8+ T cell immunity and viral clearance in severe SARS-CoV-2 infection"],"prefix":"10.1172","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4056-7429","authenticated-orcid":true,"given":"Mostafa M.","family":"Eltobgy","sequence":"first","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed M.","family":"Shamseldin","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."},{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, Helwan University, Cairo, Egypt."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen D.","family":"Whitham","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba M.","family":"Amer","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0250-2210","authenticated-orcid":true,"given":"Jeffrey R.","family":"Atkinson","sequence":"additional","affiliation":[{"name":"Department of Neurology, College of Medicine and Wexner Medical Center,"},{"name":"Neuroscience Research Institute, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa","family":"Badr","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse M.","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gauruv","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yara Y.","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rabab","family":"El-Mergawy","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Perez","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E.","family":"Faber","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5768-7884","authenticated-orcid":true,"given":"Maciej","family":"Pietrzak","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Webb","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Nursing, University of South Florida, Tampa, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam D.","family":"Kenney","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Destiny","family":"Bissell","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihad I.","family":"Omran","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shady","family":"Estfanous","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, Helwan University, Cairo, Egypt."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kylene P.","family":"Daily","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Yousif","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa R.","family":"Joldrichsen","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"McNamara","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahesh","family":"KC","sequence":"additional","affiliation":[{"name":"Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark E.","family":"Peeples","sequence":"additional","affiliation":[{"name":"Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, Ohio, USA."},{"name":"Infectious Diseases Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily A.","family":"Hemann","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hazem E.","family":"Ghoneim","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahid M.","family":"Nimjee","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9839-384X","authenticated-orcid":true,"given":"Estelle","family":"Cormet-Boyaka","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianrong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prosper N.","family":"Boyaka","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob S.","family":"Yount","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."},{"name":"Infectious Diseases Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0906-6319","authenticated-orcid":true,"given":"Benjamin M.","family":"Segal","sequence":"additional","affiliation":[{"name":"Department of Neurology, College of Medicine and Wexner Medical Center,"},{"name":"Neuroscience Research Institute, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Purnima","family":"Dubey","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amal O.","family":"Amer","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio, USA."},{"name":"Infectious Diseases Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2012-7"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30183-5"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.2648"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2002032"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2588-y"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20200652"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1051-9"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc6027"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0291332"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.140329"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20220621"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202111-2493OC"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1111\/all.14866"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc8511"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.600405"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1038-6"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17292-4"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00827"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-01122-w"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1089\/vim.2022.0123"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/immadv\/ltab015"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20201707"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04702-4"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-022-01831-0"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00588-x"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25015-6"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04802-1"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.58"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13775"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2000373"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-025-01142-9"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2202012119"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12910"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiad037"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.09.050"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/nature04651"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2012.69"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.785457"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00792-0"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-06138-8"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2013.02.008"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.171830"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.07.054"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abk1741"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.886431"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01724-6"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1186\/s12931-025-03200-1"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1010359"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.04.004"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.12.001"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2016-0361OC"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.11.4106-4114.2000"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc6261"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-021-00750-4"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2021.06.018"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.05.010"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.607069"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0402-6"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2017.11.007"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-023-01104-y"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb8925"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0346-x"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1186\/s12879-024-09490-y"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1046639"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiad260"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108728"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42455-4"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01970"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1804556115"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.785222"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-021-00881-3"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0100978"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20041463"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adg5461"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abl4509"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20201241"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)00510-X"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-022-00642-4"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2100433"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1500812"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.158153"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/199896\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:35:07Z","timestamp":1790091307000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/199896"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,22]]},"references-count":81,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,8,11]]},"published-print":{"date-parts":[[2026,9,22]]}},"alternative-id":["10.1172\/jci.insight.199896"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.199896","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,22]]},"article-number":"e199896"}}