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Polymerase delta-interacting protein-2 (Poldip2) mediates lung inflammation and vascular permeability after lipopolysaccharide-induced acute respiratory distress syndrome; however, whether it also affects the pathological consequences of SARS-CoV-2 infection is completely unknown. Here, we assessed the role of Poldip2 in inflammation, immune cell infiltration and lung tissue damage in response to SARS-CoV-2. Our data show that Poldip2 expression was elevated in human lung vascular endothelium after infection. In a Poldip2-deficient heterozygous mouse model, acute clinical symptoms were not affected. However, seven days after infection, Poldip2 knockdown reduced viral load, decreased infiltration of myeloperoxidase (MPO)-positive neutrophils into inflamed lungs,\u00a0and reduced tissue damage. Poldip2 also modulated the inflammatory response to viral infection in a heterogeneous manner, reflecting its diverse regulatory roles. These data support the concept that targeting Poldip2 could potentially attenuate severe lung injury following SARS-CoV-2 infection.<\/jats:p>","DOI":"10.1371\/journal.pone.0348065","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T17:39:52Z","timestamp":1777484392000},"page":"e0348065","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Poldip2 deficiency attenuates lung disease severity in a mouse model of COVID-19"],"prefix":"10.1371","volume":"21","author":[{"given":"Ruinan","family":"Hu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandra","family":"Valdivia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taylor","family":"White","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6064-2836","authenticated-orcid":true,"given":"Willy","family":"Ju","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maegan L.","family":"Brockman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongyan","family":"Qu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georgette","family":"Gafford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giji","family":"Joseph","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha","family":"Burton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leda","family":"Bassit","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tysheena P.","family":"Charles","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raymond F.","family":"Schinazi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca D.","family":"Levit","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cynthia A.","family":"Derdeyn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathy K.","family":"Griendling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4924-6506","authenticated-orcid":true,"given":"Bernard","family":"Lass\u00e8gue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina S.","family":"Hernandes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"pone.0348065.ref001","unstructured":"World Health Organization. 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