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Type I IFN (IFN-I) is a hallmark response to acute viral infections, and alveolar macrophages (AMs) constitute the first line of airway defense against opportunistic bacteria. Our study reveals that virus-induced IFNAR1 (IFN-I receptor) signaling directly impairs AM-dependent antibacterial protection. Using Ifnar1 conditional knockout mouse models, in vivo antibodies, bone marrow chimeric mice, and AM reconstitution, we demonstrate that IFN-I intrinsically targets AMs to drive hypersusceptibility to SPn following influenza A virus infection. Importantly, we show that respiratory syncytial virus and human metapneumovirus infection induces robust IFN-I signaling in AMs, coinciding with lethal susceptibility to secondary SPn pneumonia. In contrast, seasonal human coronavirus induces neither significant IFN-I signaling in AMs nor immune predisposition to SPn. Therefore, we conclude that IFN-I inhibition of AMs represents a crucial mechanism underlying antibacterial complications following otherwise asymptomatic or mild respiratory viral infections.<\/jats:p>","DOI":"10.1165\/rcmb.2024-0552oc","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T15:45:21Z","timestamp":1738165521000},"page":"264-274","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":8,"title":["Type I Interferon Targets Alveolar Macrophages to Promote Bacterial Pneumonia after Viral Infection"],"prefix":"10.1093","volume":"73","author":[{"given":"Sunil","family":"Palani","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Bashir","family":"Uddin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology"},{"name":"Department of Medicine, Sylhet 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