Type I Interferon Targets Alveolar Macrophages to Promote Bacterial Pneumonia after Viral Infection

Exposure to influenza A virus, respiratory syncytial virus, and human metapneumovirus is well known to increase the risk of <i>Streptococcus pneumoniae</i> (<i>SPn</i>) pneumonia in humans. 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 <i>Ifnar1</i> conditional knockout mouse models, <i>in vivo</i> antibodies, bone marrow chimeric mice, and AM reconstitution, we demonstrate that IFN-I intrinsically targets AMs to drive hypersusceptibility to <i>SPn</i> 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 <i>SPn</i> pneumonia. In contrast, seasonal human coronavirus induces neither significant IFN-I signaling in AMs nor immune predisposition to <i>SPn</i>. Therefore, we conclude that IFN-I inhibition of AMs represents a crucial mechanism underlying antibacterial complications following otherwise asymptomatic or mild respiratory viral infections.