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

Abstract

Exposure to influenza A virus, respiratory syncytial virus, and human metapneumovirus is well known to increase the risk of Streptococcus pneumoniae (SPn) 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 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.