Segmented filamentous bacteria reprogramming of alveolar macrophages limits postinfluenza bacterial pneumonia

Respiratory viral infection induces depletion and dysfunction of alveolar macrophages (AMs), resulting in high-susceptibility to life-threatening bacterial pneumonia. Colonization of the intestine by segmented filamentous bacteria (SFB) reprograms AM to resist depletion. Hence, we examined whether SFB protected mice against secondary bacterial infection by <i>Streptococcus pneumoniae</i>, <i>Haemophilus influenzae</i>, or <i>Staphylococcus aureus</i> after influenza A virus (IAV) infection. SFB protected mice against these infections based on pathogen loads and disease symptoms. AM depletion and transplant indicated that SFB-induced AM reprogramming was necessary and sufficient for such protection. Ex vivo analysis revealed that AMs from SFB-colonized mice not only resisted IAV-induced depletion but also were epigenetically reprogrammed to preferentially use oxidative phosphorylation and complement-dependent phagocytosis, which enabled efficient killing of bacteria. AM from SFB-colonized mice held their enhanced antibacterial phenotype even when transplanted into an inflamed interferon-rich post-IAV environment. Thus, gut microbiota composition influences susceptibility to bacterial pneumonia, especially after respiratory viral infection.