Gut microbiota enhances neutrophil resolution in immunocompromised hosts to improve response to pneumococcal pneumonia.

Abstract

Streptococcus pneumoniae is a major cause of disease and death worldwide, particularly in neonatal, elderly, and immunodeficient patients. We examined the impact of the gut microbiota on lung disease (known as the gut-lung axis) using traditional immunocompetent as well as novel immunocompromised mouse models of S. pneumoniae lung infection. Adaptive immunity against S. pneumoniae depends largely on T-independent II (TI-II) antibodies against the bacterial polysaccharide capsule. We found that colonization with the gut commensal Segmented Filamentous Bacteria (SFB) increased anti-S. pneumoniae TI-II antibodies, but did not further enhance protection against S. pneumoniae in wild type mice. Indeed, basal B cell activity in the absence of SFB colonization was sufficient to provide essential protection against S. pneumoniae. However, in adaptive immune-compromised mice, we demonstrated a gut-lung axis of communication, as SFB colonization modulated the innate immune response to enhance protection against S. pneumoniae lung infection. Neutrophils are important first responders during pneumonia, but proper neutrophil resolution is essential to prevent excessive tissue damage. We found that SFB colonization led to more efficient clearance of lung neutrophils at 3 days after infection, which correlated with a decrease in CD47, a transmembrane glycoprotein that inhibits clearance of apoptotic cells, on lung neutrophils in SFB+ immunocompromised mice. This accompanied a shift in lung neutrophils from CD18hiCD62L−/lo inflammatory neutrophils to CD18−/loCD62Lhi pro-resolution neutrophils. These data demonstrate that a gut commensal modulates the innate immune response to enhance protection against a lung infection.