Pneumolysin expression by streptococcus pneumoniae protects colonized mice from influenza virus-induced disease

•S. pneumoniae colonization protects from influenza virus-induced lung pathology.•Protection requires the bacterial virulence factor pneumolysin.•Pneumolysin-expressing S. pneumoniae prevents virus-induced depletion of alveolar macrophages.•Alveolar macrophages function as “gatekeepers” against virus-induced lung pathology.

The response to influenza virus (IAV) infection and severity of disease is highly variable in humans. We hypothesized that one factor contributing to this variability is the presence of specific respiratory tract (RT) microbes. One such microbe is Streptococcus pneumoniae (Sp) that is carried asymptomatically in the RT of many humans. In a mouse co-infection model we found that in contrast to secondary bacterial infection that exacerbates disease, Sp colonization 10 days prior to IAV protects from virus-induced morbidity and lung pathology. Using mutant Sp strains, we identified a critical role for the bacterial virulence factor pneumolysin (PLY) in mediating this protection. Colonization with the PLY-sufficient Sp strain induces expression of the immune-suppressive enzyme arginase 1 in alveolar macrophages (aMø) and correlates with attenuated recruitment and function of pulmonary inflammatory cells. Our study demonstrates a novel role for PLY in Sp-mediated protection by maintaining aMø as “gatekeepers” against virus-induced immunopathology.