CD73 controls neutrophil responsiveness to type I interferon impairing antibacterial responses during secondary pneumococcal pneumonia

Streptococcus pneumoniae (pneumococcus) are asymptomatic colonizers of the nasopharynx but can progress to pulmonary and systemic pathogens upon influenza A virus (IAV) infection. Polymorphonuclear cells (PMNs) are key for controlling S. pneumoniae , but their antibacterial function is impaired by IAV. Using a mouse model that allows transition of pneumococci from colonizers to disease-causing pathogens upon IAV co-infection, we examined the signaling pathways impairing PMN responses. We found that type I interferons (IFN) produced upon IAV infection drives impairment of PMN antibacterial responses as treatment with IFN inhibited pneumococcal killing by PMNs ex vivo , and in vivo blocking of IFN receptor 1 (IFNAR1) in IAV infected mice rescued PMN function. In exploring what controls PMN responsiveness to IFN, we tested CD73, an ectonucleotidase that regulates PMN responses in primary pneumococcal pneumonia. CD73 was required for the ability of neutrophils to respond to IFN. While wildtype and CD73KO mice had comparable IFNAR expression on PMNs and IFNɑ and IFNꞵ levels upon co-infection, CD73KO PMNs expressed significantly lower levels of the interferon stimulated protein IFIT1 and were less responsive to IFN-mediated inhibition of antimicrobial activity ex vivo . In exploring mechanisms, we found that IFN and CD73 elevated reactive oxygen species production by PMN in response to IAV, which impaired their ability to kill pneumococci. Importantly, co-infected CD73KO mice cleared bacteremia and survived significantly better than wildtype controls. These findings suggest that CD73 impairs host defense against IAV/ S. pneumoniae co-infection in part by sensitizing PMNs to type I IFN-mediated inhibition of antibacterial function.