Differential Type I Interferon Signaling Is a Master Regulator of Susceptibility to Postinfluenza Bacterial Superinfection.

Approximately 114,000 hospitalizations and 40,000 annual deaths in the United States are associated with influenza A virus (IAV) infections. Frequently, these deaths are due to community-acquired Gram-positive bacterial species, many of which show increasing resistance to antibiotic therapy. Severe complications, including parapneumonic empyema and necrotizing pneumonia, can arise, depending on virulence factors expressed by either the virus or bacteria. Unfortunately, we are unable to control the expression of these virulence factors, making host responses a logical target for therapeutic interventions. Moreover, interactions between virus, host, and bacteria that exacerbate IAV-related morbidities and mortalities are largely unknown. Here, we show that type I interferon (IFN) expression can modulate susceptibility to methicillin-resistant Staphylococcus aureus (MRSA) infection, with IFN-β reducing host susceptibility to MRSA infection while IFN-α increases susceptibility. Our data indicate that treatments designed to augment IFN-β and/or inhibit IFN-α production around day 7 post-IAV infection could reduce susceptibility to deadly superinfections.