Influenza-Induced Inflammation Drives Pneumococcal Otitis Media

Influenza A virus (IAV) predisposes individuals to secondary infections with the bacterium Streptococcus pneumoniae (the pneumococcus). Infections maymanifest as pneumonia, sepsis, meningitis, or otitis media (OM). It remains controversial as to whether secondary pneumococcal disease is due to the induction of an aberrant immune response or IAV-induced immunosup-pression. Moreover, as the majority of studies have been performed in the context of pneumococcal pneumonia, it remains un-clear how far these findings can be extrapolated to other pneumococcal disease phenotypes such as OM. Here, we used an infant mouse model, humanmiddle ear epithelial cells, and a series of reverse-engineered influenza viruses to investigate how IAV pro-motes bacterial OM. Our data suggest that the influenza virus HA facilitates disease by inducing a proinflammatory response in the middle ear cavity in a replication-dependent manner. Importantly, our findings suggest that it is the inflammatory response to IAV infection that mediates pneumococcal replication. This study thus provides the first evidence that inflammation drives pneumococcal replication in the middle ear cavity, which may have important implications for the treatment of pneumococcal OM. Streptococcus pneumoniae is a Gram-positive bacterium thatcolonizes the nasopharynx of up to 80 % of preschool children (1). Generally, S. pneumoniae colonization is transient and asymptomatic. However, in the presence of influenza A virus (IAV), S. pneumoniae is able to disseminate to other sites in th