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Transition from pneumococcal colonization to invasive disease is not well understood. Studies have shown that such a transition can occur as a result of influenza A virus (IAV) coinfection. We investigated the pneumococcal (serotype 19F, strain EF3030, and isogenic mutants) and airway epithelial transcriptomes with and without IAV (A/California/07 2009 pH1N1) infection. Pneumococcus and influenza coinfection leads to enhanced bacterial transcriptional programs related to growth, nutrient availability, and energy biosynthesis, suggesting conversion to an invasive phenotype. Influenza-induced secondary EF3030 infection influences human bronchial epithelial cell (HBEC) microtubules and extracellular matrix. Notably, sialic acid (NanR) utilization is a central regulon in EF3030 mono/coinfection with pH1N1 on HBEC. Downregulation of sialic acid utilization during influenza coinfection improved Spn pathogenicity ex vivo but did not alter disease in vivo, suggesting other metabolic cues are also important. This study uncovers critical metabolic features of the EF3030-pH1N1 interface to inform how Spn proliferates during IAV coinfection.

(Spn) is typically an asymptomatic colonizer of the nasopharynx but it also causes pneumonia and disseminated disease affecting various host anatomical sites. Transition from colonization to invasive disease is not well understood. Studies have shown that such a transition can occur as result of influenza A virus coinfection. We investigated the pneumococcal (serotype 19F, strain EF3030) and host transcriptomes with and without influenza A virus (A/California/07 2009 pH1N1) infection at this transition. This was done using primary, differentiated Human Bronchial Epithelial Cells (nHBEC) in a transwell monolayer model at an Air-Liquid Interface (ALI), with multispecies deep RNA-seq. Distinct pneumococcal gene expression profiles were observed in the presence and absence of influenza. Influenza coinfection allowed for significantly greater pneumococcal growth and triggered the differential expression of bacterial genes corresponding to multiple metabolic pathways; in totality suggesting a fundamentally altered bacterial metabolic state and greater nutrient availability when coinfecting with influenza. Surprisingly, nHBEC transcriptomes were only modestly perturbed by infection with EF3030 alone in comparison to that resulting from Influenza A infection or coinfection, which had drastic alterations in thousands of genes. Influenza infected host transcriptomes suggest significant loss of ciliary function in host nHBEC cells. Influenza A virus infection of nHBEC promotes pneumococcal infection. One reason for this is an altered metabolic state by the bacterium, presumably due to host components made available as result of viral infection. Influenza infection had a far greater impact on the host response than did bacterial infection alone, and this included down regulation of genes involved in expressing cilia. We conclude that influenza infection promotes a pneumococcal metabolic shift allowing for transition from colonization to disseminated disease.