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The virus-bacterial synergism implicated in secondary bacterial infections caused byStreptococcus pneumoniaefollowing infection with epidemic or pandemic influenza A virus (IAV) is well documented. However, the molecular mechanisms behind such synergism remain largely ill-defined. In pneumocytes infected with influenza A virus, subsequent infection withS. pneumoniaeleads to enhanced pneumococcal intracellular survival. The pneumococcal two-component system VisRH appears essential for such enhanced survival. Through comparative transcriptomic analysis between the ΔvisRandwtstrains, a list of 179 differentially expressed genes was defined. Among those, theclpLprotein chaperone gene and thepsaBMn+2transporter gene, which are involved in the stress response, are important in enhancingS. pneumoniaesurvival in influenza-infected cells. The ΔvisR,ΔclpLand ΔpsaBdeletion mutants display increased susceptibility to acidic and oxidative stress and no enhancement of intracellular survival in IAV-infected pneumocyte cells. These results suggest that the VisRH two-component system senses IAV-induced stress conditions and controls adaptive responses that allow survival ofS. pneumoniaein IAV-infected pneumocytes.Author summaryS. pneumoniaeis an inhabitant of the human nasopharynx that is capable of causing a variety of infections contributing to an estimated 1.6 million deaths each year. Many of these deaths occur as result of secondaryS. pneumoniaeinfections following seasonal or pandemic influenza. AlthoughS. pneumoniaeis considered a typical extracellular pathogen, an intracellular survival mechanism has been more recently recognized as significant in bacterial pathogenesis. The synergistic effects between influenza A andS. pneumoniaein secondary bacterial infection are well documented; however, the effects of influenza infections on intracellular survival ofS. pneumoniaeare ill-defined. Here, we provide evidence that influenza infection increasesS. pneumoniaeintracellular survival in pneumocytes. We demonstrate that the poorly understood VisRH signal transduction system in pneumococcus controls the expression of genes involved in the stress response thatS. pneumoniaeneeds to increase intracellular survival in influenza A-infected pneumocytes. These findings have important implications for understanding secondary bacterial pathogenesis following influenza and for the treatment of such infections in influenza-stricken patients. |
