Expression profiling by high throughput sequencing
Summary
Secondary bacterial infections (‘superinfection’) are a major reason for excessive mortality and hospitalizations during influenza virus infections. Here we present a longitudinal study of gene-expression changes in murine lungs during superinfection, with an initial influenza A virus (IAV) infection and a subsequent S. pneumonia (SP) infection. In addition to the well characterized impairment of the innate immune response, we identified superinfection-specific alterations in endothelial functions, including rapid downregulation in angiogenic activity and vascular regulators. Superinfection-specific alterations were also evident in analysis of cellular states related to the host’s immune resistance against pathogens. We found that only a few hours after secondary bacterial challenge, superinfected mice manifested an excessive induction of immune resistance, and in addition, there was a substantial rewiring of the resistance program: interferon-regulated genes are switched from positive to negative correlations with resistance, whereas genes of fatty-acid metabolism are switched from negative to positive correlations with resistance. Thus, the transcriptional resistance state is reprogrammed toward repressed interferon signaling and induced fatty acid metabolism. Our findings suggest new insights into the remodeling of the host defense upon superinfection, providing promising targets for future therapeutic interventions.
Overall design
For the secondary pneumococcal infection model: anesthetized mice were administered with IAV and 5 days later were infected with S. pneumoniae.
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