Staphylococcus aureus is a predominant cause of fatal pneumonia following influenza A virus (IAV) infection. Herein we investigate the influence of antecedent IAV infection on S. aureus virulence gene expression. Using a murine model, comparing the USA300 and USA300ΔsaeR/S strains, we demonstrate that S. aureus pathogenesis following IAV infection is SaeR/S dependent. Furthermore, we show that IAV modulates the lung environment to rapidly up-regulate S. aureus virulence factors containing the SaeR-binding domain. Data demonstrate that the pathogen response to IAV infection impacts host outcome and provides evidence that the ability of S. aureus to sense and respond to the lung environment determines severity of pneumonia.
subsp. is a highly pathogenic intracellular bacterium that suppresses host inflammation by impairing the metabolic shift from oxidative phosphorylation to glycolysis. Decreased mitochondrial metabolism is central to initiating a metabolic shift to glycolysis and regulating inflammation, but subsp. manipulation of host mitochondrial function has not been explored. We demonstrate, using extracellular flux analysis, that subsp. infection initially improves host macrophage mitochondrial bioenergetics in a capsule-dependent manner. Enhancement of mitochondrial function by subsp. allowed for modest replication and inhibition of apoptosis early after infection. However, using live cell imaging, we found that subsp. facilitated the loss of mitochondrial function at later time points during infection in a capsule-independent fashion. This loss of function was paired with oncosis and rapid bacterial replication. Inhibition of oncosis reduced intracellular bacterial numbers, underscoring the requirement for this process during subsp. infection. These findings establish that temporal mitochondrial manipulation by subsp. is critical for maintenance of a noninflammatory environment and subsequently aids in optimal replication and dissemination of this pathogenic organism.
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