Novel Requirement for Staphylococcal Cell Wall-Anchored Protein SasD in Pulmonary Infection.

Abstract

ABSTRACTStaphylococcus aureus can complicate preceding viral infections, including influenza virus. A bacterial infection combined with a preceding viral infection, known as superinfection, leads to worse outcomes than a single infection. Most of the pulmonary infection literature focuses on the changes in immune responses to bacteria between homeostatic and virally infected lungs. However, it is unclear how much of an influence bacterial virulence factors have in single or superinfection. Staphylococcal species express a broad range of cell wall-anchored proteins (CWAs) that have roles in host adhesion, nutrient acquisition, and immune evasion. We screened the importance of these CWAs using mutants lacking individual CWAs in vivo in both bacterial pneumonia and influenza superinfection. In bacterial pneumonia, the lack of individual CWAs leads to various decreases in bacterial burden, lung damage, and immune infiltration into the lung. However, the presence of a preceding influenza infection partially abrogates the requirement for CWAs. In the screen, we found that the uncharacterized CWA S. aureus surface protein D (SasD) induced changes in both inflammatory and homeostatic lung markers. We further characterized a SasD mutant (sasD A50.1) in the context of pneumonia. Mice infected with sasD A50.1 have decreased bacterial burden, inflammatory responses, and mortality compared to wild-type S. aureus. Mice also have reduced levels of interleukin-1β (IL-1β), likely derived from macrophages. Reductions in IL-1β transcript levels as well as increased macrophage viability point at differences in cell death pathways. These data identify a novel virulence factor for S. aureus that influences inflammatory signaling within the lung.IMPORTANCE Staphylococcus aureus is a common commensal bacterium that can cause severe infections, such as pneumonia. In the lung, viral infections increase the risk of staphylococcal pneumonia, leading to combined infections known as superinfections. The most common virus associated with S. aureus pneumonia is influenza, and superinfections lead to worse patient outcomes than either infection alone. While there is much known about how the immune system differs between healthy and virally infected lungs, the role of bacterial virulence factors in single and superinfection is less understood. The significance of our research is identifying bacterial components that play a role in the initiation of lung injury, which could lead to future therapies to prevent pulmonary single or superinfection with S. aureus.