show Abstracthide AbstractInfluenza infection is substantially worsened by the onset of secondary pneumonia caused by bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). The bidirectional interaction between the influenza-injured lung microenvironment and MRSA is poorly understood. By conditioning MRSA ex vivo in bronchoalveolar lavage fluid collected from mice at various timepoints of influenza infection, we found that the influenza-injured lung microenvironment dynamically induces MRSA to increase cytotoxin expression while decreasing metabolic pathways. LukAB, a SaeRS two-component system dependent cytotoxin, is particularly important to the severity of post-influenza MRSA pneumonia. LukAB's activity is likely shaped by the post-influenza lung microenvironment, as LukAB binds to (and is activated by) heparan sulfate (HS) oligosaccharide sequences shed from the epithelial glycocalyx after influenza. Our findings indicate that post-influenza MRSA pneumonia is shaped by bidirectional host-pathogen interactions: host injury triggers changes in bacterial expression of toxins, the activity of which may be shaped by host-derived HS fragments. Overall design: We analyzed whole lung RNA-sequencing analysis on control mice (IN Saline D0 + IT Saline D10), influenza A/PR/8/34 infection alone (IN PR8 D0 + IT Saline D10), USA300 MRSA primary pneumonia (IN Saline D0 + IT MRSA D10), and PR8 with MRSA secondary pneumonia (IN PR8 D0 + IT MRSA D10).