Rescue of alveolar wall liquid secretion blocks fatal lung injury by influenza-staphylococcal coinfection

Secondary lung infection by inhaled Staphylococcus aureus (SA) is a common and lethal event in individuals infected with influenza A virus (IAV). It is unclear how IAV disrupts host defense to promote SA infection in lung alveoli, where fatal lung injury occurs. We addressed this issue using the first real-time determinations of alveolar responses to IAV in live, intact, perfused lungs. Our findings show IAV infection blocked defensive alveolar wall liquid (AWL) secretion and induced airspace liquid absorption, thereby reversing normal alveolar liquid dynamics and inhibiting alveolar clearance of inhaled bacteria. Loss of AWL secretion resulted from dephosphorylation, hence inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel in alveolar epithelium, and airspace liquid absorption was caused by alveolar epithelial stimulation of the epithelial Na+ channel (ENaC). Loss of AWL secretion promoted alveolar stabilization by SA and alveolar damage by the secreted SA toxin, alpha hemolysin, but rescue of AWL secretion protected against fatal SA-induced lung injury in IAV-infected mice. These findings reveal a central role for AWL secretion in alveolar defense against inhaled bacteria and identify AWL inhibition as a critical mechanism of IAV lung pathogenesis. AWL rescue may represent a new therapeutic approach for IAV-SA coinfection. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/499169v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@180caceorg.highwire.dtl.DTLVardef@82ce71org.highwire.dtl.DTLVardef@1bf9358org.highwire.dtl.DTLVardef@628fec_HPS_FORMAT_FIGEXP M_FIG C_FIG