Short-course intranasal LAT9997 therapy limits post-influenza bacterial pneumonia by recalibrating lung immunity

Secondary bacterial pneumonia causes substantial morbidity and mortality following influenza A virus (IAV) infection, yet no therapies exist that address the underlying immune dysfunction and epithelial damage that predispose to bacterial superinfection. Here, we demonstrate that short-course intranasal treatment with LAT9997, a synthetic peptide derived from human growth hormone, protects against severe IAV infection and subsequent Streptococcus pneumoniae superinfection. Significantly, just two intranasal doses administered on days 1 and 2 post-IAV infection, with no further treatment, improved survival from 0% to 85%, reduced bacterial burden in the airways, and markedly attenuated lung pathology. Mechanistically, LAT9997 selectively suppressed epithelial AKT Ser473 phosphorylation, rebalancing infection-induced signalling to reduce viral dissemination, limit lung damage, and preserve barrier integrity during the viral phase. This early intervention established a protective airway immune environment characterized by preserved alveolar macrophages, restrained neutrophil recruitment, and reduced inflammatory mediators. During subsequent bacterial challenge, innate immune cells displayed phenotypic markers of controlled activation, including enhanced neutrophil viability, reduced inflammatory surface markers, and restrained protease activity, occurring without broad alterations in cell numbers. These findings provide proof-of-concept that brief, host-directed therapy during acute viral infection can durably prevent post-viral bacterial pneumonia by modulating lung immunity and preserving barrier integrity.