Targeting virulence factors Psl and PcrV restores host defense in bronchiectasis and cystic fibrosis models.

Chronic Pseudomonas aeruginosa infection is a central driver of bronchiectasis and contributes to progressive lung decline in patients with cystic fibrosis (CF), even in the era of CFTR modulators. A major limitation in the field is that conventional mouse models fail to develop persistent, biofilm-associated lung infection, restricting mechanistic studies and preclinical evaluation. Here, we establish clinically relevant infection models by combining CF-like mouse strains (βENaC-overexpressing and CFTR-deficient mice) with agarose bead-embedded P. aeruginosa that forms persistent, tobramycin-refractory biofilms. Using intravital lung microscopy, we show that alveolar macrophages initially respond by surrounding biofilms but progressively dissociate from the biofilms during persistent infection. Neutrophils are also recruited but fail to clear bacteria. Administration of gremubamab (MEDI3902), a bispecific antibody targeting the virulence factors Psl and PcrV, preserves alveolar macrophages in persistent biofilm infection, restores bacterial sensing and phagocytosis, limits excessive neutrophilic inflammation, and significantly improves bacterial clearance and survival. Together, these findings establish a clinically relevant persistent P. aeruginosa infection model and highlight gremubamab as a promising virulence-targeted therapy to potentially overcome bacterial immune evasion while restoring host defense in mouse models of bronchiectasis and CF.