Blocking HXA 3 -mediated neutrophil elastase release during S. pneumoniae lung infection limits pulmonary epithelial barrier disruption and bacteremia

• DOI: 10.1128/mbio.01856-24
• Publication Date: 2024-08-09T13:00:56Z
• Authors: Shuying Xu; Shumin Tan; Patricia Romanos; Jennifer L. Reedy; Yihan Zhang; Michael K. Mansour; Jatin M. Vyas; Joan Mecsas; Hongmei Mou; John M. Leong
• Keywords: Pneumolysin; Neutrophil elastase

ABSTRACT Streptococcus pneumoniae ( Sp ), a leading cause of community-acquired pneumonia, can spread from the lung into bloodstream to septicemia and meningitis, with concomitant threefold increase in mortality. Limitations vaccine efficacy rise antimicrobial resistance have spurred searches for host-directed therapies that target pathogenic immune processes. Polymorphonuclear leukocytes (PMNs) are essential infection control but also promote tissue damage pathogen spread. The major virulence factor, pneumolysin, triggers acute inflammation by stimulating 12-lipoxygenase (12-LOX) eicosanoid synthesis pathway epithelial cells. This is required systemic mouse pneumonia model produces number bioactive lipids, including hepoxilin A3 (HXA 3 hydroxy epoxide PMN chemoattractant has been hypothesized facilitate breach mucosal barriers. To understand how 12-LOX-dependent promotes dissemination during dissemination, we utilized bronchial stem cell-derived air–liquid interface cultures lack this enzyme show HXA methyl ester -ME) sufficient basolateral-to-apical transmigration, monolayer disruption, barrier breach. In contrast, transmigration response non-eicosanoid N-formyl-L-methionyl-L-leucyl-phenylalanine (fMLP) did not lead disruption or bacterial translocation. Correspondingly, -ME fMLP increased release neutrophil elastase (NE) -infected PMNs. Pharmacologic blockade NE secretion activity diminished bacteremia after pulmonary challenge mice. Thus, barrier-disrupting release, pathological events be targeted curtail disease following pneumococcal pneumonia. IMPORTANCE disease. limit pathologic host responses . Excessive polymorphonuclear leukocyte (PMN) infiltration airways Using respiratory reflect bona fide epithelium, identified as critical drive PMN-mediated inducing elastase. Inhibition protease mice limited suggesting new treatment infection.