Proton-activated chloride channel 1 is essential for innate host defense against bacterial sepsis

Because phagolysosomal bacterial clearance is essential to resolve infection, we challenged Pacc1−/− mice with intraperitoneal gram-negative E. coli sepsis. Pacc1−/− mice displayed increased bacterial burden, immune cell infiltration, inflammation, and lethality. In contrast, phagocytosis-independent E. coli lipopolysaccharide (LPS)-induced endotoxemia yielded comparable WT and Pacc1−/− survival, as well as similar inflammatory responses.

Finally, we engineered Pacc1-floxed (fl/fl) mice crossed with a myeloid lineage Cre-deleter strain to interrogate myeloid cell–intrinsic PACC1 in vivo. Consistent with a predominate role for PACC1 during phagocytosis and bacterial clearance in these cells, LysM-Cre/Pacc1fl/fl mice exhibited impaired E. coli sepsis survival but indifferent endotoxemia phenotypes. In conclusion, PACC1 links sterilizing phagolysosomal activity with immune networks in sepsis pathobiology.