The role of proton-activated chloride channel 1 (PACC1) in bacterial pneumonia and sepsis

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B590
Abstract ID: 5784

Presenting Author:
Lucien P Garo , PhD Candidate at Boston Univ. Chobanian & Avedisian Sch. of Med.

Abstract:

Bacterial infections remain a leading cause of global mortality despite available interventions. Tissue-resident macrophages coordinate initial host defense against many invading pathogens. In particular, phagocytosis and phagolysosomal acidification by macrophages and other myeloid cells are critical to combat infection. Our lab has uncovered a novel role for PACC1, a recently discovered acid-sensitive chloride channel, in macrophages for bacterial immunity. To study PACC1 in vivo, we directed the generation of a PACC1 knockout (^-/-) mouse using CRISPR/Cas9. Infection responses were investigated with models of Escherichia coli intraperitoneal sepsis and pneumococcal pneumonia, while immunologic responses were studied by flow cytometry and ELISA. Phagocytosis was assessed via acid-sensitive bioparticles. PACC1^-/- mice, compared to wild type controls, presented with higher bacterial loads and decreased survival following infection. This was associated with hyperinflammation, including excessive cytokine/chemokine release and influx of myeloid cells that failed to control bacteria. PACC1^-/- myeloid cells showed impaired phagolysosomal acidification. Most recently, we have generated myeloid cell conditional PACC1 knockout and overexpression mice for further interrogation. In summary, PACC1 loss results in susceptibility to infection, and dysregulated inflammation and phagocytosis. Our findings suggest PACC1 is essential for protective innate host defense against bacteria.