Host Pore-Forming Protein Complex Neutralizes the Acidification of Endocytic Organelles to Counteract Intracellular Pathogens

Many intracellular pathogens invade cells via endocytic organelles and have adapted to the drop in pH along the endocytic pathway. However, the strategy by which the host cell counteracts this pathogen adaptation remains unclear. beta gamma-CAT is an aerolysin-like pore-forming protein and trefoil factor complex in the frog Bombina maxima. We report here that beta gamma-CAT, as a host-secreted factor with an intrinsic channel-forming property, is the first example of a molecule that actively neutralizes the acidification of endocytic organelles to counteract Listeria monocytogenes infection. Immunodepletion of endogenous beta gamma-CAT largely impaired the control of L. monocytogenes by frog cells. beta gamma-CAT elevates the pH of L. monocytogenes-containing vacuoles to limit the vacuole escape of L. monocytogenes to cytosol. Furthermore, beta gamma-CAT promotes intracellular L. monocytogenes clearance via autophagy and by that the nonlytic expulsion of the bacteria from host cells. Finally, beta gamma-CAT attenuated the dissemination of L. monocytogenes in vivo. These findings reveal a novel host strategy and effectors that combat pathogen adaptation to acidic conditions along the endocytic pathway.