Leishmania amazonensis impairs phagosome acidification in B-1 phagocytes as an unrecognized parasite infection and proliferation mechanism.

Leishmaniasis is a neglected disease affecting people from tropical and subtropical areas. It is caused by protozoan parasites called Leishmania and transmitted by sandflies during blood meal. In phagocytic cells such as macrophages, L. amazonensis modulates endosomal/lysosomal trafficking pathways to form large parasitophorous vacuoles (PV) enabling parasite survival and proliferation. In this work, we report that upon invasion in a subset of phagocytic B (termed B-1P) cells, L. amazonensis survives and proliferates at high rates inside abnormally large and non-acid PV. Mechanistically, we show that the biogenesis of enlarged non-acidic lysosomal compartment is not directly linked to the regulation of the LYST/Beige gene that controls the expansion of Leishmania-PV in macrophages, but to the fusion of intracellular vesicles lacking V-ATPase, a proton pump required for the acidification. Finally, we show that B-1P cells host parasites that proliferate inside large non-acidic vacuoles at infection sites in immunocompetent mice. Thus, these pathophysiological alterations favor parasitic proliferation under in vitro and ex vivo conditions and reveal a heretofore unrecognized but key mechanistic role for B-1P cells in the progression of leishmaniasis. This study provides new experimental insights into a novel parasite evasion mechanism that might impact the host response during human disease development.