Sphingolipid Degradation by Leishmania major Is Required for Its Resistance to Acidic pH in the Mammalian Host

Leishmania parasites alternate between flagellated promastigotes in sand flies and nonflagellated amastigotes in mammals, causing a spectrum of serious diseases. To survive, they must resist the harsh conditions in phagocytes (including acidic pH, elevated temperature, and increased oxidative/nitrosative stress) and evade the immune response. Recent studies have highlighted the importance of sphingolipid (SL) metabolism in Leishmania virulence. In particular, we have generated a Leishmania major iscl(-) mutant which is deficient in SL degradation but grows normally as promastigotes in culture. Importantly, iscl(-) mutants cannot induce pathology in either immunocompetent or immunodeficient mice yet are able to persist at low levels. In this study, we investigated how the degradation of SLs might contribute to Leishmania infection. First, unlike wild-type (WT) L. major, iscl(-) mutants do not trigger polarized T cell responses in mice. Second, like WT parasites, iscl(-) mutants possess