Fig. 1.

L-arginine metabolic pathways and their influence on Leishmania infection. Classical activation of MΦs via stimulation of Th1 cytokines (IFN-γ plus LPS or IFN-γ plus TNF-α) results in an enhanced expression of CAT-2B, increased L-arginine availability and iNOS activity, ultimately leading to parasite killing. Conversely, Th2-mediated activation of MΦs (via IL-4, IL-13, and TGF-β) enhances CAT-2B expression and arginase activity, resulting in parasite growth. In suboptimally activated MΦs (primed by low concentrations of IFN-γ), CAT-2B is moderately induced, but iNOS and arginase remain relatively inactivated, allowing Leishmania amastigotes (Am) to take up and use available L-arginine for their proliferation. While it is unclear which molecules are responsible for the transport of L-arginine across the parasitophorous (PV) membrane, at least one permease, LdAAP3, has been identified as a transporter of L-arginine across the membrane of L. donovani promastigotes. Once inside the amastigotes, L-arginine can be utilized by parasite-derived NOS or arginase. While Leishmania-derived arginase is involved in polyamine synthesis necessary for the parasite growth, the exact role of Leishmania-derived NOS during infection is unclear