L-arginine and cationic amino acid transporter 2B regulate growth and survival of Leishmania amazonensis amastigotes in macrophages

Leishmania spp. are obligate intracellular parasites, requiring a suitable microenvironment for their growth within host cells. We previously reported that the growth of Leishmania amazonensis amastigotes in murine macrophages (M phi s) was enhanced in the presence of gamma interferon (IFN-gamma, a Th1 cytokine normally associated with classical M phi activation and killing of intracellular pathogens. In this study, we provided several lines of evidence suggesting that IFN-gamma-mediated parasite growth enhancement was associated with L-arginine transport via mouse cationic amino acid transporter 2B (mCAT-2B). (i) mRNA expression of Slc7A2, the gene encoding for mCAT-2B, as well as L-arginine transport was increased in IFN-gamma-treated M phi s. (ii) Supplementation of L-arginine in Nl(cultures increased parasite growth. (iii) Parasite growth enhancement in wild-type M phi s was inhibited in the presence of nonmetabolized L-arginine analogues. (iv) IFN-gamma-mediated parasite growth was absent in M phi s derived from mCAT-2B-deficient mice. Although we detected a clear upregulation of mCAT-2B and L-arginine transport, no measurable iNOS or arginase activities were observed in IFN-gamma-treated, infected M phi s. Together, these data suggest an involvement of a novel L-arginine usage independent of iNOS and arginase activities during IFN-gamma-mediated parasite growth enhancement. A possible role of mCAT-2B in supplying L-arginine directly to the parasites for their proliferation is discussed.