l-Arginine and Cationic Amino Acid Transporter 2B Regulate Growth and Survival ofLeishmania amazonensisAmastigotes in Macrophages

Abstract

Leishmaniaspp. are obligate intracellular parasites, requiring a suitable microenvironment for their growth within host cells. We previously reported that the growth ofLeishmania amazonensisamastigotes in murine macrophages (Mφs) was enhanced in the presence of gamma interferon (IFN-γ), a Th1 cytokine normally associated with classical Mφ activation and killing of intracellular pathogens. In this study, we provided several lines of evidence suggesting that IFN-γ-mediated parasite growth enhancement was associated withl-arginine transport via mouse cationic amino acid transporter 2B (mCAT-2B). (i) mRNA expression ofSlc7A2, the gene encoding for mCAT-2B, as well asl-arginine transport was increased in IFN-γ-treated Mφs. (ii) Supplementation ofl-arginine in Mφ cultures increased parasite growth. (iii) Parasite growth enhancement in wild-type Mφs was inhibited in the presence of nonmetabolizedl-arginine analogues. (iv) IFN-γ-mediated parasite growth was absent in Mφs derived from mCAT-2B-deficient mice. Although we detected a clear upregulation of mCAT-2B andl-arginine transport, no measurable iNOS or arginase activities were observed in IFN-γ-treated, infected Mφs. Together, these data suggest an involvement of a novell-arginine usage independent of iNOS and arginase activities during IFN-γ-mediated parasite growth enhancement. A possible role of mCAT-2B in supplyingl-arginine directly to the parasites for their proliferation is discussed.