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 (Ms) was enhanced in the presence of gamma interferon (IFN-), a Th1 cytokine normally associated with classical M activation and killing of intracellular pathogens. In this study, we provided several lines of evidence suggesting that IFN--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--treated Ms. (ii) Supplementation of L-arginine in M cultures increased parasite growth. (iii) Parasite growth enhancement in wild-type Ms was inhibited in the presence of nonmetabolized L-arginine analogues. (iv) IFNmediated parasite growth was absent in Ms 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--treated, infected Ms. Together, these data suggest an involvement of a novel L-arginine usage independent of iNOS and arginase activities during IFN--mediated parasite growth enhancement. A possible role of mCAT-2B in supplying L-arginine directly to the parasites for their proliferation is discussed. Protozoan parasites in the genus Leishmania are obligate intracellular pathogens that can cause a wide spectrum of diseases, ranging from benign cutaneous lesions to life-threatening visceral infections. Leishmania spp. exhibit a dimorphic life cycle, in which parasites are transmitted by a sand fly vector as flagellated promastigotes and reside within mammalian macrophages (Ms) as amastigotes. The fate of intracellular amastigotes depends largely on the activation status of Ms, which is greatly influenced by various cytokines and chemokines (19,