The species of Leishmania responsible for past and current epidemics of visceral leishmaniasis (VL) in India is widely assumed to be Leishmania donovani. L. tropica, a rarely studied Old World species commonly associated with anthroponotic cutaneous disease, was discovered to be responsible for much of the visceral leishmaniasis that is currently epidemic in northeast India. Four of 16 visceral isolates were typed as L. tropica by monoclonal antibodies, isoenzymes, and kDNA analysis. L. tropica has now been shown to cause at least three distinct disease outcomes: cutaneous lesions, visceral infection associated with unexplained systemic illness recently described in veterans of operation desert storm, and classic kala-azar. The host-, parasite-, and vector- related factors which might explain these vastly different outcomes are currently being explored. Experimental studies on L. tropica sp. have been difficult because of the inability to obtain infective forms of the parasite and the absence of animal models. Metacyclic promastigotes of L. tropica were identified based on prior observations that the differentiation of promastigotes to an infective form is accompanied by structural modifications of the surface lipophosphoglycan. An anti-lPG monoclonal antibody specific for L. tropica was found to identify metacyclic promastigotes. Virulence comparisons of the Indian visceral L. tropica were identified based on prior observations that the differentiation of promastigotes to an infective form is accompanied by structural modifications of the surface ipophosphoglycan. An anti-LPG amonoclonal antibody specific for L. tropica was found to identify metacyclic promastigotes. Virulence comparisons of the Indian visceral L. tropica isolates with isolates from cutaneous patients revealed a difference in their virulence for BALB/c mice, suggesting that their different clinical associations may be at least in part parasite determined. The ability of Leishmania promastigotes to infect macrophages without activating them to produce immunoregulatory cytokines, in particular, IL-12, has recently been suggested as a strategy to delay the development of cell-mediated immunity. L. major metacyclic promastigotes failed to stimulate strong induction of any of the monokines examined during in vitro infection of mouse bone marrow-derived macrophages (BMMo). Coexposure of the cells to the parasite and other microbila stimuli resulted in complete inhibition of IL-12 (p40) mRNA induction and IL-12 release. In contrast, mRNA and protein levels for IL-1alpha, IL-1beta, TNF-alpha, and inducible NO synthase (iNOS) were only partially reduced, and signals for IL-10 and MCP-1/JE were actually enhanced. Selective and complete inhibition of IL-12 was observed in infected BMMo from resistant and susceptible as well as IL-10 knockout mice. Impairment of early IL- 12 induction is suggested to underlie the relatively prolonged survival of the parasite that is associated with all leishmanial infections, including those producing selflimiting disease.