ABSTRACT
INTRODUCTION More than a dozen identified and characterized species of the genus Leishmania cause diseases ranging from simple selfhealing cutaneous lesions to debilitating and lethal (if untreated) visceral leishmaniasis (VL) known as kala-azar (Table 1). Other less frequent forms are mucosal leishmaniasis (ML) a highly disfiguring disease of oral and nasal cavities, and diffuse cutaneous leishmaniasis (DCL) with hundreds of nodular lesions spread over the body. Self-limiting visceral infections with some Leishmania-L. infantum (1), L. donovani (2), and possibly L. tropica (3)—may also occur. These asymptomatic individuals as well as cured cases would later develop disease if their immune responses are depressed by drugs or human immunodeficiency virus (HIV) infection, indicating nonsterile immunity following cure (4). Persistence of parasites in humans and in resistant mouse strains long after recovery of the initial lesion has been documented (5,6) and leishmaniasis recidivans (reappearance of new satellite lesions) around the original healed lesion is occasionally seen with L. tropica infection. In this respect, leishmaniasis is considered as an opportunistic infection (7). All forms of leishmaniasis are naturally transmitted by the bites of more than 70 different species of female sandflies either from infected humans (anthroponotic leishmaniasis) or from infected animals (zoonotic). The life cycle in the sandfly vector is confined to the alimentary tract and involves replication as extracellular flagellated promastigotes in the posterior midgut, differentiation to an infectious, nondividing metacyclic promastigote stage in the anterior gut, and inoculation into the skin of low numbers (100-1000) of metacyclics when the infected sandfly seeks another blood meal. Parasites that are inoculated into the skin are taken up by macrophages, and produce a spectrum of chronic diseases. Despite the incredible diversity of parasite and vector species, the establishment of Leishmania infection in the mammalian host involves the parasitization of macrophages in the skin and persistence and replication of nonflagellated amastigote-stage parasites in the phagolysosome of these host cells. While their presence in dendritic cells (DCs), neutrophils, and even fibroblasts has been described, there is no evidence that amastigotes can actively replicate in a cell other than a macrophage. Macrophages possess primary defense mechanisms, including activation of macrophage oxidative metabolism and synthesis and
release of arachidonic acid metabolites, that are induced by the attachment and engulfment of microbial agents. The major source of reactive oxygen intermediates (ROIs) in macrophages is the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which is a multimeric enzyme complex. Once assembled, the oxidase transfers an electron from NADPH to molecular oxygen, producing O2—which can dismutate to hydrogen peroxide (H2O2). ROI act together with reactive nitrogen intermediates (RNI), derived from nitric oxide, in the early stage of intracellular infection to regulate both tissue recruitment of mononuclear inflammatory cells and the initial extent of microbial replication. Previous studies have shown that RNI alone are necessary and sufficient for control of visceral infection, and although mature granulomas have traditionally been associated with control of such infections, these structures fail to limit intracellular parasite replication in the absence of iNOS (8). During the early establishment of infection in the skin and lymphoid organs, Leishmania produce multiple effects on macrophage and DC functions that inhibit their innate anti-microbial defenses and impair their capacity to initiate T helper 1 cell immunity. Generally, there is a good association between the organism and type of disease it produces in humans however, L. tropica usually the causative agent of anthroponotic CL (ACL) may cause VL as was seen in U.S. soldiers returning from the Middle East (3) and L. infantum the causative agent of zoonotic VL can cause CL (9). Approximately 350 million people are believed to be at risk of infection and the annual incidence of new cases is about two million, mostly in children and young adults (1.5 million CL and the rest VL). Infection is more common in men than in women, but this may reflect increased exposure to sandflies. Although disease occurs irrespective of age, children aged one to four years are particularly at risk of infection in the Mediterranean regions, and childhood infection may account for more than half of all cases in some of these countries. The current estimated prevalence is 12 million distributed in 88 countries (10). These figures do not include epidemics, which can claim the lives of tens of thousands individuals, eliminate communities and cause massive migration (11). The burden of disease expressed in disability-adjusted life years (DALYs) is estimated to be almost 2 million (Table 1) (12).
