Receptor-mediated phagocytosis of Leishmania: implications for intracellular survival

Abstract

The extracellular promastigote stage of Leishmania spp. is transmitted to mammals by a sand fly vector. Leishmania promastigotes ligate host macrophage receptors, triggering phagocytosis and subsequent internalization, a crucial step for survival. Parasites transform intracellularly to the amastigote stage. Many studies document different receptors detecting promastigotes and amastigotes, but the relative importance of each interaction is ill-defined. Recent studies suggest that the macrophage receptors utilized during phagocytosis impact the intracellular fate of the parasite. This review summarizes the receptors implicated in Leishmania phagocytosis over the past 30 years. It then proceeds to weigh the evidence for or against their potential roles in intracellular parasite trafficking.

Figure 1. Receptors for Leishmania entry into host phagocytes

Leishmania employ several receptor-mediated entry pathways into host macrophages, PMNs, or DCs. Promastigotes are depicted in blue, amastigotes in red, macrophages or DCs in brown, and PMNs in green. (a) GP63, which is highly expressed in promastigotes, convert C3 opsonins into C3b, the natural ligand for CR1. CR1, with factor I, cleave C3b into iC3b, facilitating binding to CR3. CR3 may also mediate direct binding to promastigotes via a yet unknown surface epitope on promastigotes. The terminal sugar residues on LPG could be recognized by MR, though this has not been proven. MR is not present in phagocytic compartments that have uptaken virulent metacyclic promastigotes. GP63 also binds fibronectin, which then bridges the parasite to FnRs. (b) LPG expression on amastigotes is less robust than on promastigotes, allowing the scarcely expressed GP63 to access C3 protein, and subsequently CR3. Antibody and fibronectin detection of amastigotes leads to ligation of FcγRs and FnRs, respectively. (c) Immediately following inoculation by the sand fly, promastigotes parasitize predominantly PMNs. Promastigotes enter PMNs via CR3, and then enter macrophages or DCs while contained in the short-lived granulocyte. Promastigotes and amastigotes may also directly enter DCs via DC-SIGN, but the ligand on the parasite surface has yet to be identified.