Leishmania donovani causes human visceral leishmaniasis. The parasite infectious cycle comprises extracellular flagellated promastigotes that proliferate inside the insect vector, and intracellular nonmotile amastigotes that multiply within infected host cells. Using primary macrophages infected with virulent metacyclic promastigotes and high spatiotemporal resolution microscopy, we dissect the dynamics of the early infection process. We find that motile promastigotes enter macrophages in a polarized manner through their flagellar tip and are engulfed into host lysosomal compartments. Persistent intracellular flagellar activity leads to reorientation of the parasite flagellum toward the host cell periphery and results in oscillatory parasite movement. The latter is associated with local lysosomal exocytosis and host cell plasma membrane wounding. These findings implicate lysosome recruitment followed by lysosome exocytosis, consistent with parasite-driven host cell injury, as key cellular events in Leishmania host cell infection. This work highlights the role of promastigote polarity and motility during parasite entry.

A key feature of many pathogenic microorganisms is the presence of a dense glycocalyx at their surface, composed of lipid-anchored glycoproteins and non-protein-bound polysaccharides. These surface glycolipids are important virulence factors for bacterial, fungal and protozoan pathogens. The highly complex glycoconjugate lipophosphoglycan (LPG) is one of the dominant surface macromolecules of the promastigote stage of all Leishmania parasitic species. LPG plays critical pleiotropic roles in parasite survival and infectivity in both the sandfly vector and the mammalian host. Here, we review the composition of the Leishmania glycocalyx, the chemical structure of LPG and what is currently known about its effects in the mammalian host, specifically. We will then discuss the current approaches employed to elucidate LPG functions. Finally, we will provide a viewpoint on future directions that this area of investigation could take to unravel in detail the biological activity of the specific molecular elements composing the structurally complex LPG.