The protozoan is in the smaller of its two forms, called an amastigote, which is round, non-motile, and only 3–7 micrometers in diameter. Inside the stomach of the sandfly, the amastigotes quickly transform into elongated and motile forms called the promastigotes. Promastigote is spindle-shaped, triple the size of the amastigote, and has a single flagellum that allows mobility. The promastigotes live extracellularly in the alimentary canal, reproducing asexually, then migrate to the proximal end of the gut where they become poised for a regurgitational transmission. As the fly bites, the promastigotes are released from the proboscis and introduced locally at the bite site.Once inside the human host, promastigotes invade macrophages. Inside the cells they transform back into the smaller amastigote form. The amastigotes replicate in the most hostile part of the macrophage cell, inside the phagolysosome, whose normal defensive response they are able to prevent. After repeated multiplication, they break down their host cell by sheer pressure of mass, but there is some recent speculation that they are able to leave the cell by triggering the exocytosis response of the macrophage. The daughter cells protozoans then migrate to fresh cells or through the bloodstream to find new hosts. In this way the infection is progressive, spreading to the hosts mononuclear phagocyte system, particularly the spleen and liver. The free amastigotes in peripheral tissues are then ingested by sandfly to enter another cycle. Regulatory T and B cells
The cell-mediated immunity (CMI) that kills Leishmania also produces inflammation. If the inflammation is excessive, it can cause tissue damage.
Some clones secreted soluble factors that caused the death of CD8+ regulatory T cells but not CD4+ T cells from VL patients, which might explain the strong protective immunity of asymptomatic patients. Non-protective immunity
VL patients are unable to clear their infections because they lack CMI. This anergy may be limited to Leishmania antigens or extend to mitogens and other antigens as the disease progresses. In addition to skin test negativity, VL patient PBMC do not proliferate or secrete IL-2 or IFN-γ in response to Leishmania antigens. Memory T cells may be depleted in VL patient PBMC. Since IL-10 is known to suppress innate and acquired immunity and prevent IFN-γ from activating macrophages, its role in VL has been studied extensively and elevated IL-10 production is often used as a marker of non-protective immunity in VL. Elevated levels of IL-10 in the plasma, infected tissues, and PBMC of VL patients accompany the anergy of VL. PKDL patients also have elevated IL-10 levels. VL patients with the highest IL-10 levels are more likely to be unresponsive to treatment and progress to PKDL. PBMC secretion of IL-10 without the addition of Leishmania antigen (endogenous) is inversely correlated with antigen specific IFN-γ secretion but Leishmania antigen specific IL-10 and IFN-γ secretion are not correlated, suggesting that endogenous secretion is more important in pathology. Addition of anti-IL-10 increases proliferation and IFN-γ secretion by PBMC from some patients. Both CD4+ and CD8+ T cells have been shown to contribute to IL-10 secretion by VL PBMC.