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Leishmania and its Survival Mechanisms

Authors of a recent review article discuss how the Leishmania parasite interacts with the immune system of its mammalian host, and how these interactions affect both the parasite and the host.

Leishmaniasis is a neglected tropical disease and major public health problem that is endemic in 98 countries. It is caused by different species of the protozoan parasite Leishmania and is transmitted by the bite of its sand fly vector.

In a recent review article in Cellular Immunology, Olivier Séguin, and Albert Descoteaux, both from the INRS—Institut Armand-Frappier and the Center for Host-Parasite Interactions, Laval, Canada, discuss how the Leishmania parasite interacts with the immune system of its mammalian host, and how these interactions affect both the parasite and the host.

Leishmania is a very complex and specialised parasite that possesses the ability to survive and thrive within its human host,” the authors write.

“To survive, Leishmania uses an arsenal of pathogenicity factors that includes LPG [lipophosphoglycan] and GP63 to modify the phagosome into a parasitophorous vacuole, modulate the expression and secretion of cytokines, modulate the immune cells flux to the infection site and modulate the antigen presentation favouring a Th2 inefficient response.”

This parasite has a complex life cycle involving two distinct stages: the promastigote form in the female sand fly vector and the amastigote form in the mammalian host.

Leishmania In the Sand Fly

Leishmania promastigotes multiply and become infectious in the midgut of the sand fly. The infectious promastigotes then migrate to the sand fly esophagus before being inoculated into the mammalian host. When the sand fly bites the mammalian host, the parasites are transferred into the bite wound and are taken up by the host’s inflammatory cells.

Some parasite mortality within the gut of infected sand flies is essential for establishment of infection in the mammalian host. After death, these parasites display the lipid phosphatidylserine (PS) on their surface, a mechanism which allows them to aid survival of the live parasites in the host. This is because the PS tag on the dead parasites dampens down the host’s immune response to the live parasites.

Leishmania In the Mammalian Host

Leishmania uses macrophages, a type of white blood cell in the host to avoid the host’s immune system. After Leishmania infects the macrophage via phagocytosis, it resides within phagosome compartments in the cell, modifying them into parasitophorous vacuoles. Pathogenicity factors play a central role in this modification process that helps to promote parasite survival. These factors include LPG and GP63 (a zinc-dependent metalloprotease on the surface of Leishmania).

“GP63 also counteracts various innate immune response actors such as natural killer (NK) cells through direct inactivation,” the authors say.

“This metalloprotease is indeed able to suppress the proliferation of IL-2-activated NK cells and affects expression of receptors at their surface. NK cells play an important role in the response to L. major through the production of IFN-γ which assists in driving an effective Th1 response.”

In particular, GP63 can inhibit complement activity which is typically an important aspect of the host’s innate immune response to elimination of pathogens. Inactivation of this process by Leishmania is therefore an important step in its survival in the mammalian host.

GP63 also activates several protein tyrosine phosphatases that act along various cell signalling pathways, thereby modulating the pattern of secretion of phagocytic cell cytokines in favour of inhibiting host responses associated with infection control. By stimulating cleavage of a membrane fusion regulator known as VAMP8, GP63 also allows Leishmania to avoid phagocytosis. In addition, GP63 changes expression of surface receptors in NK cells and inhibits their proliferation. It also cleaves the surface co-receptor CD4 in T lymphocytes. As a consequence, “[s]ince CD4 is requires for T lymphocyte activation, its cleavage by GP63 is likely to reduce T lymphocyte responses to antigen presenting cells,” the authors emphasize.

Another protease, cysteine peptidase CPB, which the parasite needs to survive in the macrophage, is another pathogenicity factor that controls the virulence of Leishmania by regulating GP63 expression, although the mechanism involved is still unknown.

However, despite these advances in the understanding of the mechanisms by which Leishmania can survive in the mammalian host, the authors stress that a lot remains unknown about how the parasite modifies the phagosome, modulates the immune response, and migrates throughout the host body.

“A better understanding of this complex parasitic relationship will also require to take into consideration host genetic factors as well as the diversity of parasite species and strains,” they conclude.