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Leishmania and its Survival Mechanisms

SEP 30, 2016 | NICOLA M. PARRY, BVSC, MRCVS, MSC, DIPACVP

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.
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