Mechanisms of CD36-mediated parasitophorous vacuole maturation in macrophages infected with Leishmania amazonensis

Univ Of Massachusetts Med Sch Worcester, Worcester MA

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Abstract

Leishmaniasis is a neglected tropical disease affecting more than 12 million people and causing 20-40 thousand deaths every year in tropical and subtropical regions. To infect humans and promote disease, Leishmania parasites use sophisticated virulence mechanisms to evade host cell defenses and exploit cellular resources. During Leishmaniasis, amastigote forms of the parasite sustain the infection and cause disease symptoms through repeated cycles of intracellular proliferation, escape to the extracellular milieu and then re-invasion of naive cells. Macrophages are main cell type infected by amastigotes because they efficiently recognize and internalize amastigotes through receptor-mediated phagocytosis. Yet, macrophages are unable to kill these intracellular parasites, which instead establish a specialized replicative niche in a modified phagolysosome-like compartment, known as the parasitophorous vacuole (PV). This proposal is focused on the study of a newly identified host factor exploited by Leishmania parasites for successful invasion and niche establishment, the scavenger receptor CD36. After using Drosophila as screening platform, we discovered that the scavenger receptor CD36 was required for biogenesis of the enlarged parasitophorous vacuole of L. amazonensis. This organelle dilutes the toxic effects of nitric oxide and allows parasite proliferation. Given the importance of the PV as intracellular niche for Leishmania replication, we propose in Aim 1 to investigate the mechanisms by which CD36 regulates the PV size. Aim 2 is focused in the identification of the CD36 binding domain and the parasite component that binds to CD36 and triggers PV enlargement.