Leishmania major Promastigotes Evade LC3-Associated Phagocytosis through the Actionof GP63

Christine Matte¹, Pierre-André Casgrain¹, Olivier Séguin¹, Neda Moradin¹, Wan Jin Hong^2,3, Albert Descoteaux¹*

PLOS Pathogens. June 9 2014 | DOI:10.1371/journal.ppat.1005690

Speaker: Chung-Ching Kuo (郭重慶)                                  Time: 15:00~16:00, Mar. 30, 2017

Commentator: Jyh-Wei Shin, Ph.D. (辛致煒 教授)            Place: Room 601

Abstract:

Leishmania is a genus of trypanosomes which is found in parts of the tropics, subtropics, and southern Europe. They are spread by sandflies and their primary hosts are vertebrates. Leishmania parasitizes macrophages and evades phagocytosis through the inhibition of phagolysosome biogenesis. In this study, authors provide evidences that Leishmania promastigotes evade LC3-associated phagocytosis (LAP) through a mechanism involving GP63-mediated cleavage of VAMP8 and exclusion of NOX2 from phagosomes. The Leishmania genus use surface virulence factors such as lipophosphoglycan and the metalloprotease GP63 to interfere with phagolysosome biogenesis and sabotage macrophage antimicrobial functions. Importantly, during phagocytosis, GP63 is released from the parasite and rapidly gains access to various intracellular compartments where it cleaves a number of regulators of macrophage function, including regulators of membrane fusion. One such molecule is the soluble N-ethylmaleimide-sensitive factor-attachment protein receptor Vesicle-associated membrane protein 8 (VAMP8), which authors recently showed to control the earlyrecruitment of the NADPH oxidase (NOX2) to phagosomes [1]. Targeting of VAMP8 through GP63 enables Leishmania promastigotes to inhibit assembly of the NOX2 complex on phagosomes, thereby impairing the ability of infected cells to process antigens for cross-presentation and to activate T cells. The authors provide a better understanding of Leishmania pathogenesis and a strategy exploited by an intracellular pathogen to interfere with the host antimicrobial machinery.

References:

1.     Matheoud D, Moradin N, Bellemare-Pelletier A, Shio MT, Hong WJ, Olivier M, et al. Leishmania evades host immunity by inhibiting antigen cross-presentation through direct cleavage of the SNARE VAMP8. Cell Host Microbe. 2013; 14: 15–25.