title: Leishmania evades host immunity by inhibiting antigen cross-presentation through direct cleavage of the SNARE VAMP8.
abstract: During phagocytosis, microorganisms are taken up by immune cells into phagosomes. Through membrane-trafficking events mediated by SNARE proteins, phagosomes fuse with lysosomes, generating degradative phagolysosomes. Phagolysosomes contribute to host immunity by linking microbial killing within these organelles with antigen processing for presentation on MHC class I or II molecules to T cells. We show that the intracellular parasite Leishmania evades immune recognition by inhibiting phagolysosome biogenesis. The Leishmania cell surface metalloprotease GP63 cleaves a subset of SNAREs, including VAMP8. GP63-mediated VAMP8 inactivation or Vamp8 disruption prevents the NADPH oxidase complex from assembling on phagosomes, thus altering their pH and degradative properties. Consequently, the presentation of exogenous Leishmania antigens on MHC class I molecules, also known as cross-presentation, is inhibited, resulting in reduced T cell activation. These findings indicate that Leishmania subverts immune recognition by altering phagosome function and highlight the importance of VAMP8 in phagosome biogenesis and antigen cross-presentation.
authors.affiliation: Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, QC H3C 3J7, Canada.
authors.forename: Diana
authors.initials: D
authors.lastname: Matheoud
authors.forename: Neda
authors.initials: N
authors.lastname: Moradin
authors.forename: Angélique
authors.initials: A
authors.lastname: Bellemare-Pelletier
authors.forename: Marina Tiemi
authors.initials: MT
authors.lastname: Shio
authors.forename: Wan Jin
authors.initials: WJ
authors.lastname: Hong
authors.forename: Martin
authors.initials: M
authors.lastname: Olivier
authors.forename: Etienne
authors.initials: E
authors.lastname: Gagnon
authors.forename: Michel
authors.initials: M
authors.lastname: Desjardins
authors.forename: Albert
authors.initials: A
authors.lastname: Descoteaux
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D006224:Cricetinae; D045142:Cross-Priming; D005260:Female; D006790:Host-Parasite Interactions; D006801:Humans; D057131:Immune Evasion; D007891:Leishmania / Q000201:enzymology / Q000276:immunology*; D007896:Leishmaniasis / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D008666:Metalloendopeptidases / Q000276:immunology / Q000378:metabolism; D008807:Mice, Inbred BALB C; D010588:Phagosomes / Q000276:immunology; D059748:Proteolysis; D050683:R-SNARE Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D050683:R-SNARE Proteins; C491831:Vamp8 protein, mouse; D008666:Metalloendopeptidases; C055146:glycoprotein gp63, Leishmania