title: Cysteine Peptidase B Regulates Leishmania mexicana Virulence through the Modulation of GP63 Expression.
abstract: Cysteine peptidases play a central role in the biology of Leishmania. In this work, we sought to further elucidate the mechanism(s) by which the cysteine peptidase CPB contributes to L. mexicana virulence and whether CPB participates in the formation of large communal parasitophorous vacuoles induced by these parasites. We initially examined the impact of L. mexicana infection on the trafficking of VAMP3 and VAMP8, two endocytic SNARE proteins associated with phagolysosome biogenesis and function. Using a CPB-deficient mutant, we found that both VAMP3 and VAMP8 were down-modulated in a CPB-dependent manner. We also discovered that expression of the virulence-associated GPI-anchored metalloprotease GP63 was inhibited in the absence of CPB. Expression of GP63 in the CPB-deficient mutant was sufficient to down-modulate VAMP3 and VAMP8. Similarly, episomal expression of GP63 enabled the CPB-deficient mutant to establish infection in macrophages, induce the formation of large communal parasitophorous vacuoles, and cause lesions in mice. These findings implicate CPB in the regulation of GP63 expression and provide evidence that both GP63 and CPB are key virulence factors in L. mexicana.
authors.affiliation: INRS- Institut Armand-Frappier and the Center for Host-Parasite Interactions, Laval, Canada.
authors.forename: Pierre-André
authors.initials: PA
authors.lastname: Casgrain
authors.affiliation: The Research Institute of the McGill University Health Centre, Montréal, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Martel
authors.affiliation: Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: W Robert
authors.initials: WR
authors.lastname: McMaster
authors.affiliation: Centre for Immunology and Infection, Department of Biology, University of York, Wentworth Way Heslington, York, United Kingdom.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Mottram
authors.affiliation: The Research Institute of the McGill University Health Centre, Montréal, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Olivier
authors.affiliation: INRS- Institut Armand-Frappier and the Center for Host-Parasite Interactions, Laval, Canada.
authors.forename: Albert
authors.initials: A
authors.lastname: Descoteaux
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003545:Cysteine / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000502:physiology*; D007894:Leishmania mexicana / Q000472:pathogenicity*; D016773:Leishmaniasis, Cutaneous / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D010447:Peptide Hydrolases / Q000378:metabolism; D015800:Protozoan Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D015800:Protozoan Proteins; D037521:Virulence Factors; D010447:Peptide Hydrolases; D008666:Metalloendopeptidases; C055146:glycoprotein gp63, Leishmania; D003545:Cysteine