Professor Albert Descoteaux of INRS-Institut Armand-Frappier Research Centre and his team have discovered novel virulence strategies employed by the Leishmania parasite. These scientific breakthroughs recently published in the prestigious PLOS Pathogens journal represent two important clues to understanding the cellular and molecular mechanisms governing the parasitic infections that cause leishmaniasis, a neglected tropical disease endemic in one hundred countries.
Leishmania uses macrophages, a type of white blood cell that neutralizes pathogenic micro-organisms, as host cells to circumvent the immune system. Upon infecting the macrophage, Leishmania enters a vacuole that it hijacks by manipulating the host cell membrane fusion machinery. Research results revealed that GP63, a zinc-dependent metalloprotease found on the surface of Leishmania, plays a central role in this process.
By promoting the cleavage of the VAMP8 membrane fusion regulator, GP63 allows Leishmania major to evade LC3-associated phagocytosis, a process whose purpose is to boost the antimicrobial properties of macrophages. Researchers have also found that cysteine peptidase CPB, which the parasite needs to survive in the macrophage, controls the virulence of Leishmania mexicana by regulating GP63 expression through an as yet unknown mechanism.
These two proteases occupy a central role in the biology of Leishmania and contribute to the formation and growth of parasitophorous vacuoles where the parasite develops and replicates. Researchers have thus uncovered a new Leishmania virulence mechanism heavily influenced by GP63 and CPB proteases.
"Our results give us a better understanding of Leishmania pathogenesis and identify a new strategy used by intracellular pathogens to disrupt the host cell's antimicrobial," stated Professor Descoteaux. This discovery will be useful in developing preventive or therapeutic measures against leishmaniasis.
Two articles have been published in PLOS Pathogens:
- "Cysteine Peptidase B Regulates Leishmania mexicana Virulence through the Modulation of GP63 Expression" presents the results of research carried out by Pierre-André Casgrain (master's student), Caroline Martel, W. Robert McMaster, Jeremy C. Mottram, Martin Olivier, and Albert Descoteaux. The researchers received financial support from the Canadian Institutes of Health Research, the Medical Research Council, and the Centre for Host-Parasite Interactions. doi:10.1371/journal.ppat.1005658
- "Leishmania major Promastigotes Evade LC3-Associated Phagocytosis through the Action of GP63" was written by Christine Matte (research assistant), Pierre-André Casgrain (master's student), Olivier Séguin (doctoral student), Neda Moradin (doctoral student), Wan Jin Hong, and Albert Descoteaux. The Canadian Institutes of Health Research and the Centre for Host-Parasite Interactions funded this research. doi:10.1371/journal.ppat.1005690