Abstract
To colonize phagocytes, Leishmania subverts microbicidal processes through components of its surface coat that include lipophosphoglycan and the GP63 metalloprotease. How these virulence glycoconjugates are shed, exit the parasitophorous vacuole (PV), and traffic within host cells is poorly understood. Here, we show that lipophosphoglycan and GP63 are released from the parasite surface following phagocytosis and redistribute to the endoplasmic reticulum (ER) of macrophages. Pharmacological disruption of the trafficking between the ER and the Golgi hindered the exit of these molecules from the PV and dampened the cleavage of host proteins by GP63. Silencing by RNA interference of the soluble N-ethylmaleimide-sensitive-factor attachment protein receptors Sec22b and syntaxin-5, which regulate ER-Golgi trafficking, identified these host proteins as components of the machinery that mediates the spreading of Leishmania effectors within host cells. Our findings unveil a mechanism whereby a vacuolar pathogen takes advantage of the host cell's secretory pathway to promote egress of virulence factors beyond the PV.
Highlights
The protozoan parasite Leishmania causes a spectrum of human diseases known as the leishmaniases [1]
Leishmania promastigotes are internalized by phagocytes into a highly modified phagosome that promotes parasite growth and differentiation into the amastigote form
We found that post-phagocytosis, Leishmania co-opts the host cell secretory pathway to promote the egress of its virulence factors out of the phagosome
Summary
The protozoan parasite Leishmania causes a spectrum of human diseases known as the leishmaniases [1]. Infectious insect-stage promastigotes are inoculated in mammals upon the blood meal of the vector and are internalized by phagocytes where they differentiate into mammalian-stage amastigotes [2]. To avoid destruction within phagocytes, promastigotes derail phagolysosome biogenesis and function, shut down microbicidal pathways, and sabotage immune processes [3,4,5,6,7,8,9,10] Subversion of these host defence processes is achieved to a large extent through the action of the two major components of the Leishmania promastigote surface coat: the metalloprotease GP63 and lipophosphoglycan (LPG), a polymer of repeating Galβ1,4Manα1-PO4 units attached to the promastigote surface via a glycosylphosphatidylinositol anchor [11, 12]. As LPG and GP63 are highly down-modulated or absent in mammalian-stage amastigotes [20, 21], their role is to create an environment permissive for the establishment of infection and propitious to promastigote-to-amastigote differentiation within phagocytes
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