title: Trypanosoma cruzi subverts the sphingomyelinase-mediated plasma membrane repair pathway for cell invasion.
abstract: Upon host cell contact, the protozoan parasite Trypanosoma cruzi triggers cytosolic Ca(2+) transients that induce exocytosis of lysosomes, a process required for cell invasion. However, the exact mechanism by which lysosomal exocytosis mediates T. cruzi internalization remains unclear. We show that host cell entry by T. cruzi mimics a process of plasma membrane injury and repair that involves Ca(2+)-dependent exocytosis of lysosomes, delivery of acid sphingomyelinase (ASM) to the outer leaflet of the plasma membrane, and a rapid form of endocytosis that internalizes membrane lesions. Host cells incubated with T. cruzi trypomastigotes are transiently wounded, show increased levels of endocytosis, and become more susceptible to infection when injured with pore-forming toxins. Inhibition or depletion of lysosomal ASM, which blocks plasma membrane repair, markedly reduces the susceptibility of host cells to T. cruzi invasion. Notably, extracellular addition of sphingomyelinase stimulates host cell endocytosis, enhances T. cruzi invasion, and restores normal invasion levels in ASM-depleted cells. Ceramide, the product of sphingomyelin hydrolysis, is detected in newly formed parasitophorous vacuoles containing trypomastigotes but not in the few parasite-containing vacuoles formed in ASM-depleted cells. Thus, T. cruzi subverts the ASM-dependent ceramide-enriched endosomes that function in plasma membrane repair to infect host cells.
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
authors.forename: Maria Cecilia
authors.initials: MC
authors.lastname: Fernandes
authors.forename: Mauro
authors.initials: M
authors.lastname: Cortez
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Flannery
authors.forename: Christina
authors.initials: C
authors.lastname: Tam
authors.forename: Renato A
authors.initials: RA
authors.lastname: Mortara
authors.forename: Norma W
authors.initials: NW
authors.lastname: Andrews
mesh_terms: D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology* / Q000235:genetics; D002518:Ceramides / Q000235:genetics / Q000378:metabolism; D014355:Chagas Disease / Q000378:metabolism* / Q000473:pathology; D004705:Endocytosis; D005089:Exocytosis / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*; D013109:Sphingomyelins / Q000235:genetics / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000378:metabolism*
chemical_list: D002518:Ceramides; D013109:Sphingomyelins; D013108:Sphingomyelin Phosphodiesterase; D002118:Calcium