Open AccessThe antioxidant response favors Leishmania parasites survival, limits inflammation and reprograms the host cell metabolism
Author(s) -
Marta Reverte,
Remzi Onur Eren,
Baijayanti Jha,
Chantal Desponds,
Tiia Snäkä,
Florence Prével,
Nathalie Isorce,
Lon Fye Lye,
Katherine Owens,
Ulisses Gazos Lopes,
Stephen M. Beverley,
Nicolás Fasel
Publication year - 2021
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1009422
Subject(s) - biology , microbiology and biotechnology , leishmania , intracellular parasite , nadph oxidase , signal transduction , reactive oxygen species , intracellular , inflammation , tumor necrosis factor alpha , respiratory burst , immune system , proinflammatory cytokine , transcription factor , mediator , immunology , biochemistry , parasite hosting , world wide web , computer science , gene
The oxidative burst generated by the host immune system can restrict intracellular parasite entry and growth. While this burst leads to the induction of antioxidative enzymes, the molecular mechanisms and the consequences of this counter-response on the life of intracellular human parasites are largely unknown. The transcription factor NF-E2-related factor (NRF2) could be a key mediator of antioxidant signaling during infection due to the entry of parasites. Here, we showed that NRF2 was strongly upregulated in infection with the human Leishmania protozoan parasites, its activation was dependent on a NADPH oxidase 2 (NOX2) and SRC family of protein tyrosine kinases (SFKs) signaling pathway and it reprogrammed host cell metabolism. In inflammatory leishmaniasis caused by a viral endosymbiont inducing TNF-α in chronic leishmaniasis, NRF2 activation promoted parasite persistence but limited TNF-α production and tissue destruction. These data provided evidence of the dual role of NRF2 in protecting both the invading pathogen from reactive oxygen species and the host from an excess of the TNF-α destructive pro-inflammatory cytokine.