The antioxidant response favors Leishmania parasites survival, limits inflammation and reprograms the host cell metabolism

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-alpha in chronic leishmaniasis, NRF2 activation promoted parasite persistence but limited TNF-alpha 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-alpha destructive pro-inflammatory cytokine. Author summary When entering host cells, Leishmania parasites have evolved ingenious ways to resist an array of microbicidal mechanisms, such as oxidative burst, generated by the host immune system to restrict parasite growth. Recent studies have highlighted the NF-E2-related factor 2 (NRF2) as being responsible for conferring resistance to oxidative stress in Leishmania infection by the induction of cytoprotective genes. However, the mechanisms by which the antioxidant response is induced by parasitic infection and the impact on parasite survival are largely unknow. Here, we showed that NRF2 was strongly upregulated in Leishmania infection and participated in Leishmania parasite survival. We described that NRF2 expression was dependent on NADPH oxidase 2 and SRC family of protein tyrosine kinases (SFKs) signaling, leading to it being translocated into the nucleus and activating specific downstream genes. Furthermore, we observed that cell surface contact by Leishmania and phagocytosis were important to reprogram host cell metabolism in an NRF2-dependent manner. In addition, when we focused on Leishmania guyanensis parasites, which bear an endosymbiotic dsRNA virus known to exacerbate the disease and dissemination of the infection, we concluded that NRF2 limited inflammation and pathology by controlling the levels of the anti-Leishmania cytokine TNF-alpha which can cause tissue destruction in patients suffering of mucocutaneous leishmaniasis. Thus, the activation of the host oxidative stress pathway is likely an important subversion mechanism that Leishmania parasites use to promote their own persistence but also a protective mechanism for the host to limit inflammation in co-infections or in immunocompromised situations