Abstract
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.
Highlights
Macrophages are myeloid immune cells specialized in the recognition and elimination of invading pathogens [1,2]
To determine whether activation of the NF-E2-related factor 2 (NRF2) pathway occured with different L. spp., bone marrow derived macrophages (BMDMs) from C57BL/6 wild-type (WT) mice were infected with different L. species for 4 hours including L. guyanensis (Lgy) harboring, or not, the Leishmania RNA virus 1 (LRV1) endosymbiont
We observed that all tested L. spp. showed similar levels of NRF2 protein at 4 hrs and NRF2 activation was sustained at 8 hrs post-infection, we could observe some differences in expression level mainly in species inducing visceral leishmaniasis (S1A Fig)
Summary
Macrophages are myeloid immune cells specialized in the recognition and elimination of invading pathogens [1,2] They can, be colonized by protozoan parasites such as Toxoplasma gondi, Trypanosoma cruzi or Leishmania (L.) spp., offering them an environment to complete their life cycle and multiply. In South America, up to 10% of the cases progress to persistent chronic inflammation resulting in distant secondary lesions leading to mucocutaneous leishmaniasis (MCL), with destruction of the mucosal tissues [4,5] Such aggressive symptomatic outcomes may be due to co-infections with other viruses [6,7] or the presence of a cytoplasmic double stranded RNA (dsRNA) virus, Leishmania RNA virus 1 (LRV1) nested mainly within L. braziliensis (LbrLRV1+) or L. guyanensis (Lgy) (LgyLRV1+) parasites. MCL patients have increased levels of TNF-α produced by specific intermediate monocytes [11] that could explain destruction of mucosal tissues observed in these patients [12]
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