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SYSTEMS APPROACH REVEALS NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2/PROTEIN KINASE R CROSSTALK IN HUMAN CUTANEOUS LEISHMANIASIS
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Leishmania
parasites infect macrophages, causing a wide spectrum of human diseases, from cutaneous to visceral forms. In search of novel therapeutic targets, we performed comprehensivein vitroandex vivomapping of the signaling pathways upstream and downstream of antioxidant transcription factor [nuclear factor erythroid 2-related factor 2 (Nrf2)] in cutaneous leishmaniasis (CL), by combining functional assays in human and murine macrophages with a systems biology analysis ofin situ(skin biopsies) CL patient samples. First, we show the PKR pathway controls the expression and activation of Nrf2 inLeishmania amazonensisinfectionin vitro. Nrf2 activation also required PI3K/Akt signaling and autophagy mechanisms. Nrf2- or PKR/Akt-deficient macrophages exhibited increased levels of ROS/RNS and reduced expression ofSod1Nrf2-dependent gene and reduced parasite load.L. amazonensiscounteracted the Nrf2 inhibitor Keap1 through the upregulation of p62viaPKR. This Nrf2/Keap1 observation was confirmedin situin skin biopsies fromLeishmania-infected patients. Next, we explored theex vivotranscriptome in CL patients, as compared to healthy controls. We found the antioxidant response element/Nrf2 signaling pathway was significantly upregulated in CL, including downstream target p62.In silicoenrichment analysis confirmed upstream signaling by interferon and PI3K/Akt, and validated ourin vitrofindings. Our integratedin vitro, ex vivo, andin silicoapproach establish Nrf2 as a central player in human cutaneous leishmaniasis and reveal Nrf2/PKR crosstalk and PI3K/Akt pathways as potential therapeutic targets.
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