Leishmania Parasites Differently Regulate Antioxidant Genes in Macrophages Derived From Resistant and Susceptible Mice

Abstract

Macrophage–Leishmania interactions are central to parasite growth and disease outcome. Macrophages have developed various strategies to fight invaders, including oxidative burst. While some microorganisms seem to survive and even thrive in an oxidative environment, others are susceptible and get killed. To counter oxidative stress, macrophages switch the expressions of cytoprotective and detoxifying enzymes, which are downstream targets of the nuclear factor erythroid 2-related factor 2 (Nrf2), to enhance cell survival. We have explored the transcription of NRF2 and of its target genes and compared the effect of the parasite on their transcription in bone marrow-derived macrophages (BMdMs) from Leishmania-resistant and Leishmania-susceptible mice. While heme oxygenase 1 (HO-1) transcription is independent of the genetic background, the transcription of glutathione reductase (Gsr) and of cysteine/glutamate exchange transporter (Slc7a11), involved in glutathione accumulation, was differentially regulated in BMdMs from both mouse strains. We also show that, except for HO-1, known to favor the survival of the parasite, the transcription of the selected genes, including Gsr, CD36, and catalase (CAT), was actively repressed, if not at all time points at least at the later ones, by the parasite, especially in Balb/c BMdMs. Consistent with these results, we found that the silencing of NRF2 in this study increases the survival and multiplication of the parasite.

Comparative transcriptomic analysis of long noncoding RNAs in Leishmania-infected human macrophages

“…In the literature, the antioxidant response to La infection was evaluated at a systemic level, showing increased SOD2 levels and activity in the liver of infected mice ( Gasparotto et al, 2017 ). Our data also corroborates data from L. major -infected BALB/c or C57BL/6 macrophages, where GSR was upregulated ( Bichiou et al, 2021 ). The increased level of detoxification molecules agrees with high glutathione levels in the La -infected macrophages ( Muxel et al, 2019 ; Mamani-Huanca et al, 2021 ).…”

Transcriptional signatures in human macrophage-like cells infected by Leishmania infantum, Leishmania major and Leishmania tropica

“…At 24h post-infection, among the 398 genes upregulated exclusively in L . infantum -infected cells were the cytokines IL1B, IL1A, IL6 the IL12 receptor subunit β1 (IL12RB1), the immunomodulator CSF2, the transcription factor NFE2L2 (that plays a key role in the response to oxidative stress), GCLC and GCLM (codifying for two subunit of glutamate–cysteine ligase, a key enzyme involved in glutathione synthesis) and SLC7A11 (coding for a transporter of cystine and glutamate and involved in GSH production) [ 34 , 35 ]. Also, several genes coding for matrix metalloproteases (i.e., MMP3, MMP9, MMP10, MMP12, MMP13, MMP19) were found to be upregulated.…”

Leptospiral lipopolysaccharide dampens inflammation through upregulation of autophagy adaptor p62 and NRF2 signaling in macrophages

“…Our results confirmed that p62 induces translocation of NRF2 upon infection with leptospires. Other microbes such as Epstein-Barr virus (EBV) or parasite Leshmania major have been shown to activate the p62/NRF2 axis [53, 54], hence showing an important role of NRF2 in response to pathogens. However, to date, the role of NRF2 translocation in response to pathogens remains unclear.…”

“…We therefore hypothesize that leptospires would not benefit from induction of antioxidant program in the host cells. Interestingly, active repression of these NRF2-dependent antioxidant targets was previously shown upon infection with live Leshmania major parasite [54, 56] Whether leptospires could also actively prevent upregulation of NRF2 antioxidant targets remains to be addressed.…”