Nicolas Fasel

Localization of human MHC class I-restricted T cell epitopes in the circumsporozoite (CS) protein of the human parasite Plasmodium falciparum is an important objective in the development of antimalarial vaccines. To this purpose, we synthesized a series of overlapping synthetic 20-mer peptides, spanning the entire sequence of the 7G8 CS molecule except for the central repeat B cell domain. The P.f.CS peptides were first tested for their ability to bind to the human MHC class I HLA-A2.1 molecule on T2, a human cell line. Subsequently, the use of a series of shorter peptide analogues allowed us to determine the optimal A2.1 binding sequence present in several of the 20-mers. Binding P.f.CS peptides were further tested for their capacity to activate PBL from HLA-A2.1+ immune donors living in a malaria-endemic area. Specific IFN-gamma production was detected in the supernatant of cultures of PBL from exposed individuals. Cytotoxic T cell lines and clones were derived from the PBL of one...

IP 1106-04-382-98Miguel X. van Bemmelen ... [et al.]. -- En: Molecular andbiochemical parasitology (Aug. 2000); p. 1-14. --;ISSN 0166-6851 -- Generation and characterization of malaria-specific human CD8+ lymphocyte clones : effect of;natural polymorphism on T cell recognition and endogenouscognate antigenpresentation by liver cells / Anilsa;Bonelo ... [et al.]. -- En: European journal of immunology. --no. 30 (2000); p. 3079-3088 -- HLA-A*0201;restricted CD8+ T-lymphocyte responses to malaria : identification of newPlasmodium falciparum epitopes by;IFN-Y Elispot / John Mario Gonzalez ... [et al.]. -- En: Parasite immunology. -- Vol. 22, no. 10 (Oct. 2000);p. 501-514 -- Los linfocitos T CD8+ en la respuesta inmunecelular : ?comofuncionan?, ?como se evaluan? /;John Mario Gonzalez ... [et al.]. -- En: Revista Asociacion Colombiana deAlergia, Asma e Inmunologia. -- Vol.;8, no. 2 (1999); p. 19-24.;ARTICULO(S) EN REVISTA: Expression and one-step purification ofPlasmodiumproteins in Dictyostelium

Mitochondria regulate steroid hormone synthesis, and in turn sex hormones regulate mitochondrial function for maintaining cellular homeostasis and controlling inflammation. This crosstalk can explain sex differences observed in several pathologies such as in metabolic or inflammatory disorders. Nod-like receptor X1 (NLRX1) is a mitochondria-associated innate receptor that could modulate metabolic functions and attenuates inflammatory responses. Here, we showed that in an infectious model with the human protozoan parasite,Leishmania guyanensis, NLRX1 attenuated inflammation in females but not in male mice. Analysis of infected female and male bone marrow derived macrophages showed both sex- and genotype-specific differences in both inflammatory and metabolic profiles with increased type I interferon production, mitochondrial respiration, and glycolytic rate inNlrx1-deficient female BMDMs in comparison to wild-type cells, while no differences were observed between males. Transcriptomi...

Ribonuclease Inhibitor (RNH1) is a ubiquitously expressed leucine-rich repeat protein. The human RNH1 gene evolved via gene duplication and is conserved among mammalian species. RNH1 binds to and inhibits pancreatic type ribonucleases. Further, RNH1 contains numerous cysteine residues whose sulfhydryl groups might play key structural roles and protect from oxidative damage (Dickson et al Prog. Nucleic Acid Res. Mol. Biol 2005). Despite of all these observations, the precise biological role of RNH1in vivo remains unexplored. Here, we describe an essential role for Rnh1 in the regulation of erythropoiesis by controlling erythroid differentiation. To understand the biological function of Rnh1, Rnh1-deficient (Rnh1-/-) mice were generated. Rnh1-/- embryos die between embryonic days E8.5 to E10 due to severe decrease in erythroid cells. Similar percentages of c-Kit+CD41+ cells (Hematopoietic stem/progenitor cells) were present in Rnh1-/- yolk sacs compared to control genotypes, however differentiation of mature erythroid cells was impaired. Rnh1 is expressed in erythroid cells and its expression coincides with the site of primitive erythropoiesis in the yolk sac. Gene expression studies revealed that levels of hematopoietic transcription factors (TF) in Rnh1-deficient yolk sacs were normal, but their target genes were down-regulated. These results indicate that a post-transcriptional mechanism that affects TF gene function. Supporting this, protein levels of the erythroid transcription factor GATA1 and PPARγ, previously shown to control the proliferation and differentiation of erythroid progenitors, were selectively impaired. Whereas myeloid transcription factors C/EBPa and C/EBPb were not affected in Rnh1-/- embryos, suggesting that Rnh1 deficiency specifically affects the translation of erythroid transcription factors. At the molecular level, using the human erythroid K562 cell line, we show that RNH1 is recruited to the ribosome complex and binds to the ribosomal proteins. RNH1-deficiency decreased polysome formation and conversely its overexpression increased polysome formation. Increased expression of RNH1 also increased globin gene expression in K562 cells. These results suggest that RNH1 associates with ribosomes and regulates the translation of erythroid-specific genes, which are necessary for erythroid differentiation. Furthermore, Rnh1 haploinsufficiency leads to decreased erythropoiesis in the spleen of adult mice. Ribosomal haploinsufficiency in several ribosomal genes is known to impair ribosome function and cause macrocytic anemia in Diamond–Blackfan anemia (DBA), a congenital bone marrow failure syndrome, and the 5q- syndrome, a subtype of myelodysplastic syndrome (Narla et al Int. J. Hematol 2011). Recently it has been shown that ribosomal haploinsufficiency can specifically cause a decrease in GATA1 mRNA translation (Ludwig et al Nature Med 2014). Similar to these ribosomal genes, we demonstrate that Rnh1 associates with ribosomes and its deficiency impairs the translation of Gata1 and other erythroid-specific transcription factors, which leads to arrest in erythroid maturation. Collectively our results unravel the important biological function of Rnh1 in the regulation of erythropoiesis, and point to novel therapeutic targets for disorders of erythropoiesis involving ribosomal defects. Summary Figure: RNH1 is recruited to ribosomal complex and is involved in translation of erythroid specific transcription factors (TF) e.g.GATA1. These TFs are necessary for differentiation of progenitor cells in to erythroid cells. RNH1 deficiency impairs the translation of GATA1 and other erythroid-specific transcription factors, which leads to arrest in erythroid maturation. Summary Figure:. RNH1 is recruited to ribosomal complex and is involved in translation of erythroid specific transcription factors (TF) e.g.GATA1. These TFs are necessary for differentiation of progenitor cells in to erythroid cells. RNH1 deficiency impairs the translation of GATA1 and other erythroid-specific transcription factors, which leads to arrest in erythroid maturation. Summary Figure: RNH1 is recruited to ribosomal complex and is involved in translation of erythroid specific transcription factors (TF) e.g.GATA1. These TFs are necessary for differentiation of progenitor cells in to erythroid cells. RNH1 deficiency impairs the translation of GATA1 and other erythroid-specific transcription factors, which leads to arrest in erythroid maturation. Disclosures No relevant conflicts of interest to declare.

Publisher Summary This chapter reviews the properties of inducible protein expression vectors and describes a recombinant plasmid vector developed to induce expression of foreign proteins in polarized epithelial cells. The ability to induce foreign protein expression is desirable in investigating the role of specific components of complex cellular functions, such as cell proliferation and the cell cycle, metabolic pathways, membrane trafficking, and organelle biogenesis. Inducible systems are not restricted to the upregulation of foreign protein expression but can also downregulate the expression of distinct gene products by controlled destabilization of the corresponding messenger RNA (mRNA) species using antisense RNA. Glucocorticoid hormones modulate physiological responses and developmental functions in target cells via specific receptors that act as transcription factors. After binding to their cognate cytoplasmic receptors, glucocorticoids can stimulate or repress the transcription of glucocorticoid-regulated genes by binding to specific DNA sequences—that is, the glucocorticoid-responsive elements in their promoter region.

The deduced amino acid sequence of Leishmania major sw3 cDNA reveals the presence of characteristic histone H1 amino acid motifs. However, the open reading frame is of an unusually small size for histone H1 (105 amino acids) because it lacks the coding potential for the central hydrophobic globular domain of linker histones present in other eukaryotes. Here, we provide biochemical evidence that the SW3 protein is indeed a L. major nuclear histone H1, and that it is differentially expressed during the life cycle of the parasite. Due to its high lysine content, the SW3 protein can be purified to a high degree from L. major nuclear lysates with 5% perchloric acid, a histone H1 preparative method. Using an anti-SW3 antibody, this protein is detected as a 17 kDa or as a 17/19 kDa doublet in the nuclear subfraction in different L. major strains. The nuclear localization of the SW3 protein is further supported by immunofluorescence studies. During in vitro promastigote growth, both the sw3 cytoplasmic mRNA and its protein progressively accumulate within parasites from early log phase to stationary phase. Within amastigotes, the high level of H1 expression is maintained but decreases when amastigotes differentiate into promastigotes. Together, these observations suggest that the different levels of this histone H1 protein could influence the varying degrees of chromatin condensation during the life-cycle of the parasite, and provide us with tools to study this mechanism.

Cells such as epithelial or neuronal cells, when fully differentiated, exhibit a clear functional asymmetry related to morphological asymmetry. Differences in plasma membrane composition are maintained by the presence of intercellular tight junctions which prevent lateral diffusion of membrane components,1 and by cytoskeletal elements that interact with plasma membrane proteins and restrict their movement.2,3 The rules that govern intracellular sorting and polarized delivery of membrane proteins to the cell surface is complex and still poorly understood.

Differential expression of cell surface antigens is thought to play an important role in development of mouse lymphoid cells. It is therefore important to understand how cell-surface expression of specific molecules is regulated. One of the first T-cell markers described is Thy-1, which is expressed at low levels in stem cells and progenitors of bone marrow cells, and at a ten-fold higher level in T cells (Miiller-Sieburg et al. 1986). Thy1 antigen, which can be induced at the surface of healthy mouse B cells by interleukin-4 (Snapper et al. 1988), is constitutively expressed on nervous tissues, dentritic epidermal cells, and fibroblasts (for a review see Reif and Schlesinger 1989). Similar to several other cell surface proteins, Thy-1 is anchored in the lipid bilayer via a glycosylphosphatidylinositol (GPI) added posttranslationally near the COOH-terminus after removal of an hydrophobic polypeptide extension and can be released from the membranes by phosphatidyl-inositol specific phospholipase (PI-PLC; Low and Kincade 1985; Ferguson and Williams 1988). Genetic variants leading to changes in cell surface expression provide additional tools for structural and regulatory studies. Several Thy-1 negative mutant T-lymphoma lines have been isolated (Hyman 1973, 1988). Taking advantage of two mouse Thy-1 allelic forms differing by a single amino acid substitution and referred to as Thy-l.1 (isolated from AKR/J mouse) and Thy-l.2 (BALB/e and other strains; Reif and Allen 1964; Williams and Gagnon 1982), nine complementation classes of Thy-1 negative mutants (class A-I) have been described (Hyman 1988). In six of them (class A, B, C, E, F, and H), the Thy-1 protein is normally synthesized but is aberrantly processed due to mutations affecting GPI anchor biosynthesis or addition. Among these different lines, the B mutant class (S1A -b thymoma) actively secretes a

<p><b>A.</b> Dot blot analysis of two parasite samples obtained from separate lesion biopsies in an infected patient: <i>Lb</i> 2169 and <i>Lb</i> 2192. Live parasites (1 to 4 µg total proteins) were spotted on a nitrocellulose membrane for LRV dsRNA detection by dot blot (J2 antibody). <i>Lg</i> M4147 LRV<sup>high</sup> and LRV<sup>neg</sup> were used as positive and negative controls. Upper panel: dsRNA detection by dot blot (J2). Lower panel: verification of protein quantity by Ponceau staining. <b>B.</b> J2 anti-dsRNA analysis of <i>Lb</i> 2169 by fluorescence microscopy. Green: dsRNA (J2 Ab). Blue: DAPI. <b>C.</b> Isolation of viral genomic dsRNA from the <i>Lb</i> 2169 strain. Intact and DNase-digested total nucleic acids from <i>Lb</i> 2169 parasites and <i>Lg</i> M4147 LRV<sup>high</sup> as a control, were analyzed by gel electrophoresis (similarly to <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002006#pntd-0002006-g001" target="_blank">Figure 1A</a>). Note: with high resolution gels such as presented here (in contrast to <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002006#pntd-0002006-g001" target="_blank">Figure 1</a>), the viral genome often appears as a doublet.</p

<p>C57BL/6 mice infected with LRV1+ <i>Lg</i> or LRV1- <i>Lg</i> parasites. (A) Mice were sacrificed 4 weeks post infection and IFN-γ levels were analysed in the supernatant (SN) of restimulated cells with recombinant LRVc by ELISA to assess the cellular immune response against LRVc (white LRV1- <i>Lg</i> and black LRV1+ <i>Lg</i>) or control mice (grey). (B) Mice were bled 8 weeks post infection. Sera were collected and tested for the presence of IgG specific to the LRV1c protein by ELISA (see <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0005240#sec002" target="_blank">Materials and Methods</a>). IgG were analyzed form sera of infected mice (white LRV1- <i>Lg</i> and black LRV1+ <i>Lg</i>) or control mice (grey). Results are means±SEM. Statistical significance tested by a two-way ANOVA, using Prism5 Graphpad software (n = 5, *: P<0.05, **: P<.005, ***: P<0.0005). Representative of 2 independent experiments.</p

<p>In addition to the three <i>L. aethiopica</i> cryobank lines tested, <i>Lg</i> M4147 LRV1+ was added as a positive control. <b>A. PCR amplification.</b> A portion of the LRV capsid protein open reading frame (489 and 486 bp for LRV1 and LRV2 respectively) was amplified from total cDNA using LRV universal primers (<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002836#pntd.0002836.s005" target="_blank">Table S1</a>). As a cDNA quality control, a 372 bp fragment of the beta-tubulin gene was also amplified. <b>B. LRV dsRNA visualization.</b> Total RNA was analyzed on agarose gel. Ribosomal RNA (rRNA) and the complete 5.3 kb LRV genomic dsRNA are indicated.</p

Glycosyl phosphatidylinositol (GPI)-anchored proteins contain in their COOH-terminal region a peptide segment that is thought to direct glycolipid addition. This signal has been shown to require a pair of small amino acids positioned 10-12 residues upstream of an hydrophobic C-terminal domain. We analysed the contribution of the region separating the anchor acceptor site and the C-terminal hydrophobic segment by introducing amino acid deletions and substitutions in the spacer element of the GPI-anchored Thy-1 glycoprotein. Deletions of 7 amino acids in this region, as well as the introduction of 2 charged residues, prevented the glycolipid addition to Thy-1, suggesting that the length and the primary sequence of the spacer domain are important determinants in the signal directing GPI anchor transfer onto a newly synthesized polypeptide. Furthermore, we tested these rules by creating a truncated form of the normally transmembranous Herpes simplex virus I glycoprotein D (gDI) and demo...

Metacaspases (MCAs) are cysteine peptidases expressed in plants, fungi and protozoa, with a caspase-like histidine–cysteine catalytic dyad, but differing from caspases, for example, in their substrate specificity. The role of MCAs is subject to debate: roles in cell cycle control, in cell death or even in cell survival have been suggested. In this study, using a Leishmania major MCA-deficient strain, we showed that L. major MCA (LmjMCA) not only had a role similar to caspases in cell death but also in autophagy and this through different domains. Upon cell death induction by miltefosine or H2O2, LmjMCA is processed, releasing the catalytic domain, which activated substrates via its catalytic dyad His/Cys and a proline-rich C-terminal domain. The C-terminal domain interacted with proteins, notably proteins involved in stress regulation, such as the MAP kinase LmaMPK7 or programmed cell death like the calpain-like cysteine peptidase. We also showed a new role of LmjMCA in autophagy, a...

<p>C57BL/6 mice were vaccinated three times, 15 days apart, and sacrificed 7 days after the third vaccination. CD3+ T cells from vaccinated, or PBS injected mice (vehicle control), were purified (see <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0005240#sec002" target="_blank">Materials and Methods</a>) and transferred into naïve C57BL/6 mice. These mice were infected 1 day after with LRV1+ <i>Lg</i> parasites. (A) Change in footpad swelling of mice infected with LRV1+ <i>Lg</i>. White squares represent the group carrying CD3+ cells from vaccinated mice, black squares indicate mice carrying vehicle control (B) Parasite load measured by <i>in vivo</i> luminescence at the peak of infection. Results are means±SEM. (A) Statistical significance tested by a two-way ANOVA, using Prism5 Graphpad software (n = 5, *: P<0.05, **: P<0.005, ***: P<0.0005). Representative of 3 independent experiments. (B) Statistical significance tested by a 2-tailed Student’s t-test using Prism5 Graphpad software (n = 5, *: P<0.05, **: P<0.005, ***: P<0.0005). Representative of 2 independent experiments.</p

Inducible nitric oxide synthase (iNOS) is essential to the production of nitric oxide (NO), an efficient effector molecule against intracellular human pathogens such as Leishmania protozoan parasites. Some strains of Leishmania are known to bear a viral endosymbiont termed Leishmania RNA virus 1 (LRV1). Recognition of LRV1 by the innate immune sensor Toll-like receptor-3 (TLR3) leads to conditions worsening the disease severity in mice. This process is governed by type I interferon (type I IFNs) arising downstream of TLR3 stimulation and favoring the formation of secondary metastatic lesions. The formation of these lesions is mediated by the inflammatory cytokine IL-17A and occurs in the absence, or low level of, protective cytokine IFN-γ. Here, we described that the presence of LRV1 led to the initial expression of iNOS and low production of NO that failed to control infection. We subsequently showed that LRV1-triggered type I IFN was essential but insufficient to induce robust iNO...

The lymphatic system plays a crucial role in mounting immune response against intracellular pathogens, and recent studies have documented its role in facilitating tumor dissemination linked largely with cancer cells. However, in mucocutaneous leishmaniasis (MCL) caused by Leishmania Viannia subgenus showing infectious metastasis and resulting in severe distant secondary lesions, the route of escape of these parasites to secondary sites has not yet been investigated in detail. Our results demonstrated that when infection was associated with inflammation and additionally exacerbated by the presence of dsRNA viral endosymbiont (LRV1), lymphatic vessels could serve as efficient routes for infected cells to egress from the primary site and colonize distant organs. We challenged this hypothesis by using the intracellular Leishmania protozoan parasites Leishmania guyanensis (Lgy) associated with or without a dsRNA viral endosymbiont, exacerbating the infection and responsible for a strong ...

Leishmania parasites preferentially invade macrophages, the professional phagocytic cells, at the site of infection. Macrophages play conflicting roles in Leishmania infection either by the destruction of internalized parasites or by providing a safe shelter for parasite replication. In response to invading pathogens, however, macrophages induce an oxidative burst as a mechanism of defense to promote pathogen removal and contribute to signaling pathways involving inflammation and the immune response. Thus, oxidative stress plays a dual role in infection whereby free radicals protect against invading pathogens but can also cause inflammation resulting in tissue damage. The induced oxidative stress in parasitic infections triggers the activation in the host of the antioxidant response to counteract the damaging oxidative burst. Consequently, macrophages are crucial for disease progression or control. The ultimate outcome depends on dangerous liaisons between the infecting Leishmania s...

Leishmania RNA virus 1 (LRV1) is a double-stranded RNA virus found in some strains of the human protozoan parasite Leishmania, the causative agent of leishmaniasis, a neglected tropical disease. Interestingly, the presence of LRV1 inside Leishmania constitutes an important virulence factor that worsens the leishmaniasis outcome in a type I interferon (IFN)–dependent manner and contributes to treatment failure. Understanding how macrophages respond toward Leishmania alone or in combination with LRV1 as well as the role that type I IFNs may play during infection is fundamental to oversee new therapeutic strategies. To dissect the macrophage response toward infection, RNA sequencing was performed on murine wild-type and Ifnar-deficient bone marrow–derived macrophages infected with Leishmania guyanensis (Lgy) devoid or not of LRV1. Additionally, macrophages were treated with poly I:C (mimetic virus) or with type I IFNs. By implementing a weighted gene correlation network analysis, the g...

<p>LRV status was determined by a dot blot assay (dsRNA detection) for the eight fresh isolates, and by PCR using universal LRV-specific primers on cDNA obtained from the three cryobank lines (see <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002836#s2" target="_blank">Methods</a>). dsRNA was weakly detected in the <i>Lae</i> 315 strain (+). The four isolates selected for further analysis are highlighted in bold, as well as the L494 strain that was used for LRV sequencing. Parasites were isolated from patients suffering from cutaneous (CL) or diffuse cutaneous leishmaniasis (DCL) as indicated in the “pathology” column.</p

Significance Leishmania parasites can be infected with Leishmaniavirus (LRV1), a double-stranded RNA virus whose presence in Leishmania guyanensis parasites exacerbates disease severity in both mouse models and humans. Studies of the role of the virus on parasite biology and virulence are hampered by the dearth of isogenic lines bearing and lacking LRV, particularly in the clinically important species Leishmania braziliensis . Here, we describe a method to systematically generate LRV1-free Leishmania parasites using the parasite RNA interference (RNAi) pathway. The ability of transgene-driven RNAi to overcome the ability of LRV1 to withstand the endogenous RNAi attack suggests a third paradigm of virus–RNAi interaction where RNAi and virus replication exist in balance to maintain persistent infection.

<p><b>A.</b> Reference strain analysis (protocol A, see “Material and methods”). Green: dsRNA (J2 Ab). Blue: DAPI (standardized exposure time in all images). <b>B.</b> Phase and immunofluorescent images of <i>Lg</i> M4147 LRV<sup>high</sup> or LRV<sup>neg</sup> cells were obtained in the presence or absence of J2 antibody (protocol B). <b>C.</b> Quantitative immunofluorescence (protocol B). The fluorescent intensity per cell was assessed using Image J software on <i>Lg</i> M4147 LRV<sup>high</sup> or LRV<sup>neg</sup> cells following IFM with the J2 antibody. Cells from phase images were identified and the fluorescent intensity average over the area of the cell was recorded. 108–160 cells from 2 distinct fields were measured, and histogram plots were made using Excel software. LRV<sup>high</sup>, no primary antibody (▪, dashed line); LRV<sup>high</sup> with J2 (▪, solid line); LRV<sup>neg</sup>, no primary antibody (•, dashed line); LRV<sup>neg</sup> with J2 (•, solid line).</p

Protozoan parasites contain negatively charged polymers of a few up to several hundreds of phosphate residues. In other organisms, these poly-phosphate (polyP) chains serve as an energy source and phosphate reservoir, and have been implicated in adaptation to stress and virulence of pathogenic organisms. In this study, we confirmed first that the polyP polymerase vacuolar transporter chaperone 4 (VTC4) is responsible for polyP synthesis in Leishmania parasites. During Leishmaniain vitro culture, polyP is accumulated in logarithmic growth phase and subsequently consumed once stationary phase is reached. However, polyP is not essential since VTC4-deficient (vtc4- ) Leishmania proliferated normally in culture and differentiated into infective metacyclic parasites and into intracellular and axenic amastigotes. In in vivo mouse infections, L. majorVTC4 knockout showed a delay in lesion formation but ultimately gave rise to strong pathology, although we were unable to restore virulence by...

Emergence of survival strategies is a key step for organisms during evolution. The capacity to adapt from nutrient-rich to nutrient-poor environments led to the appearance of protein complexes regulating anabolic and catabolic pathways. The evolutionarily conserved kinase mTOR (mechanistic target of rapamycin) emerged as a crucial and central protein for regulating many different cellular functions in response to environmental changes. The kinase mTOR interacts with different partners to form two distinct complexes, which differentiate from one to the other by the presence of the regulatory-associated protein of mTOR (raptor) in the mTORC1 and the rapamycininsensitive companion of mTOR (rictor) in the mTORC2. These two mTOR complexes integrate intracellular and extracellular signals, such as presence of growth factors or amino acids, energy status, oxygen and stress, which lead to modulation of mTORC1/2-dependent signaling events. The mTORC1 regulates key cellular pathways like prot...

Regulatory Nod-like receptors (NLRs) are a subgroup of the cytosolic NLR family of pathogen recognition receptors (PRRs). These receptors can tune the innate immune responses triggered by the activation of other PRRs by either augmenting or attenuating the activated pro-inflammatory signaling cascades. Nod-like receptor X1 (NLRX1) is the only known mitochondria-associated negative regulatory NLR. NLRX1 attenuates several inflammatory pathways and modulates cellular processes such as autophagy and mitochondrial function following infection or injury. Using both in vitro expression and in vivo experimental models, NLRX1 is extensively described in the context of anti-viral signaling and host-defense against invading pathogens. More recently, NLRX1 has also gained interest in the field of cancer and metabolism where NLRX1 functions to attenuate overzealous inflammation in various inflammatory and autoimmune diseases. However, the exact function of this novel receptor is still under deb...

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 i...