Polymorphisms in the TOLLIP Gene Influence Susceptibility to Cutaneous Leishmaniasis Caused by Leishmania guyanensis in the Amazonas State of Brazil

Araújo, Felipe Jules de; Silva, Luan Diego Oliveira da; Mesquita, Tirza Gabrielle Ramos de; Pinheiro, Suzana Kanawati; Vital, Wonei de Seixas; Chrusciak‐Talhari, Anette; Guerra, Jorge Augusto de Oliveira; Talhari, Sinésio; Ramasawmy, Rajendranath

doi:10.1371/journal.pntd.0003875

Cited by 30 publications

(22 citation statements)

References 39 publications

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“…PPARα also regulates the expression of genes involved in free fatty acid metabolism, could bind to TLR4 and interfere with the inflammatory response. In addition, Tollip is a negative regulator of the TLR signaling pathway, regulates the production of the pro-inflammatory cytokines IL-6 and TNF ( 75 ) and potentially influences the response to cutaneous L. guyanensis infection ( 76 ). Mapk8ip3/JIP3 helps the TLR4 signaling cascade enhance the activation of the JNK and MEK1/2 pathways ( 77 , 78 ).…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor and miRNA-let-7e Expression Alter the Inflammatory Response in Leishmania amazonensis-Infected Macrophages

et al. 2018

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Parasite recognition by Toll-like receptors (TLRs) contributes to macrophage activation and subsequent control of Leishmania infection through the coordinated production of pro-inflammatory and microbicidal effector molecules. The modulation of microRNA (miRNA) expression by Leishmania infection potentially mediates the post-transcriptional regulation of the expression of genes involved in leishmanicidal activity. Here, the contribution of TLR signaling to the miRNA profile and gene expression was evaluated in Leishmania amazonensis-infected murine macrophages. The infectivity of L. amazonensis was higher in murine bone marrow-derived macrophages from mice knockout for myeloid differentiation factor 88 (MyD88−/−), TLR2 (TLR2−/−), or TLR4 (TLR4−/−) than wild type C57BL/6 (WT). L. amazonensis infection of WT macrophages modulated the expression of 32% of the miRNAs analyzed, while 50% were upregulated. The absence of MyD88, TLR2, and TLR4 altered the percentage of miRNAs modulated during L. amazonensis infection, including the downregulation of let-7e expression. Moreover, the absence of signals mediated by MyD88, TLR2, or TLR4 reduced nitric oxide synthase 2 (Nos2) mRNA expression during infection. Indeed, the inhibition of let-7e increased levels of the Nos2 mRNA and NOS2 (or iNOS) protein and nitric oxide (NO) production in L. amazonensis-infected macrophages (4–24 h). The absence of TLR2 and inhibition of let-7e increased the expression of the arginase 1 (Arg1) mRNA but did not alter the protein level during infection. However, higher levels of the L-arginine transporters Cat2B and Cat1 were detected in the absence of Myd88 signaling during infection but were not altered following let-7e inhibition. The inhibition of let-7e impacted the global expression of genes in the TLR pathway by upregulating the expression of recognition and adaptors molecules, such as Tlr6, Tlr9, Ly96, Tirap, Traf 6, Ticam1, Tollip, Casp8, Map3k1, Mapk8, Nfkbib, Nfkbil1, Ppara, Mapk8ip3, Hspd1, and Ube2n, as well as immunomodulators, such as Ptgs2/Cox2, Csf 2, Csf 3, Ifnb1, Il6ra, and Ilr1, impacting NOS2 expression, NO production and parasite infectiveness. In conclusion, L. amazonensis infection alters the TLR signaling pathways by modulating the expression of miRNAs in macrophages to subvert the host immune responses.

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Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor and miRNA-let-7e Expression Alter the Inflammatory Response in Leishmania amazonensis-Infected Macrophages

et al. 2018

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“…Moreover, IL-13 or RV16 alone did not alter Tollip expression, but the combination of both significantly reduced Tollip in cells with AG/GG compared with the AA genotype. Rs5743899, located in chromosome 11:1323564, is within the intron 2 of the Tollip gene [42]. How the rs5743899 AG or GG genotype regulates transcription and/or translation of Tollip particularly in the context of IL-13 and RV infection remains unclear, but Tollip promoter activity, mRNA stability and translational activity will be examined in our future studies.…”

Section: Discussionmentioning

confidence: 99%

Tollip SNP rs5743899 modulates human airway epithelial responses to rhinovirus infection

Huang

Jiang

Francisco

et al. 2016

Clin Experimental Allergy

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Background Rhinovirus (RV) infection in asthma induces varying degrees of airway inflammation (e.g., neutrophils), but the underlying mechanisms remain unclear. Objective The major goal was to determine the role of genetic variation (e.g., single nucleotide polymorphisms [SNPs]) of Toll-interacting protein (Tollip) in airway epithelial responses to RV in a type 2 cytokine milieu. Methods DNA from blood of asthmatic and normal subjects was genotyped for Tollip SNP rs5743899 AA, AG and GG genotypes. Human tracheobronchial epithelial (HTBE) cells from donors without lung disease were cultured to determine pro-inflammatory and anti-viral responses to IL-13 and RV16. Tollip knockout and wild-type mice were challenged with house dust mite (HDM) and infected with RV1B to determine lung inflammation and anti-viral response. Results Asthmatic subjects carrying the AG or GG genotype (AG/GG) compared with the AA genotype demonstrated greater airflow limitation. HTBE cells with AG/GG expressed less Tollip. Upon IL-13 and RV16 treatment, cells with AG/GG (versus AA) produced more IL-8 and expressed less anti-viral genes, which was coupled with increased NF-κB activity and decreased expression of LC3, a hallmark of the autophagic pathway. Tollip co-localized and interacted with LC3. Inhibition of autophagy decreased anti-viral genes in IL-13 and RV16 treated cells. Upon HDM and RV1B, Tollip knockout (versus wild-type) mice demonstrated higher levels of lung neutrophilic inflammation and viral load, but lower levels of anti-viral gene expression. Conclusions and Clinical Relevance Our data suggest that Tollip SNP rs5743899 may predict varying airway response to RV infection in asthma.

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“…[16][17][18][19] In humans, common genetic variation in the TOLLIP gene is associated with susceptibility to multiple intracellular infections. [20][21][22] How TOLLIP influences infectious disease host defense within the lung is not well understood. We hypothesized that TOLLIP, acting as a ubiquitin-binding autophagy receptor, negatively regulates the innate immune response after Lp infection, which results in increased susceptibility to LD.…”

Section: Introductionmentioning

confidence: 99%

TOLLIP deficiency is associated with increased resistance to Legionella pneumophila pneumonia

et al. 2019

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Legionella pneumophila (Lp) is a flagellated, intracellular bacterium that can cause Legionnaires' disease (LD). Lp activates multiple innate immune receptors, and TOLLIP dampens MyD88dependent signaling and may influence susceptibility to LD. We evaluated the effect of TOLLIP on innate immunity, pneumonia severity, and LD susceptibility in mouse lungs and human populations. To accomplish this, we evaluated the effect of TOLLIP on lung-specific Lp control and immune response and associated a common functional TOLLIP variant with Lp-induced innate immune responses and LD susceptibility in humans. After aerosol Lp infection, Tollip −/− mice demonstrated significantly fewer bacterial CFU and increased cytokine responses from BAL fluid. Tollip −/− macrophages also suppressed intracellular Lp replication in a flagellin-independent manner. The presence of a previously characterized, functionally active SNP associated with decreased TOLLIP mRNA transcript in monocytes was associated with increased TNF and IL-6 secretion after Lp stimulation of PBMC ex vivo. This genotype was separately associated with decreased LD susceptibility (309 controls, 88 cases, p = 0.008, OR 0.36, 95% CI 0.16-0.76) in a candidate gene association study. These results suggest that TOLLIP decreases lung-specific TLR responses to increase LD susceptibility in human populations. Better understanding of TOLLIP may lead to novel immunomodulatory therapies. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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Polymorphisms in the TOLLIP Gene Influence Susceptibility to Cutaneous Leishmaniasis Caused by Leishmania guyanensis in the Amazonas State of Brazil

Cited by 30 publications

References 39 publications

Toll-Like Receptor and miRNA-let-7e Expression Alter the Inflammatory Response in Leishmania amazonensis-Infected Macrophages

Toll-Like Receptor and miRNA-let-7e Expression Alter the Inflammatory Response in Leishmania amazonensis-Infected Macrophages

Tollip SNP rs5743899 modulates human airway epithelial responses to rhinovirus infection

TOLLIP deficiency is associated with increased resistance to Legionella pneumophila pneumonia

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