Leprosy and the Adaptation of Human Toll-Like Receptor 1

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
PLoS Pathogens (Impact Factor: 7.56). 07/2010; 6(7):e1000979. DOI: 10.1371/journal.ppat.1000979
Source: PubMed


Leprosy is an infectious disease caused by the obligate intracellular pathogen Mycobacterium leprae and remains endemic in many parts of the world. Despite several major studies on susceptibility to leprosy, few genomic loci have been replicated independently. We have conducted an association analysis of more than 1,500 individuals from different case-control and family studies, and observed consistent associations between genetic variants in both TLR1 and the HLA-DRB1/DQA1 regions with susceptibility to leprosy (TLR1 I602S, case-control P = 5.7 x 10(-8), OR = 0.31, 95% CI = 0.20-0.48, and HLA-DQA1 rs1071630, case-control P = 4.9 x 10(-14), OR = 0.43, 95% CI = 0.35-0.54). The effect sizes of these associations suggest that TLR1 and HLA-DRB1/DQA1 are major susceptibility genes in susceptibility to leprosy. Further population differentiation analysis shows that the TLR1 locus is extremely differentiated. The protective dysfunctional 602S allele is rare in Africa but expands to become the dominant allele among individuals of European descent. This supports the hypothesis that this locus may be under selection from mycobacteria or other pathogens that are recognized by TLR1 and its co-receptors. These observations provide insight into the long standing host-pathogen relationship between human and mycobacteria and highlight the key role of the TLR pathway in infectious diseases.


Available from: Chiea Chuen Khor, Sep 19, 2015
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    • "Pathogenesis routes in leprosy initiate with the recognition of pathogen-associated molecular patterns (PAMPs) from M. leprae by pattern recognition receptors (PRRs) and mycobacterial uptake (TLR, NOD2 and MRC1). These genes have been associated with leprosy outcome in genetic epidemiological studies [5], [6], [7], [8], [9], [10]. Further, there is a cytokine production trigger through NF-kB and vitamin D receptor pathways, which culminate in the production of proteins directly involved in microbicidal activity. "
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    ABSTRACT: Herein, we performed microarray experiments in Schwann cells infected with live M. leprae and identified novel differentially expressed genes (DEG) in M. leprae infected cells. Also, we selected candidate genes associated or implicated with leprosy in genetic studies and biological experiments. Forty-seven genes were selected for validation in two independent types of samples by multiplex qPCR. First, an in vitro model using THP-1 cells was infected with live Mycobacterium leprae and M. bovis bacillus Calmette-Guérin (BCG). In a second situation, mRNA obtained from nerve biopsies from patients with leprosy or other peripheral neuropathies was tested. We detected DEGs that discriminate M. bovis BCG from M. leprae infection. Specific signatures of susceptible responses after M. leprae infection when compared to BCG lead to repression of genes, including CCL2, CCL3, IL8 and SOD2. The same 47-gene set was screened in nerve biopsies, which corroborated the down-regulation of CCL2 and CCL3 in leprosy, but also evidenced the down-regulation of genes involved in mitochondrial metabolism, and the up-regulation of genes involved in lipid metabolism and ubiquitination. Finally, a gene expression signature from DEG was identified in patients confirmed of having leprosy. A classification tree was able to ascertain 80% of the cases as leprosy or non-leprous peripheral neuropathy based on the expression of only LDLR and CCL4. A general immune and mitochondrial hypo-responsive state occurs in response to M. leprae infection. Also, the most important genes and pathways have been highlighted providing new tools for early diagnosis and treatment of leprosy.
    PLoS ONE 06/2013; 8(6):e64748. DOI:10.1371/journal.pone.0064748 · 3.23 Impact Factor
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    • "Other variables known to be associated with disease severity were not included in this analysis, consistent with the GWAS primary analysis for DSS as well as other infectious diseases.[6], [10]–[12] Pooled odds ratios across the different sample collections were calculated using the inverse-variance, fixed effects model, as previously described.[13] This model used the weighted average of each study’s odds ratio. "
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    ABSTRACT: A recent genome-wide association study (GWAS) identified susceptibility loci for dengue shock syndrome (DSS) at MICB rs3132468 and PLCE1 rs3740360. The aim of this study was to define the extent to which MICB (rs3132468) and PLCE1 (rs3740360) were associated with less severe clinical phenotypes of pediatric and adult dengue. 3961 laboratory-confirmed dengue cases and 5968 controls were genotyped at MICB rs3132468 and PLCE1 rs3740360. Per-allele odds ratios (OR) with 95% confidence intervals (CI) were calculated for each patient cohort. Pooled analyses were performed for adults and paediatrics respectively using a fixed effects model. Pooled analysis of the paediatric and adult cohorts indicated a significant association between MICB rs3132468 and dengue cases without shock (OR = 1.15; 95%CI: 1.07 - 1.24; P = 0.0012). Similarly, pooled analysis of pediatric and adult cohorts indicated a significant association between dengue cases without shock and PLCE1 rs3740360 (OR = 0.92; 95%CI: 0.85 - 0.99; P = 0.018). We also note significant association between both SNPs (OR = 1.48; P = 0.0075 for MICB rs3132468 and OR = 0.75, P = 0.041 for PLCE1 rs3740360) and dengue in infants. This study confirms that the MICB rs3132468 and PLCE1 rs3740360 risk genotypes are not only associated with DSS, but are also associated with less severe clinical phenotypes of dengue, as well as with dengue in infants. These findings have implications for our understanding of dengue pathogenesis.
    PLoS ONE 03/2013; 8(3):e59067. DOI:10.1371/journal.pone.0059067 · 3.23 Impact Factor
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    • "A common single-nucleotide polymorphism (SNP) occurring in the transmembrane domain of TLR1 abrogates cell surface expression and signaling26 and is present in at least 20% of the human population.27 Using a human IEC line that does not express TLR128 (data not shown), we examined the ability of the wild-type TLR1 allele (I602I) and the mutant TLR1 allele (I602S) to induce CCL20 after transfection. "
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    ABSTRACT: Our gastrointestinal tract is a portal of entry for a number of bacteria and viruses. Thus, this tissue must develop ways to induce antigen-specific T cell and antibody responses quickly. Intestinal epithelial cells are a central player in barrier function and also in communicating signals from invading pathogens to the underlying immune tissue. Here we demonstrate that activation of Toll-like receptor 1 (TLR1) in the epithelium leads to the upregulation of the chemokine CCL20 during oral infection with Yersinia enterocolitica. Further, both neutralization of CCL20 using polyclonal antibody treatment and deletion of TLR1 resulted in a defect in CCR6+ dendritic cells (DCs), which produce innate cytokines that help to induce anti-Yersinia-specific T helper 17 (T(H)17) cells and IgA production. These data demonstrate a novel role for TLR1 signaling in the intestinal epithelium and demonstrate that together TLR1 and CCL20 are critical mediators of T(H)17 immunity through the activation and recruitment of DCs.Mucosal Immunology advance online publication 27 February 2013; doi:10.1038/mi.2013.5.
    Mucosal Immunology 02/2013; 6(6). DOI:10.1038/mi.2013.5 · 7.37 Impact Factor
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