Full-Exon Resequencing Reveals Toll-Like Receptor Variants Contribute to Human Susceptibility to Tuberculosis Disease

Center for Human Bacterial Pathogenesis, Department of Pathology, Baylor College of Medicine, Houston, Texas, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2007; 2(12):e1318. DOI: 10.1371/journal.pone.0001318
Source: PubMed


Tuberculosis (TB) is the leading cause of death worldwide due to an infectious agent. Data have accumulated over decades suggesting that variability in human susceptibility to TB disease has a genetic component. Toll-like receptors (TLRs) play a critical role in initiating the innate immune response to many pathogens in mouse models, but little is known about their role in human infections. Human TLRs have been reported to recognize mycobacterial antigens and initiate an immune response. We tested the hypothesis that amino acid-altering polymorphisms in five TLRs were associated with susceptibility to TB disease using a population-based case-control study with 1,312 adult TB patients and controls. Full-coding region sequencing of the five TLR genes in all 1,312 subjects yielded a data set in excess of 16 Mb. Rare nonsynonymous polymorphisms in TLR6-TLR1-TLR10 were significantly overrepresented among African-American TB cases compared with ethnically-matched control subjects. Common nonsynonymous polymorphisms in TLR6-TLR1-TLR10 also were significantly associated with TB disease in certain ethnic groups. Among African Americans, homozygotes for the common-variant haplotype TLR1-248S, TLR1-602I, and TLR6-249S had a significantly increased TB disease risk. A transmission/disequilibrium test on an independent sample found that the TLR1-248S variant was preferentially transmitted to diseased children, thereby confirming disease association. These results are consistent with recent reports implicating TLR1 variants, including TLR1-602, in significantly altered innate immune responses. Also consistent with disease association, rare TLR6 variants were defective in their ability to mediate NF-kappaB signal transduction in transfected human cells. Taken together, the data suggest that variant TLRs contribute to human susceptibility to TB disease. Extensive full-exon resequencing was critical for revealing new information about the role of TLRs in human-pathogen interactions and the genetic basis of innate immune function.

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Available from: Edward A Graviss, Oct 01, 2015
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    • "Immunogenetics studies have also implicated other innate pathways, especially those related to pathogen sensing or cytokine and chemokine production, in immunity to mycobacterial infection. Polymorphisms in TLR2, TLR9 [91], TLR1 [92], TLR8 [93], and the intracellular signaling molecule TIRAP [94] have all been associated with susceptibility to mycobacterial infection. The mechanisms for the association between TLR and mycobacterial infection are still unclear and studies in the murine model of TB seem to indicate redundant roles for TLRs and TLR-associated molecules such as MyD88 in the generation of adaptive immune responses to Mtb [95] [96] [97] [98] [99] [100]. "
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    ABSTRACT: Tuberculosis (TB) remains a serious global public health problem that results in up to 2 million deaths each year. TB is caused by the human pathogen, Mycobacterium tuberculosis (Mtb), which infects primarily innate immune cells patrolling the lung. Innate immune cells serve as barometers of the immune response against Mtb infection by determining the inflammatory milieu in the lungs and promoting the generation of adaptive immune responses. However, innate immune cells are also potential niches for bacterial replication and are readily manipulated by Mtb. Our understanding of the early interactions between Mtb and innate immune cells is limited, especially in the context of human infection. This review will focus on Mtb interactions with human macrophages, dendritic cells, neutrophils, and NK cells and detail evidence that Mtb modulation of these cells negatively impacts Mtb-specific immune responses. Furthermore, this review will emphasize important innate immune pathways uncovered through human immunogenetic studies. Insights into the human innate immune response to Mtb infection are necessary for providing a rational basis for the augmentation of immune responses against Mtb infection, especially with respect to the generation of effective anti-TB immunotherapeutics and vaccines.
    Journal of Immunology Research 08/2015; 2015:747543. DOI:10.1155/2015/747543 · 2.93 Impact Factor
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    • "Hence, attempt was made to evaluate its frequency and significance in north Indian population and to look for its association with cases. Another SNP TLR6 745 C>T was chosen as it is present in extracellular domain of the TLR6 which is important in signaling [8] and reported to be associated with TB in American African population [11], again there is a single report from India on this polymorphism from south Indian population [13]. TLR1 1805 T>G was analysed in some of these subjects to clarify the linkage with TLR1 743 A>G. "
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    ABSTRACT: Infection with M.tuberculosis possibly depends on host genetic factors and is thought to be the major cause of differential susceptibility to the disease. In the present study, 205pulmonary tuberculosis cases and 127 healthy controls were studied for the association of TLR 1(743A>G,1805 T>G) and TLR6 variant 745A>G in north Indian population. The frequency of heterozygous genotypes (AG) in TB cases (0.47) and HCs (0.61), differed significantly (p value=0.02). The association of AG genotypes in HCs was adjusted for gender as gender was observed to be a confounder and M-H OR was found to be 0.62(p=0.044). On categorizing the cases basing on AFB smear positivity, the heterozygous genotypes (AG) was found to be associated with low bacillary load (scanty and 1+) (p-value= 0.002). No association was observed for either TLR1 1805 T>G or TLR6 745C>T polymorphism. Level of serum IL6 was found to be significantly higher among healthy controls with TLR1 GG genotype compared to healthy controls with AA (p= 0.035) and AG (p= 0.005) genotypes. Thus, it may be suggested that the heterozygous condition for TLR1 743 A>G provide resistance from the disease. However, in depth study is required to understand the mechanism for possible protective responses.
    Human Immunology 06/2014; 75(8). DOI:10.1016/j.humimm.2014.06.014 · 2.14 Impact Factor
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    • "Certain mutations in the TLR genes, e.g. TLR1 and TLR6 are associated with an increased risk of acquiring M. tuberculosis[5,6]. In one study, host cells after exposure to M. tuberculosis were sensing the microbe-associated molecular pattern (MAMP) using independent PRRs like NOD2 and TLR. "
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    ABSTRACT: Mutations in the NOD2 gene are a significant risk factor to acquire intestinal failure requiring home parenteral nutrition. Tuberculous lymphadenitis is the main manifestation of extrapulmonary tuberculosis. Defects in the innate immunity, including NOD2 mutations, may increase the risk for acquiring infections caused by M. tuberculosis. An association of intestinal failure, mutations in the NOD2 gene and tuberculous lymphadenitis has not been described before. We report of two patients with intestinal failure secondary to mesenteric ischemia. Both patients presented with fever and weight loss while receiving long term home parenteral nutrition. Both of them were found to have mutations in the NOD2 gene. Catheter related infections were ruled out. FDG-PET-CT scans initially obtained in search for another infectious focus that would explain the symptoms unexpectedly showed high FDG uptake in mediastinal lymph nodes. Direct or indirect evidence proved or was highly suggestive for tuberculous lymphadenitis. Intravenous tuberculostatic therapy was started and led to a reversal of symptoms and to resolution of the lesions by FDG-PET-CT. Mutations in the NOD2 gene may put patients both at an increased risk for acquiring M. tuberculosis infections as well as at an increased risk of intestinal failure after extensive intestinal resection. Thus we suggest to specifically include reactivated and opportunistic infections in the differential diagnosis of suspected catheter related infection in patients with intestinal failure who carry mutations in their NOD2 gene.
    BMC Gastroenterology 03/2014; 14(1):43. DOI:10.1186/1471-230X-14-43 · 2.37 Impact Factor
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