Genetic Variation in Toll-Like Receptor Signalling and the Risk of Inflammatory and Immune Diseases

Corr, Sinéad C.; O’Neill, Luke A. J.

doi:10.1159/000200774

Cited by 44 publications

(36 citation statements)

References 112 publications

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“…4 Genetic variation of innate immunity may influence infection and manifestation, which has been shown for MBL and TLR single-nucleotide polymorphisms (SNPs) and various infectious and inflammatory diseases. 5,6 Specifically, an increased risk of severe CCC has been attributed to high MBL serum levels, 7 but respective genotypic data are not available. In contrast, a mutation in the TLR adaptor protein MAL/TIRAP (S180L) has been associated with a reduced risk of CCC.…”

mentioning

confidence: 99%

Mannose-Binding Lectin and Toll-Like Receptor Polymorphisms and Chagas Disease in Chile

Weitzel¹,

Zulantay²,

Hamann³

et al. 2012

The American Society of Tropical Medicine and Hygiene

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Abstract. Mannose-binding lectin (MBL) and Toll-like receptor (TLR) polymorphisms may influence susceptibility and manifestation of Trypanosoma cruzi infection. In northern Chile, we examined 61 asymptomatic patients with chronic Chagas disease (CD), 64 patients with chronic Chagas cardiomyopathy (CCC), and 45 healthy individuals. Lowproducer MBL2*B genotypes were more common in CD patients (48%) than healthy individuals (31%; adjusted odds ratio ¼ 2.3, 95% confidence interval ¼ 1.01-5.4, P ¼ 0.047) but did not differ with manifestation. In contrast, the heterozygous Toll-like receptor 4 (TLR4)-deficiency genotype D299G/T399I occurred more frequently in asymptomatic (14.8%) than CCC patients (3.1%; P ¼ 0.02). TLR1-I602S, TLR2-R753Q, TLR6-S249P, and MAL/TIRAP-S180L did not associate with CD or CCC. These findings support the complement system to be involved in defense against Trypanosoma cruzi infection and indicate that curbed TLR4 activation might be beneficial in preventing CCC.Chagas disease (CD), caused by Trypanosoma cruzi, affects up to 8 million people in Latin America, with up to 13,000 annual deaths. Infection persists lifelong. Still, only one-third of patients develop manifestations, mainly chronic Chagas cardiomyopathy (CCC). The pathogenesis of progression to chronic symptomatic CD is poorly understood, but it involves immunological and autoimmunological factors and genetic disposition.1,2 Innate immune responses contribute to host control, and T. cruzi has been shown to bind to mannose-binding lectin (MBL), which activates the lectin pathway of early complement killing and reduces host cell invasion.3 Also, T. cruzi activates the Toll-like receptor (TLR) system, particularly TLRs 2 and 4, which ultimately leads to a proinflammatory response. 4 Genetic variation of innate immunity may influence infection and manifestation, which has been shown for MBL and TLR single-nucleotide polymorphisms (SNPs) and various infectious and inflammatory diseases. 5,6 Specifically, an increased risk of severe CCC has been attributed to high MBL serum levels, 7 but respective genotypic data are not available. In contrast, a mutation in the TLR adaptor protein MAL/TIRAP (S180L) has been associated with a reduced risk of CCC. 8In the provinces of Choapa and Limarí, northern Chile, CD is highly endemic, and although Chile was declared free of domestic T. cruzi transmission in 1999, vertical transmission and management of chronically infected patients continue.9 In this area, a cohort of patients has been regularly followed-up since the 1990s. 10 In these patients and healthy individuals, we typed common SNPs that reduce the function of TLRs involved in the recognition of T. cruzi as well as low-producer MBL2 alleles and analyzed associations with CD and CCC.Patients were recruited from the CD cohort in November of 2007 and May of 2008. In the patients' villages, healthy volunteers were asked to participate as controls. All study participants were thoroughly informed about study purpose and procedures, and they signed an ...

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confidence: 99%

Mannose-Binding Lectin and Toll-Like Receptor Polymorphisms and Chagas Disease in Chile

Weitzel¹,

Zulantay²,

Hamann³

et al. 2012

The American Society of Tropical Medicine and Hygiene

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“…Accumulating evidence supports the role of dysregulated TLR signaling in the pathogenesis of infectious, autoimmune, allergic, inflammatory diseases and cancer (El-Omar and others 2008;Garantziotis and others 2008;Corr and O'Neill 2009;Rakoff-Nahoum and Medzhitov 2009;Netea and others 2012;Theodoropoulos and others 2012). Several synonymous and nonsynonymous single-nucleotide polymorphisms (SNPs) have been identified in the promoter and coding regions of TLR1, TLR2, TLR4, TLR5, TLR7, and TLR9, and their associations with infectious, inflammatory, and allergic diseases are discussed below.…”

Section: Tlr Polymorphisms and Diseasementioning

confidence: 89%

Toll-Like Receptor Polymorphisms, Inflammatory and Infectious Diseases, Allergies, and Cancer

Medvedev

2013

Journal of Interferon & Cytokine Research

123

101

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Toll-like receptors (TLRs) are germ-line-encoded innate immune sensors that recognize conserved microbial structures and host alarmins and signal expression of MHC proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These processes activate immediate and early mechanisms of innate host defense, as well as initiate and orchestrate adaptive immune responses. Several single-nucleotide polymorphisms (SNPs) within the TLR genes have been associated with altered susceptibility to infectious, inflammatory, and allergic diseases, and have been found to play a role in tumorigenesis. Critical advances in our understanding of innate immune functions and genome-wide association studies (GWAS) have uncovered complex interactions of genetic polymorphisms within TLRs and environmental factors. However, conclusions obtained in the course of such analyses are restricted by limited power of many studies that is likely to explain controversial findings. Further, linkages to certain ethnic backgrounds, gender, and the presence of multigenic effects further complicate the interpretations of how the TLR SNPs affect immune responses. For many TLRs, the molecular mechanisms by which SNPs impact receptor functions remain unknown. In this review, I have summarized current knowledge about the TLR polymorphisms, their impact on TLR signaling, and associations with various inflammatory, infectious, allergic diseases and cancers, and discussed the directions of future scientific research.

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“…The Toll-like receptors (TLRs) are critical mediators of the inflammatory response to malarial infection 3,4 and in endemic areas of the disease, gene polymorphisms affecting TLR function may be partially responsible for inter-individual variation in disease manifestation. However, there have been inconsistencies in the results of association studies of the common genetic variants of TLR4 (D299G) and TLR9 (T-1237C and T-1486C) on the clinical outcomes of malaria.…”

Section: Discussionmentioning

confidence: 99%

“…Despite its high incidence, the low mortality rate (1-2%) in malaria-infected patients even after effective clinical management highlights the importance of host factors, in addition to parasite factors and environmental determinants. The host response to malarial infection is immediate and is mediated by pattern recognition receptors of the innate immune system 3,4 . Among these, the Toll-like receptors (TLRs) are well studied in malaria [5][6][7][8][9] and are stimulated by infected red blood cells (RBCs) and/or parasite-derived metabolites, culminating in the release of pro-inflammatory cytokines such as IFN-γ, IL-12, and TNF-α, as well as nitric oxide 8,9 , which are important for controlling the acute blood-stage infection.…”

Section: Introductionmentioning

confidence: 99%

“…Of the ten TLRs in humans, the most notable are TLR4 and TLR9, whose activation and changes in expression are thought to potentially affect the clinical outcome of malaria [4][5][6][7] . While TLR4 may interact with extra-cellular ligands (such as PfGPI; Plasmodium falciparum Glycosylphosphatidylinositol) as well as intracellular ligands as it is located both on the cell surface and on endosomes, TLR9 interacts only with intracellular ligands owing to its endosomal localization 8,[10][11][12] .…”

Section: Introductionmentioning

confidence: 99%

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A meta-analysis of TLR4 and TLR9 SNPs implicated in severe malaria

Dhangadamajhi

Kar

Rout

et al. 2017

Rev. Soc. Bras. Med. Trop.

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Toll-like receptors (TLRs) are critical mediators of the inflammatory response to malarial infection, and gene polymorphisms affecting TLR function may be partially responsible for inter-individual variation in disease manifestation. However, there are inconsistencies in the associations of common genetic variants of TLR4 (D299G) and TLR9 (T-1237C and T-1486C) with malaria outcome. A comprehensive search was conducted to identify relevant and independent Plasmodium falciparum-infected casecontrol studies, and meta-analysis including six studies for each SNP was performed to obtain more precise estimates of the pooled effects of these variants. The results showed significant associations of the -1486C allele with the risk of severe malaria in allele contrast (T vs. C, p = 0.004, OR = 1.26) and homozygous (TT vs. CC, p = 0.03, OR = 1.51) genetic models. There was no association between the D299G or T-1237C variants and uncomplicated or severe malaria using any of the genetic models tested. However, in stratified analysis, -1237C was associated with the risk of severe malaria in Indian adults (TT vs. TC, p = 0.06, OR = 2.13; TT vs. TC+CC, p <0.00001, OR = 2.65), suggesting that our results must be considered preliminary. The robustness of -1486C as a risk factor warrants investigation into its functionality in malaria pathogenesis. Further, the lack of an association with the T-1237C variant was weak, and future studies examining more detailed individual data from different ethnic groups are essential for confirmation of its genetic contribution to malaria.

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Genetic Variation in Toll-Like Receptor Signalling and the Risk of Inflammatory and Immune Diseases

Cited by 44 publications

References 112 publications

Mannose-Binding Lectin and Toll-Like Receptor Polymorphisms and Chagas Disease in Chile

Mannose-Binding Lectin and Toll-Like Receptor Polymorphisms and Chagas Disease in Chile

Toll-Like Receptor Polymorphisms, Inflammatory and Infectious Diseases, Allergies, and Cancer

A meta-analysis of TLR4 and TLR9 SNPs implicated in severe malaria

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