Toll-like Receptor 4 Polymorphisms Research Articles

An updated systematic review of the association between the TLR4 polymorphism rs4986790 and cancers risk.

Background:Toll-like receptor 4 (TLR4) is a lipopolysaccharide receptor that may influence tumor progression through inflammatory response and immune response. This complex process mainly occurs within cells. The correlation between TLR4 and neoplasms has been of great interest, but discrepancies remain.Methods:We analyze the literature retrieved from five databases (Web of Science, PubMed, Embase, CNKI, and Wan Fang) to assess the intensity of association using odds ratio (ORs) and 95% confidence intervals (95% CI). Meta-regression and subgroup analysis were utilized to find sources of heterogeneity. Publication bias is estimated using contour-enhanced funnel plots, Begg’s test, and Egger’s test, and we implemented sensitivity analysis to clarify the reliability of the outcomes. We also conducted an evaluation of the sample size using trial sequential analysis (TSA) method.Results:We found a significant association between rs4986790 and tumors (dominant model: OR [95% CI] = 1.25 [1.11–1.42]; heterozygous model OR [95% CI] = 1.25 [1.11–1.41]; and additive model: OR [95% CI] = 1.25 [1.10–1.41]. Specifically, the rs4986790 minor allele G may increase the risk of gastric cancer (dominant model: OR [95% CI] = 1.62 [1.3–2.03]; heterozygous model: OR [95% CI] = 1.57 [1.24–1.97]; additive model: OR [95% CI] = 1.64 [1.31–2.05] and other tumors (dominant model: OR [95% CI] = 1.36 [1.17–1.57]; heterozygous model: OR [95% CI] = 1.43 [1.25–1.63]; additive model: OR [95% CI] = 1.35 [1.18–1.55]. Further subgroup analysis showed that this association are both present in Caucasian and Asian.Conclusion:The outcomes of our systemic review proved that the TLR4 polymorphism rs4986790 is associated with cancer, especially with gastric cancer, and this strong correlation are evident in Caucasians and Asian.

Toll-like receptor and matrix metalloproteinase single-nucleotide polymorphisms, haplotypes, and polygenic risk score differentiated between tuberculosis disease and infection

ObjectivesThe association of toll-like receptors (TLRs) and matrix metalloproteinases (MMPs) single-nucleotide polymorphisms (SNPs) among latent tuberculosis (TB) infection and active TB remained less studied. MethodsWe recruited participants with TB disease (active TB) (n = 400) and TB infection (latent TB infection) (n = 203) in this study. We genotyped SNPs in TLR1, TLR2, TLR4, MMP1, MMP8, MMP9, MMP12, and tissue inhibitor of MMP2. Single-variant analysis and haplotype analysis were performed, and a polygenic risk score (PRS) was created. ResultsWe found that SNPs in TLR1 (rs5743580, rs5743551), TLR2 (rs3804100), and MMP8 (rs2508383) were associated with different TB disease status risks. TLR1 rs5743580 was associated with a higher risk of TB disease status in genotypic, recessive, and additive models. TLR2 rs3804100 polymorphisms demonstrated significant association with TB disease status in genotypic, dominant, and additive models. In the haplotype analysis, the TLR1 haplotype was associated with a higher risk of TB disease, and the MMP12 haplotype was associated with a lower risk of TB disease. A PRS using 3 SNPs was associated with a higher risk of TB disease. ConclusionThis study revealed that SNP variants in TLR1, TLR2, and MMP8 differed among TB infection and disease. Haplotypes and PRS could potentially help predict TB disease status.

Genetic polymorphisms of toll-like receptors in leprosy patients from southern Brazil.

Leprosy is a chronic disease and also a global health issue, with a high number of new cases per year. Toll-like receptors can respond to mycobacterial molecules in the early stage of infection. As important components of the innate immune response, alterations in genes coding for these receptors may contribute to susceptibility/protection against diseases. In this context, we used a case-control study model (183 leprosy cases vs. 185 controls) to investigate whether leprosy patients and the control group, in southern Brazil, have different frequencies in TLR1 (TLR1 G>T; rs5743618), TLR2 (TLR2 T>C, rs1816702 and rs4696483), and TLR4 (TLR4 A>G, rs1927911) polymorphisms. Analysis of the TLR1 1805G>T polymorphism presented the G/G genotype more frequently in the control group. TLR2 T>C rs1816702 and TLR2 T>C rs4696483, the T/T and C/T genotype, respectively, were more frequent in the control group than in leprosy patients, suggesting protection from leprosy when the T allele is present (rs4696483). Haplotype analyses between TLR1 (rs5743618) and TLR2 (rs1816702 and rs4696483) polymorphisms suggest risk for the presence of the TCC haplotype and protection in the presence of the TCT haplotype. This study suggests that polymorphisms in TLR1 and TLR2 are factors that may contribute to development/resistance of leprosy.

Association of Toll-like receptor-4 polymorphism with SARS CoV-2 infection in Kurdish Population

Genetic variations are critical for understanding clinical outcomes of infections including server acute respiratory syndrome coronavirus 2 (SARS CoV-2). The immunological reactions of human immune genes with SARS CoV-2 have been under investigation. Toll-like receptors (TLRs), a group of proteins, are important for microbial detections including bacteria and viruses. TLR4 can sense both bacterial lipopolysaccharides (LPS) and endogenous oxidized phospholipids triggered by Covid-19 infection. Two TLR4 single nucleotide polymorphisms (SNPs), Asp299Gly and Thr399Ile have been linked to infectious diseases. No studies have focused on these SNPs in association with Covid-19. This study aims to reveal the association between Covid-19 infection with these SNPs by comparing a group of patients and a general population. Restriction fragment length polymorphisms (RFLP) were used to identify the TLR4 SNPs in both the general population (n = 114) and Covid-19 patient groups (n = 125). The results found no association between the TLR4 polymorphisms and Covid-19 infections as the data showed no statistically significant difference between the compared groups. This suggested that these TLR4 SNPs may not be associated with Covid-19 infections.

Toll-like receptor polymorphisms (TLR2 and TLR4) association with the risk of infectious complications in cardiac surgery patients.

Postoperative infection is a common healthcare-associated problem, and unfortunately, a serious complication in cardiac surgery patients. Toll-like receptors (TLRs) are crucial in activating non-specific immunity mechanisms and integrating elements of the immune system, due to interactions between specific and non-specific responses. In this study, the association of TLR2 or TLR4 with the risk of postoperative infections in cardiac surgery patients undergoing a coronary artery bypass grafting (CABG) procedures was investigated. Our research was carried out on a cohort of 299 consecutive adult patients with ischemic heart disease (IHD) who underwent a planned CABG procedure. These patients were monitored for the presence of a postoperative infection over a 30-day observation period. All patients were investigated for 2 TLR2 gene mutations - R753Q (rs5743708) and T16934A (rs4696482), and 2 polymorphisms of the TLR4 gene - D299G (rs4986790) and T399I (rs4986791). The final stage of the study was an evaluation of the hypothetical association between TLR2 and TLR4 gene variances and postoperative infections in patients undergoing CAGB procedures. The prevalence of infections in the final cohort was 15.3% (46/299). The most common infections were surgical site infections, which were diagnosed in 21 patients (45.6%), bloodstream infections in 15 patients (32.6%) and pneumonia in 10 patients (21.8%). Logistic regression demonstrated that the presence of the AG+GG of D299G (rs4986790) and CT+TT of T399I (rs4986791) variants was related to a higher incidence of infection in patients undergoing CAGB procedures. To our knowledge, this is the first study of its kind to demonstrate that TLR2 and TLR4 mutations affect the risk of post-CABG infections. Being a carrier of the AG+GG of D299G (rs4986790) or CT+TT of T399I (rs4986791), TLR4 variants constitute a postoperative risk factor for infection in patients undergoing CAGB procedures.

Association of Toll-like receptors polymorphisms with the risk of acute lymphoblastic leukemia in the Brazilian Amazon

Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children in childhood. Single-nucleotide polymorphism (SNPs) in key molecules of the immune system, such as Toll-like receptors (TLRs) and CD14 molecules, are associated with the development of several diseases. However, their role in ALL is unknown. A case–control study was performed with 152 ALL patients and 187 healthy individuals to investigate the role of SNPs in TLRs and the CD14 gene in ALL. In this study, TLR6 C > T rs5743810 [OR: 3.20, 95% CI: 1.11–9.17, p = 0.003) and TLR9 C > T rs187084 (OR: 2.29, 95% CI: 1.23–4.26, p = 0.000) seems to be a risk for development of ALL. In addition, the TLR1 T > G rs5743618 and TLR6 C > T rs5743810 polymorphisms with protection against death (OR: 0.17, 95% IC: 0.04–0.79, p = 0.008; OR: 0.48, 95% IC: 0.24–0.94, p = 0.031, respectively). Our results show that SNPs in TLRs genes may be involved in the pathogenesis of ALL and may influence clinical prognosis; however, further studies are necessary to elucidate the role of TLR1, TLR4, TLR5, TLR6, TLR9 and CD14 polymorphisms in this disease.

Genetic Polymorphism in Toll-Like Receptor 3 and Interferon Regulatory Factor 3 in Hepatitis C Virus-Infected Patients: Correlation with Liver Cirrhosis.

Host genetic factors could play a primary role in determining the risk for cirrhosis development in chronic hepatitis C virus (HCV)-infected patients. We designed this work to study the effect of single-nucleotide polymorphism (SNP) in Toll-like receptor 3 (TLR3) and interferon regulatory factor (IRF) on the risk of HCV-related cirrhosis. This study enrolled 139 Egyptian HCV-infected patients. They were divided into patients with cirrhotic (56) and noncirrhotic (83) liver. Genotyping of rs3775291 F459F (+1234C/T) and rs3775290 L412F (+1377C/T) in TLR3 and IRF3 rs2304204 (-925A/G) was performed by restriction fragment length polymorphism-polymerase chain reaction. Although there is no significant difference in genotype and allele distribution of +1377C/T of TLR3 gene between cirrhotic and noncirrhotic subjects, CC (odds ratio [OR] = 1.572, 95% confidence interval [CI]: 0.781-3.164); TT (OR = 1.463, 95% CI: 0.351-6.104) genotypes might be considered as risk factors for liver cirrhosis. On the contrary, the analysis revealed that only one genotype (CC) and one allele (C) were detected in +1234C/T SNP, with the total disappearance of CT/TT genotypes and T allele in all subjects. On the contrary, lower frequency has been found for the AG genotype of the IRF3 (-925A/G) gene in cirrhotic patients compared with noncirrhotic ones, indicating that AG is a protective genotype (OR = 0.509, 95% CI: 0.256-1.012). Our data stressed the association of AG genotype SNP in IRF3 (-925A/G) in protection against the worth outcome of HCV infection.

Single Nucleotide Polymorphisms of Toll-like Receptor 4 in Hepatocellular Carcinoma-A Single-Center Study.

Hepatocellular carcinoma (HCC) is the most common primary liver tumor leading to significant morbidity and mortality; its exact genetic background is largely unrecognized. Toll-like receptor-4 (TLR4) reacts with lipopolysaccharides, molecules found in the outer membrane of Gram-negative bacteria. In damaged liver, TLR4 expression is upregulated, leading to hepatic inflammation and injury. We tried to investigate the role of the two most common single-nucleotide polymorphisms (SNPs) of TLR4 in HCC-genesis. Aged > 18 years old, cirrhotic patients were included in this study. Exclusion criteria were non-HCC tumors and HIV co-infection. TLR4 SNPs association with HCC occurrence was the primary endpoint, and associations with all-cause and liver-related mortality, as well as time durations between diagnosis of cirrhosis and HCC development or death and diagnosis of HCC and death were secondary endpoints. A total of 52 out of 260 included patients had or developed HCC. TLR4 SNPs showed no correlation with primary or secondary endpoints, except for the shorter duration between HCC development and death in patients with TLR4 mutations. Overall, TLR4 SNPs showed no correlation with carcinogenesis or deaths in patients with liver cirrhosis; patients with TLR4 SNPs that developed HCC had lower survival rates, a finding that should be further evaluated.

Toll-like receptor-1, -2, and -6 genotypes in relation to salivary human beta-defensin-1, -2, -3 and human neutrophilic peptide-1.

To examine whether functional gene polymorphisms of toll-like receptor (TLR)1, TLR2, and TLR6 are related to the salivary concentrations of human beta-defensins (hBDs)-1, -2, -3, and human neutrophilic peptide (HNP)-1. Polymorphisms of TLR1 (rs5743618), TLR2 (rs5743708), and TLR6 (rs5743810) were genotyped by PCR-based pyrosequencing from the salivary samples of 230 adults. Salivary hBD-1, -2, -3, and HNP-1 concentrations were measured using enzyme-linked immunosorbent assay. General and periodontal health examinations, including panoramic radiography, were available for all participants. The genotype frequencies for wild types and variant types were as follows: 66.5% and 33.5% for TLR1, 95.5% and 4.5% for TLR2, and 25.1% and 74.9% for TLR6, respectively. The TLR2 heterozygote variant group exhibited higher salivary hBD-2 concentrations than the TLR2 wild-type group (p= .038). On the contrary, elevated hBD-2 concentrations were detected in the TLR6 wild-type group compared with the TLR6 heterozygote and homozygote variant group (p= .028). The associations between TLR6 genotypes and salivary hBD-2 concentrations remained significant after adjusting them for periodontal status, age, and smoking. hBD-2 concentrations in saliva are related to TLR2 and TLR6 polymorphisms, but only the TLR6 genotype seems to exhibit an independent association with the salivary hBD-2 concentrations.

Association of Lactoferrin and Toll-like Receptor 2 Genotypes with Mastitis and Milk Components in Vietnamese Holstein Cattle.

Simply SummaryMastitis disease causes huge losses for the dairy industry worldwide. The molecular markers have been shown to be a promising tool for the diagnosis of mastitis infections and the selection of animals with better mastitis resistance. In this study, we surveyed the mastitis incidence in Vietnamese Holstein cows. We also examined the association of polymorphisms in Lactoferrin (LTF) and Toll-like receptor 2 (TLR2) genes with mastitis score and milk component traits. Our results indicated that the interaction between TLR2 genotypes and diseases has a significant impact on the fat and protein percentage of mink. Therefore, TLR2 polymorphism could be used for the selection of cows with better milk compositions.Mastitis is one of the most widespread diseases in dairy cows and causes huge losses for the dairy industry. Molecular markers can be used for the quick diagnosis of mastitis infection, consequently reducing the loss caused by this disease. Lactoferrin (LTF) and Toll-like receptor 2 (TLR2) have been suggested as candidate genes for mastitis; however, their associations with the mastitis incidence and milk components have not been reported in Vietnamese Holstein cows. This study examined the association of TLR2 and LTF polymorphisms with subclinical mastitis and milk components in the Holstein breed raised in Vietnam. Among 192 samples, we identified 44 mastitis-positive samples (22.92%). The mastitis significantly reduced the fat and lactose components in milk (p < 0.001) but increased the protein concentration in milk. A total of 94 (49%) and 98 (51%) cows had AA and AB genotypes for the LTF gene, respectively. No significant association was found between the LTF genotypes and the milk component traits or mastitis incidence (p > 0.05). The interaction between LTF and mastitis incidence was significantly associated with the protein percentage (p = 0.01). A total of 78, 76, and 38 cows had genotypes GG, GT, and TT for the TLR2 gene, respectively. TLR2 genotypes were not significantly associated with mastitis incidence (p > 0.05) but were significantly associated with pH value (p = 0.03). The interaction between TLR2 and mastitis incidence was significantly associated with the fat (p = 0.02) and protein percentage (p = 0.04). Further studies are required to confirm the roles of LTF and TFL2 in mastitis in the Holstein breed in Vietnam.

Polymorphisms in toll-like receptor 3 and 4 genes as prognostic and outcome biomarkers in melanoma patients.

Melanoma is one of the most aggressive tumors, and in the setting of rising incidence and mortality, there is an urgent need to identify new prognostic markers. Toll-like receptors (TLRs), are aberrantly expressed in numerous cancers, including melanoma. TLR signaling provides a microenvironment that is involved in antitumor immune response, chronic inflammation, cancer cell proliferation and evasion of immune destruction. In the present study, we investigated whether single nucleotide polymorphisms (SNPs) in TLR3 and TLR4 genes are associated with clinicopathologic features, progression and survival of melanoma patients. The study was conducted on 120 melanoma patients. DNA extracted from peripheral blood was genotyped for TLR3 polymorphisms rs5743312 and rs3775291 (L412F) and TLR4 polymorphisms rs4986790 (D299G) and rs4986791 (T399I), by TaqMan Real-Time PCR Assays. Kaplan-Meier survival curves were compared by the log-rank test. TLR3 polymorphism L412F was associated with a higher mitotic index ( P = 0.035). TLR4 D299G and T399I polymorphisms were associated with indicators of melanoma severity, nodal metastases ( P = 0.005 and P = 0.007, respectively) and advanced stage III ( P = 0.005 and P = 0.004, respectively). Cox regression analysis showed that the presence of tumor-infiltrating lymphocytes (TILs) predicted better overall survival (HR = 0.318; P = 0.004). TLR4 T399I polymorphism was significantly associated with worse survival, P = 0.025. The overall survival rates were significantly lower for patients carrying variant allele T of TLR4 T399I SNP (TC and TT genotypes combined) ( P = 0.008, log-rank test), compared to wild-type genotype CC. Our findings indicate that TLR4 polymorphisms T399I (rs4986791) and D299G (rs4986790) could be potential prognostic and survival markers for melanoma patients.

Association of toll-like receptors single nucleotide polymorphisms with HBV and HCV infection: research status.

BackgroundHepatitis B virus (HBV) and hepatitis C virus (HCV) infections have become increasingly severe worldwide and are a threat to public health. There have been a number of studies conducted recently on the relationship of single nucleotide polymorphisms (SNPs) to innate immune receptor genes such as toll-like receptors (TLRs). Some literature suggests that SNPs of TLRs are associated with HBV and HCV infection. We summarized the role of TLRs gene polymorphisms associated with HBV and HCV infections and explored their possible mechanisms of action.MethodologyPubMed and Web of Science were used to perform the literature review. Related articles and references were identified and used to analyze the role of TLRs gene polymorphism in HBV and HCV infection.ResultsTLRs gene polymorphisms may have beneficial or detrimental effects in HBV and HCV infection, and some SNPs can affect disease progression or prognosis. They affect the disease state by altering gene expression or protein synthesis; however, the mechanism of action is not clearly understood.ConclusionsSingle nucleotide polymorphisms of TLRs play a role in HBV and HCV infection, but the mechanism of action still needs to be explored in future studies.

Toll-Like Receptor Signalling Pathways and the Pathogenesis of Retinal Diseases.

There is growing evidence that the pathogenesis of retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD) have a significant chronic inflammatory component. A vital part of the inflammatory cascade is through the activation of pattern recognition receptors (PRR) such as toll-like receptors (TLR). Here, we reviewed the past and current literature to ascertain the cumulative knowledge regarding the effect of TLRs on the development and progression of retinal diseases. There is burgeoning research demonstrating the relationship between TLRs and risk of developing retinal diseases, utilising a range of relevant disease models and a few large clinical investigations. The literature confirms that TLRs are involved in the development and progression of retinal diseases such as DR, AMD, and ischaemic retinopathy. Genetic polymorphisms in TLRs appear to contribute to the risk of developing AMD and DR. However, there are some inconsistencies in the published reports which require further elucidation. The evidence regarding TLR associations in retinal dystrophies including retinitis pigmentosa is limited. Based on the current evidence relating to the role of TLRs, combining anti-VEGF therapies with TLR inhibition may provide a longer-lasting treatment in some retinal vascular diseases.

Evolution of toll-like receptor gene family in amphibians

The evolutionary position and lifestyle of amphibians highlights the important roles of the immune system in adaptive radiation and their adaptation to a complex pathogenic environment. Toll-like receptors (TLRs) are membrane-like sensors that recognize and bind conserved molecular motifs in pathogens to initiate downstream immune responses. To understand the evolutionary patterns of TLRs in amphibians, we analyzed TLR genes from the genomes and transcriptomes of 102 amphibian species. Phylogenetic results showed that 578 intact amphibian TLR sequences belonged to 16 TLR genes and were divided into seven subfamilies. The TLR4 subfamily was only identified in the Anura. Purification selection plays a leading role in amphibian TLR evolution and mean ω (dN/dS) values ranged from 0.252 for TLR7 to 0.381 for TLR19. Furthermore, the ω values of different domains were significantly different. We found positive selection patterns for 141 of 12,690 codons (1.1%) in all amphibian TLRs, most of which were located in leucine-rich repeats (LRRs). We also observed low to moderate levels of single-nucleotide polymorphisms (SNPs) in Pelophylax nigromaculatus and Bombina orientalis. This study provided critical primers, meaningful information regarding TLR gene family evolution in amphibians, and insights into the complex evolutionary patterns and implications of TLR polymorphisms.

Clinical Implication of Toll-Like Receptors (TLR2 and TLR4) Polymorphisms in Adult Patients with Acute B-cell Lymphoblastic Leukemia.

Backgrounds:Neutropenia after intensive chemotherapy of acute lymphoblastic leukemia (ALL) could lead to infectious complications that affect outcome of acute leukemia patients. Many single-nucleotide polymorphisms (SNPs) of Toll-like receptors (TLRs) can affect the genetic susceptibility to infections. We investigated the impact of different SNPs on the incidence of developing sepsis and pneumonia in patients with newly diagnosed B-ALL following induction chemotherapy. Subjects and methods:We analyzed three SNPs in the TLR2 (Arg753Gln) and TLR4 (Asp299Gly& Thr399Ile) genes using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) in a case control study of 40 precursor B-ALL patients and 50 control subjects. The risk of developing sepsis and pneumonia were assessed by multiple logistic regression analyses. Results:The presence of the TLR-2 AG polymorphism was significantly associated with pneumonia in B-ALL patients. Furthermore, TLR4 Thr399Ile AG was a risk factor for sepsis in B-ALL patients. Moreover; Significant association between TLR-2 AA, TLR-4 CC and TL-4 AA genotypes and longer OS were detected in studied B-ALL patients. Conclusion:We concluded that TLR-4 (AG and CT) genotypes are associated with high susceptibility to sepsis and pneumonia respectively; while, TLR-2, TLR-4 AA and TLR-4 CC genotypes could predict good B-ALL patients outcome.

Evaluation of Polymorphisms in Toll-Like Receptor Genes as Biomarkers of the Response to Treatment of Erythema Nodosum Leprosum.

Erythema nodosum leprosum (ENL) is an inflammatory complication caused by a dysregulated immune response to Mycobacterium leprae. Some Toll-like receptors (TLRs) have been identified as capable of recognizing antigens from M. leprae, triggering a wide antimicrobial and inflammatory response. Genetic polymorphisms in these receptors could influence in the appearance of ENL as well as in its treatment. Thus, the objective of this work was to evaluate the association of genetic variants of TLRs genes with the response to treatment of ENL with thalidomide and prednisone. A total of 162 ENL patients were recruited from different regions of Brazil and clinical information was collected from their medical records. Genomic DNA was isolated from blood and saliva samples and genetic variants in TLR1 (rs4833095), TLR2 (rs3804099), TLR4 (rs1927914), and TLR6 (rs5743810) genes were genotyped by TaqMan real-time PCR system. In order to evaluate the variants' association with the dose of the medications used during the treatment, we applied the Generalized Estimating Equations (GEE) analysis. In the present sample, 123 (75.9%) patients were men and 86 (53.1%) were in treatment for leprosy during the ENL episode. We found an association between polymorphisms in TLR1/rs4833095, TLR2/rs3804099, TLR4/rs1927914, and TLR6/rs5783810 with the dose variation of thalidomide in a time-dependent manner, i.e., the association with the genetic variant and the dose of the drug was different depending on the moment of the treatment evaluated. In addition, we identified that the association of polymorphisms in TLR1/rs4833095, TLR2/rs3804099, and TLR6/rs5783810 with the dose variation of prednisone also were time-dependent. Despite these associations, in all the interactions found, the influence of genetic variants on dose variation was not clinically relevant for therapeutic changes. The results obtained in this study show that TLRs polymorphism might play a role in the response to ENL treatment, however, in this context, they could not be considered as useful biomarkers in the clinical setting due small differences in medication doses. A larger sample size with patients with a more genetic profile is fundamental in order to estimate the association of genetic variants with the treatment of ENL and their clinical significance.

Prognostic impact of toll-like receptors gene polymorphism on outcome of COVID-19 pneumonia: A case-control study

Toll-like receptor 3 (TLR3) and TLR7 genes are involved in the host immune response against viral infections including SARS-COV-2. This study aimed to investigate the association between the TLR3(rs3775290) and TLR7(rs179008) polymorphisms with the prognosis and susceptibility to COVID-19 pneumonia accompanying SARS-COV-2 infection. This case-control study included 236 individuals: 136 COVID-19 pneumonia patients and 100 age and sex-matched controls. Two polymorphisms (TLR3 rs3775290 and TLR7 rs179008) were genotyped by allelic discrimination through TaqMan real-time PCR. This study also investigated predictors of mortality in COVID-19 pneumonia through logistic regression. The mutant ‘T/T' genotypes and the ‘T' alleles of TLR3(rs3775290) and TLR7(rs179008) polymorphisms were significantly associated with increased risk of COVID-19 pneumonia. This study did not report association between the mutant ‘T/T' genotypes of TLR3(rs3775290) and TLR7(rs179008) and the disease outcome. In multivariate analysis, the independent predictors of mortality in COVID-19 pneumonia were male sex, SPO2 ≤ 82%, INR > 1, LDH ≥ 1000 U/l, and lymphocyte count<900/mm3 (P < 0.05).

Cell-Specific Expression Pattern of Toll-Like Receptors and Their Roles in Animal Reproduction.

Toll-like receptors (TLRs), a part of the innate immune system, have critical roles in protection against infections and involve in basic pathology and physiology. Secreted molecules from the body or pathogens could be a ligand for induction of the TLR system. There are many immune and non-immune types of cells that express at a least single TLR on their surface or cytoplasm. Those cells may be a player in a defense system or in the physiological regulation mechanisms. Reproductive tract and organs contain different types of cells that have essential functions such as hormone production, providing an environment for embryo/fetus, germ cell production, etc. Although lower parts of reproductive organs are in a relationship with outsider contaminants (bacteria, viruses, etc.), upper parts should be sterile to provide a healthy pregnancy and germ cell production. In those areas, TLRs bear controller or regulator roles. In this chapter, we will provide current information about physiological functions of TLR in the cells of the reproductive organs and tract, and especially about their roles in follicle selection, maturation, follicular atresia, ovulation, corpus luteum (CL) formation and regression, establishment and maintenance of pregnancy, sperm production, maturation, capacitation as well as the relationship between TLR polymorphism and reproduction in domestic animals. We will also discuss pathogen-associated molecular patterns (PAMPs)-induced TLRs that involve in reproductive inflammation/pathology.

Toll-like receptor (TLR2, TLR4) polymorphisms and their influence on the incidence of urinary tract infections in children with and without urinary tract malformation

Toll-like receptors (TLRs) contribute to the innate immune system. They are an element of non-specific immunity, which enables organisms to react quickly to foreign antigens, without being previously exposed to them. TLRs are pattern recognition receptors. TLR gene polymorphisms are widely investigated in connection with various infections. The aims of the study were: to investigate the role of TLR2 and TLR4 polymorphisms in the course of urinary tract infections (UTIs); to test for differences in distribution of these polymorphisms between children with urinary tract malformations suffering from recurrent UTI (rUTI), children with malformations but without rUTI and healthy controls; to determine whether these polymorphisms predispose to rUTI; and to analyse how polymorphisms and urine neutrophil gelatinase-associated lipocalin (NGAL) and interleukin 8 (IL-8) concentrations affect one another. The group consisted of 133 children (1-18 years old), 68 female and 65 male. The group was divided into 4 subgroups: A (rUTI with urinary tract malformations), B (urinary tract malformations without rUTI), C (rUTI) and D (healthy controls). Polymorphisms were analysed using PCR-RFLP. IL-8 and NGAL urine concentrations were established using immunoenzymatic methods. TLR2 Arg753Gln and TLR4 Arg299Gly appeared significantly more often among children with rUTI. No correlation between urine IL-8 and urine NGAL and polymorphisms was found. Urine NGAL concentration was significantly higher among children with urinary tract malformations. TLR2 Arg753Gln and TLR4 Asp299Gly may predispose to rUTI. Urine NGAL concentration suggests the presence of kidney tissue injury, of varying degrees, among children with urinary tract malformations.

Associations Among Disseminated Intravascular Coagulation, Thrombocytopenia Cytokines/Chemokines and Genetic Polymorphisms of Toll-Like Receptor 2/4 in Chinese Patients with Sepsis.

Objectives(s)Toll-like receptors (TLRs) on platelets have been extensively studied. Both TLR2 and TLR4 have been shown to augment platelet activation and alter its function from a hemostatic regulator to an immune sentinel. However, few studies have investigated the relationship between genetic polymorphisms in TLR2, TLR4 and platelets. We investigated whether genetic polymorphisms of TLR2 and TLR4 were related to thrombocytopenia and coagulation failure in Chinese patients with sepsis.Basic MethodsAdult Chinese patients with sepsis in the intensive care unit of a university medical center were monitored for up to 28 days. Thrombocytopenia and disseminated intravascular coagulation (DIC), diagnosed using Japanese Association for Acute Medicine (JAAM) criteria, were observed as the primary outcomes. Single-nucleotide polymorphisms (SNPs) in TLR2 (rs111200466, rs5743708) and TLR4 (rs11536889, rs145801336, rs11536896, rs7869402) in patients with sepsis were detected by polymerase chain reaction. The data were analyzed using chi-square and rank sum tests.ResultsThe genotype of TLR2 (rs111200466) (Del/Del) was associated with the initial DIC. The genotype of TLR4 (rs11536889) (C/C&C/G) was associated with initial DIC, DIC onset during hospitalization and platelet counts. Furthermore, both DIC and platelet counts were associated with cytokines and chemokines, especially the IL10.ConclusionOur results demonstrate that in Chinese sepsis patients, the rs111200466 SNP in TLR2 and rs11536889 SNP in TLR4 are associated with thrombocytopenia and DIC, with potential effects on the TLR4 pathways of platelets.