Earthworms are affected by physical stress, like injury, and by exposure to xenobiotics, such as the toxic metal cadmium (Cd), which enters the environment mainly through industry and agriculture. The stress response to the single and the combination of both stressors was examined in regenerative and unharmed tissue of Lumbricus terrestris to reveal if the stress response to a natural insult like injury (amputation) interferes with Cd detoxification mechanisms. We characterized the roles of metallothionein 1 (MT1) and MT2 isoforms, heat shock protein 70 as well as immune biomarkers such as the toll-like receptors (TLR) single cysteine cluster TLR and multiple cysteine cluster TLR. The role of the activated transcription factors (ATFs) ATF2, ATF7, and the cAMP responsive element binding protein as putative regulatory intersection as well as a stress-dependent change of the essential trace elements zinc and calcium was analyzed. Phosphorylated AMP activated protein kinase, the cellular energy sensor, was measured to explore the energy demand, while the energy status was determined by detecting carbohydrate and protein levels. Taken together, we were able to show that injury rather than Cd is the driving force that separates the four treatment groups - Control, Cd exposure, Injury, Cd exposure and injury. Interestingly, we found that gene expression differed regarding the tissue section that was analyzed and we hypothesize that this is due to the migration of coelomocytes, earthworm immune cells, that take over a key role in protecting the organism from a variety of environmental challenges. Surprisingly, we discovered a role for MT1 in the response to multiple stressors and an isoform-specific function for the two newly characterized TLRs. In conclusion, we gathered novel information on the relation of innate immunity, wound healing, and Cd detoxification mechanisms in earthworms.

Chronic lymphocytic thyroiditis, commonly known as HD, is one of the most common thyroid disorders. Due to the diverse factors affecting the etiopathogenesis of this disease (hormonal disorders and genetic and environmental factors), as well as the direct involvement of the immune system, scientists are increasingly willing to undertake research aimed at explaining the impact of the loss of immune tolerance and reactivity of autoantigens on the development of the disease. One of the directions of research in recent years is the role of the innate immune response, particularly Toll-like receptors (TLRs), in the pathogenesis of HD. The purpose of this study was to determine the importance of Toll-like receptor 2 (TLR2) expression on selected populations of immune cells, namely, monocytes (MONs) and dendritic cells (DCs), in the course of HD. Particular attention was paid to the analysis of TLR2\'s correlation with clinical parameters and the possibility its use as a potential biomarker molecule in the diagnostic process. Based on the obtained results, we found a statistically significant increase in the percentage of all analyzed populations of immune cells, i.e., mDC BDCA-1+CD19-, pDC BDCA-1+CD123, classical MONs CD14+CD16-, and non-classical MONs CD14+CD16+ showing on their surface TLR2 expression in patients diagnosed with HD compared to the healthy volunteers. Moreover, in the study group, we noted a more than 6-fold increase in the concentration of the soluble form of TLR2 in plasma compared to healthy patients. In addition, the correlation analysis showed significant positive correlations between the level of TLR2 expression on selected subpopulations of immune cells and biochemical indicators of thyroid function. Based on the obtained results, we can assume that TLR2 may be involved in the immunopathogenesis of HD.

Schizophrenia is a common psychiatric disorder that exhibits a variety of symptoms. The exact etiology and pathogenesis are still doubtful. However, genetic and environmental factors seem to have a role. Years ago, the role of the immune system was focused on auto-antibodies, cytokines, different types of immune cells and immune genes. The Toll-like receptors (TLR) are a cornerstone of the innate immune system, particularly TLR4. TLR4 primarily recognises gram-negative lipopolysaccharides bacteria. This case-control study, for the first time to our knowledge, examined the role of TLR4 gene polymorphisms in 142 Egyptian schizophrenic patients and 175 healthy controls. Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), four single nucleotide polymorphisms (SNPs) were investigated in the TLR4 gene rs11536889, rs10759931, rs1927911, and rs1927914. The Positive and Negative Syndrome Scale (PANSS) was used in diagnosis and assessment. A statistically significant association was observed between rs11536889, rs1927911 and rs1927914, but no association was found between rs10759931. There was no association between the different SNP genotypes and PANSS, except between rs1927914 and general psychopathologic symptoms. This study shows a strong association between TLR4 rs11356889 and rs1927911 minor alleles and schizophrenia. These findings could be additional evidence for the immune system\'s role in schizophrenia development. However, more studies with a more significant sample number, TLR4 protein assessment, and a larger number of SNPs are recommended.

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).

Introduction The endosomal toll-like receptors (TLR) TLR3, TLR7, and TLR9 are localized in immune cells, recognize the viral pattern associated molecular pattern (PAMPs), and start signaling cascades for immune defense response and genetic factor is known to affect the dengue virus infection therefore in our study we study the association of endosomal Toll-like receptors 3 polymorphism rs3775291, rs3775290, and rs3775296 with rs179008 A/T and rs179009C/T polymorphisms of TLR7 and rs187084 (C/T), rs5743836 (C/T) of TLR9 gene with dengue and controls. Materials and methods Ninety-eight cases of dengue virus (DV) infection and 98 healthy controls were enrolled. Clinical details were recorded and cases were classified as severe or non-severe dengue, based on WHO 2009 classification. Genotypes were determined by Sanger sequencing using the genetic analyzer. Results An increased risk of DV infection was observed in cases as compared to controls, with TLR 3 rs3775291 CT genotype (OR = 4.34, P-value: 0.031, CI = 1.14-16.5), Likewise in TLR7 rs179008 AT (OR = 2.12, P-value: 0.034, CI = 1.06-4.26) and rs179009 CT (OR = 2.04, P-value: 0.040, CI = 1.03-4.05) same as in TLR9 rs187084 CT (OR = 1.97, P-value: 0.046, CI = 1.013-3.84) and rs5743836 (OR = 2.38, P-value: 0.009, CI = 1.24-5.57). In the above polymorphisms, mutant allele was observed in a significantly higher number in cases. The values are: for TLR3 rs3775291 T allele (OR 2.167, CI = 1.3-3.61, P-value: 0.003). TLR7 rs179008 T allele (OR 1.90, P-value: 0.021, CI = 1.07-3.35) and in TLR9 rs187084 (OR 1.91, P-value: 0.014, CI = 1.137-3.24) rs5743836 (OR 2.29, P-value: 0.0018, CI = 1.36-3.87). No significant association was observed in the genotypic frequency of severe versus non-severe dengue. Conclusion TLR3, 7, and 9 gene polymorphism might confer host genetic susceptibility to dengue in the North Indian population.

During in vitro fertilisation (IVF), pharmacological activation of the murine X chromosome-encoded receptor proteins Toll-like receptor (TLR) 7 and TLR8 reportedly results in male-biased litters by selectively disrupting the motility of X-bearing sperm cells. Thus-in the context of agonist treatment during IVF-these receptors act as \'suicidal\' segregation distorters that impair their own transmission to the next generation. Such behaviour would, from an evolutionary perspective, be strongly selected against if present during natural fertilisation. Consequently, TLR7/8 biology in vivo must differ significantly from this in vitro situation to allow these genes to persist in the genome. Here, we use our current understanding of male germ cell biology and TLR function as a starting point to explore the mechanistic and evolutionary aspects of this apparent paradox.

BACKGROUND: Cavernous angiomas (CAs) are vascular malformations that may result in stroke.
METHODS: Herein, we evaluate a CA patient with chronic migraine who experienced 2 documented symptomatic hemorrhages after receiving respective high doses of botulinum toxin (Btx).
CONCLUSIONS: Recently, bacterial lipopolysaccharide has been reported to contribute to CA development through Toll-like receptor signaling, causing hemorrhagic angiogenic proliferation. Lipopolysaccharide and Btx share a common intracellular signaling pathway driving CA development and hemorrhage. Significance of these observations is demonstrated by previous works on plasma molecules showing prognostic associations with symptomatic hemorrhages in human CA, related to the same canonical pathways. Authors suggest careful tracking of the association of Btx and hemorrhage in CA patients.

Recently, the roles of toll-like receptor (TLR) polymorphisms in inflammatory bowel disease (IBD) were intensively explored, with conflicting results. Therefore, we performed this study to better assess the relationship between TLR polymorphisms and the risk of IBD. Eligible studies were searched in PubMed, Medline, Embase, and Web of Science. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate associations between TLR polymorphisms and IBD. Significant associations with the risk of IBD were detected for the TLR1 rs5743611, TLR4 rs4986790, TLR4 rs4986791, and TLR6 rs5743810 polymorphisms in overall analyses. Further subgroup analyses according to ethnicity of participants revealed that the TLR1 rs5743611, TLR4 rs4986790, TLR4 rs4986791, TLR6 rs5743810, and TLR9 rs352140 polymorphisms were significantly associated with the risk of IBD in Caucasians. Moreover, the TLR4 rs4986790 polymorphism was significantly correlated with the risk of IBD in West Asians, while the TLR9 rs352140 polymorphism was significantly associated with the risk of IBD in Africans. When we stratified available data according to type of disease, we found similar positive results for TLR1 rs5743611, TLR4 rs4986790, TLR4 rs4986791, and TLR6 rs5743810 polymorphisms. Our findings indicate that TLR1 rs5743611, TLR4 rs4986790, TLR4 rs4986791, TLR6 rs5743810, and TLR9 rs352140 polymorphisms may serve as genetic biomarkers of IBD in certain ethnicities. However, further well-designed studies are still warranted to confirm our findings.

BACKGROUND: Toll-like receptor (TLR) single nucleotide polymorphisms (SNPs) have been associated with regulation of TLR expression and development of active tuberculosis (TB). The objectives of this study were to determine whether TLR8 and TLR9 SNPs were associated with the development of latent TB infection (LTBI) and the subsequent pulmonary TB (PTB) in a Chinese Han population.
METHODS: Two independent samples were enrolled. The first sample contained 584 TB cases and 608 controls; the second sample included 204 healthy controls, 201 LTBI subjects and 209 bacteria-confirmed active PTB patients. Three SNPs (rs3764880, rs187084 and rs5743836) were genotyped. The associations between the SNPs and risk of LTBI or PTB were investigated using unconditional logistic regression analysis.
RESULTS: The A-allele of TLR8 rs3764880 SNP was protective against the development of TB in males (A vs G, OR = 0.58, 95%CI = 0.37-0.91). The AA genotype of rs3764880 SNP was found to increase the risk of PTB among females with an OR of 4.81 (1.11-20.85). The G allele of TLR9 SNP rs187084 was found to increase the risk of PTB (G vs A, P = 0.01, OR = 1.48, 95% CI = 1.10-2.00), the significance was also observed under dominant genetic models. The GA-genotype of TLR9 rs187084 SNP was found to increase the risk of PTB with an OR of 1.68 (1.07-2.65), but was found to decrease the risk of MTB infection with an OR = 0.64 (0.41-0.98). TLR9_rs5743836 SNP was excluded from the data analyses, because the minimum allele frequency was< 1%.
CONCLUSIONS: Our findings in two independent samples indicated that SNPs in TLR8 and TLR9 were associated with the development of TB, and highlight that SNPs may have different effects on disease pathogenesis and progression.

Genetic studies are continuing to generate volumes and variety of data that can be used to examine the genetic effects. Often the effect of a genetic variant varies by nongenetic measures, what is traditionally defined as gene-environment interaction (G×E). If the G×E term is neglected, estimates of the main effects can be substantially biased. We derive a general and convenient approximation to the magnitude of bias in the estimates due to omitting the G×E term. We show that the approximation is reasonably accurate in finite samples. We then apply the approximation in a study of Alzheimer\'s disease.