Systematic review and meta-analysis of human Toll-like receptors genetic polymorphisms for susceptibility to tuberculosis infection

Varshney, Deepika; Singh, Sanjiv; Sinha, Ekata; Mohanty, Keshar Kunja; Kumar, Santosh; Barik, Sushanta Kumar; Patil, Shripad A.; Katara, Pradhumn

doi:10.1016/j.cyto.2021.155791

Cited by 18 publications

(20 citation statements)

References 48 publications

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“…Interestingly, the CT genotype of rs352139 has been recently shown to be associated with an increased risk of Epstein-Barr virus-related infectious mononucleosis, which points to a role in the susceptibility to herpesviruses different from CMV (41). Further studies on tuberculosis (42,43) and malaria (44) have reached comparable conclusions.…”

Section: Discussionmentioning

confidence: 75%

Influence of single-nucleotide polymorphisms in TLR3 (rs3775291) and TLR9 (rs352139) on the risk of CMV infection in kidney transplant recipients

et al. 2022

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Risk stratification for cytomegalovirus (CMV) infection after kidney transplantation (KT) remains to be determined. Since endosomal toll-like receptors (TLRs) are involved in viral sensing, we investigated the impact of common single-nucleotide polymorphisms (SNPs) located within TLR3 and TLR9 genes on the occurrence of overall and high-level (≥1,000 IU/ml) CMV infection in a cohort of 197 KT recipients. Homozygous carriers of the minor allele of TLR3 (rs3775291) had higher infection-free survival compared with reference allele carriers (60.0% for TT versus 42.3% for CC/CT genotypes; P-value = 0.050). Decreased infection-free survival was observed with the minor allele of TLR9 (rs352139) (38.2% for TC/CC versus 59.3% for TT genotypes; P-value = 0.004). After multivariable adjustment, the recessive protective effect of the TLR3 (rs3775291) TT genotype was confirmed (adjusted hazard ratio [aHR]: 0.327; 95% CI: 0.167–0.642; P-value = 0.001), as was the dominant risk-conferring effect of TLR9 (rs352139) TC/CC genotypes (aHR: 1.865; 95% CI: 1.170–2.972; P-value = 0.009). Carriers of the TLR9 (rs352139) TC/CC genotypes showed lower CMV-specific interferon-γ-producing CD4+ T-cell counts measured by intracellular cytokine staining compared with the TT genotype (median of 0.2 versus 0.7 cells/μl; P-value = 0.003). In conclusion, TLR3/TLR9 genotyping may inform CMV infection risk after KT.

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Section: Discussionmentioning

confidence: 75%

Influence of single-nucleotide polymorphisms in TLR3 (rs3775291) and TLR9 (rs352139) on the risk of CMV infection in kidney transplant recipients

et al. 2022

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“…TLR2 and its co-receptors TLR1, TLR6 and RP105 promote cellular activation upon Mtb encounter as characterized in in vitro systems [25,26,29,[51][52][53][54]. In humans, TLR2, TLR1, and TLR6 gene polymorphisms resulting in confirmed or predicted impairment of receptor expression or function have been associated with susceptibility but also protection from TB disease [13][14][15][16][17], suggesting that TLR requirements in human TB disease are complex. Similarly, translation of TLR2 contributions to Mtb control and tissue pathology in vivo, using Tlr2deficient (C57BL/6) mice, has returned varying results [23].…”

Section: Discussionmentioning

confidence: 99%

“…Whether differential expression of CXCL5 and other CXCR2 ligands as well as CXCR2 by neutrophils [57] (as defined by the microbiota or other factors) underpins differences in lung pathology of WT and Tlr2 À/À mice the in the study by Gopalakrishnan et al [24] (neutrophil-associated destructive pathology in Tlr2 À/À ) as compared to our experiments (no difference in cell necrosis and neutrophil recruitment, e.g., Figure 1) will require formal investigation. Better understanding of the nature and extent of Mtb and microbiome requirements for TLR-contributions might be required for the interpretation of associations, or lack thereof, between TLR polymorphisms and TB susceptibility in different human cohorts [14][15][16].…”

Section: Discussionmentioning

confidence: 99%

“…This family of pattern recognition receptors has been studied extensively for their roles in the host response to Mtb infection. Of the 10 human TLRs, genetic variants in several TLR-encoding genes have been associated with TB susceptibility [13][14][15][16][17]. This may reflect diversity among mycobacteria-derived TLR agonists such as lipoproteins, lipoglycans (TLR2/1) [18][19][20], proteins (TLR4) [21] and DNA (TLR9) [22].…”

Section: Introductionmentioning

confidence: 99%

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Distinct contributions of the innate immune receptors TLR2 and RP105 to formation and architecture of structured lung granulomas in mice infected with Mycobacterium tuberculosis

et al. 2022

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Granulomas are key histopathological features of Mycobacterium tuberculosis (Mtb) infection, with complex roles in pathogen control and dissemination. Thus, understanding drivers and regulators of granuloma formation is important for improving tuberculosis diagnosis, treatment, and prevention. Yet, molecular mechanisms underpinning granuloma formation and dynamics remain poorly understood. Here we used low‐dose Mtb infection of C57BL/6 mice, which elicits structured lung granulomas composed of central macrophage clusters encased by a lymphocyte mantle, alongside the disorganized lymphocyte and macrophage clusters commonly observed in Mtb‐infected mice. Using gene‐deficient mice, we observed that Toll‐like receptor (TLR) 2 and the TLR‐related Radioprotective 105 kDa protein (RP105) contributed to the extent and spatial positioning of pathology in infected lung tissues, consistent with functional cooperation between TLR2 and RP105 in the innate immune recognition of Mtb. In mice infected with the highly virulent Mtb clinical isolate HN878, TLR2, but not RP105, positively regulated the extent of central macrophage regions within structured granulomas. Moreover, RP105, but not TLR2, promoted the formation of structured lung granulomas, suggesting that the functions of RP105 as an innate immune sensor for Mtb reach beyond its roles as TLR2 co‐receptor. TLR2 and RP105 contributions to lung pathology are governed by Mtb biology, as neither receptor affected the frequency or architecture of structured granulomas in mice infected with the reference strain Mtb H37Rv. Thus, by revealing distinctive as well as cooperative functions of TLR2 and RP105 in lung pathology, our data identify TLRs as molecular determinants of TB granuloma formation and architecture, and expand understanding of how interactions between innate immune receptors and Mtb shape TB disease manifestation.

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“…An increased prevalence of the A allele was also seen in ART-naive HIV+ patients who developed active TB, according to Kaushik et al [ 59 ]. Varshney D et al showed that TLR gene polymorphisms may be linked to TB susceptibility and showed that polymorphisms in the TLR1–2 , TLR4 , TLR6 as well as TLR9 genes have a protective effect in particular ethnic populations [ 82 ].…”

Section: Toll-like Receptorsmentioning

confidence: 99%

Role of TLRs in HIV-1 Infection and Potential of TLR Agonists in HIV-1 Vaccine Development and Treatment Strategies

et al. 2023

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Toll-like receptors (TLRs), as a family of pattern recognition receptors, play an important role in the recognition of HIV-1 molecular structures by various cells of the innate immune system, but also provide a functional association with subsequent mechanisms of adaptive immunity. TLR7 and TLR8 play a particularly important role in the innate immune response to RNA viruses due to their ability to recognise GU-rich single-stranded RNA molecules and subsequently activate intracellular signalling pathways resulting in expression of genes coding for various biological response modifiers (interferons, proinflammatory cytokines, chemokines). The aim of this review is to summarise the most recent knowledge on the role of TLRs in the innate immune response to HIV-1 and the role of TLR gene polymorphisms in the biology and in the clinical aspects of HIV infections. In addition, the role of TLR agonists as latency reversing agents in research to treat HIV infections and as immunomodulators in HIV vaccine research will be discussed.

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Systematic review and meta-analysis of human Toll-like receptors genetic polymorphisms for susceptibility to tuberculosis infection

Cited by 18 publications

References 48 publications

Influence of single-nucleotide polymorphisms in TLR3 (rs3775291) and TLR9 (rs352139) on the risk of CMV infection in kidney transplant recipients

Influence of single-nucleotide polymorphisms in TLR3 (rs3775291) and TLR9 (rs352139) on the risk of CMV infection in kidney transplant recipients

Distinct contributions of the innate immune receptors TLR2 and RP105 to formation and architecture of structured lung granulomas in mice infected with Mycobacterium tuberculosis

Role of TLRs in HIV-1 Infection and Potential of TLR Agonists in HIV-1 Vaccine Development and Treatment Strategies

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