TLR9 Polymorphisms Are Associated with Altered IFN-γ Levels in Children with Cerebral Malaria

Sam-Agudu, Nadia A.; Greene, Jennifer; Opoka, Robert O.; Kazura, James W.; Boivin, Michael J.; Zimmerman, Peter A.; Riedesel, Melissa; Bergemann, Tracy L.; Schimmenti, Lisa A.; John, Chandy C.

doi:10.4269/ajtmh.2010.09-0467

Cited by 49 publications

(45 citation statements)

References 49 publications

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“…In order to verify the genetic contributions of these variants to malaria with more precision, we performed a comprehensive search and pooled the results of independent studies for meta-analysis. Our meta-analysis results for the TLR4D299G variant were consistent with those of previous studies on diverse ethnicities from different malarial endemic regions 2,20,22 , with no difference in the genotype or allele frequency distributions of the D299G polymorphism between UM and SM subjects. Although the contribution of the 299G minor allele has been controversial in children 7,20,22,23 , adult studies show no association 2,21,24 with the exception of maternal anemia in pregnant women 25 .…”

Section: Discussionsupporting

confidence: 79%

“…Although some studies have reported no association between T-1486C and malaria susceptibility or severity 7,20,22,24,27,30 , we observed that the -1486C allele was a risk factor for severe malaria and high parasite load, which is in line with previous findings 21,24 . Moreover, -1486C has been associated with an increased risk of low birth weight in term infants born to P. falciparum-infected pregnant women 25 .Consistent with these findings, the meta-analysis of the T-1486C variant revealed a significant association with SM under the allele contrast (T vs. C) and homozygous (TT vs. CC) genetic models.…”

supporting

confidence: 82%

“…Although, the -1237C allele of TLR9 has been associated with disease susceptibility 7 and risk of severe malaria 2,20,21 , our meta-analysis results did not reveal a significant association. …”

Section: Discussioncontrasting

confidence: 42%

“…The TLR9 gene, located on chromosome 3p21.3, spans up to 5kb and consists of two exons. Although the inhibition of TLR9 activation by its antagonist or deficiency in mice confers protection against cerebral malaria 17,18 , the two most common promoter variants of TLR9, T-1237C (rs5743836) and T-1486C(rs187084), have a cis-regulatory effect on TLR9 expression 19 , with various consequences for disease outcome or altered cytokine levels in malaria 20 .…”

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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Section: Discussionsupporting

confidence: 79%

supporting

confidence: 82%

Section: Discussioncontrasting

confidence: 42%

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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“…Therefore the significance if any, of the detection of malaria products by TLR2 and TLR9 to the development of CM is currently unknown. However despite the conflicting data regarding TLRs in murine models of CM, a polymorphisms in TLR9 has been associated with altered levels of IFNγ in children with CM [92].…”

Section: T Cells Cd11c+ Dendritic Cells and The Increased Expressionmentioning

confidence: 99%

Evaluating the role of Toll-like receptors in diseases of the central nervous system

Carty

Bowie

2011

Biochemical Pharmacology

134

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A key part of the innate immune system is a network of pattern recognition receptors (PRRs) and their associated intracellular signalling pathways. Toll-like receptors (TLRs) are one such group of PRRs that detect pathogen associated molecular patterns (PAMPs). Activation of the TLRs with their respective agonists results in the activation of intracellular signalling pathways leading to the expression of proinflammatory mediators and anti-microbial effector molecules. Activation of the innate immune system through TLRs also triggers the adaptive immune response, resulting in a comprehensive immune program to eradicate invading pathogens. It is now known that immune surveillance and inflammatory responses occur in the central nervous system (CNS). Furthermore it is becoming increasingly clear that TLRs have a role in such CNS responses andare also implicated in the pathogenesis of a number of conditions in the CNS, such as Alzheimer's, stroke and multiple sclerosis. This is likely due to the generation of endogenous TLR agonists in these conditions which amplifies a detrimental neurotoxic inflammatory response. However TLRs in some situations can be neuroprotective, if triggered in a favourable context. This review aims to examine the recent literature on TLRs in the CNS thus demonstrating their importance in a range of infectious and non-infectious diseases of the brain.

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