Common Polymorphisms of Toll‐Like Receptors 4 and 9 Are Associated with the Clinical Manifestation of Malaria during Pregnancy

Mockenhaupt, Frank P.; Hamann, Lutz; Gaertner, Christiane von; Bedu-Addo, George; Kleinsorgen, Cordula von; Schumann, Ralf R.; Bienzle, Ulrich

doi:10.1086/505152

Cited by 120 publications

(104 citation statements)

References 14 publications

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“…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. Despite the fact that the stratified analysis did not detect a statistically significant association in Indian adults, its association in African children, both in T vs. C and TT vs. CC models, suggests that the findings are robust, at least in children.…”

supporting

confidence: 61%

“…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 . This could be due to a lack of adequate studies, ethnic differences, or the fact that the effect of 299G may vary with age groups.…”

Section: Discussionmentioning

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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supporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

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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“…Indeed, TLR9 signaling plays a protective role in the development of autoimmunity by modulating Treg activity in autoimmune-prone MRL mice (45). Furthermore, common polymorphisms of TLR9 are reported to be associated with the clinical manifestation of malaria during pregnancy (46). It is quite possible that malaria parasites cleverly exploit this machinery by providing a large amount of TLR9 stimulant.…”

Section: Discussionmentioning

confidence: 99%

Malaria Parasites Require TLR9 Signaling for Immune Evasion by Activating Regulatory T Cells

Hisaeda

Tetsutani

Imai

et al. 2008

The Journal of Immunology

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Malaria is still a life-threatening infectious disease that continues to produce 2 million deaths annually. Malaria parasites have acquired immune escape mechanisms and prevent the development of sterile immunity. Regulatory T cells (Tregs) have been reported to contribute to immune evasion during malaria in mice and humans, suggesting that activating Tregs is one of the mechanisms by which malaria parasites subvert host immune systems. However, little is known about how these parasites activate Tregs. We herein show that TLR9 signaling to dendritic cells (DCs) is crucial for activation of Tregs. Infection of mice with the rodent malaria parasite Plasmodium yoelii activates Tregs, leading to enhancement of their suppressive function. In vitro activation of Tregs requires the interaction of DCs with parasites in a TLR9-dependent manner. Furthermore, TLR9−/− mice are partially resistant to lethal infection, and this is associated with impaired activation of Tregs and subsequent development of effector T cells. Thus, malaria parasites require TLR9 to activate Tregs for immune escape.

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“…In the first study, TLR4 Asp299 Gly was associated with an increased risk of maternal anemia, and TLR4 Asp299 Gly and the C allele at TLR9 −1486 were associated with subsequent infant lowbirth weight in pregnant Ghanaian women with malaria. 22 In the second, the risk of severe malaria in Ghanaian children was increased 1.5-fold and 2.6-fold with TLR4 Asp299 Gly and TLR4 Thr399 Ile , respectively. 23 Another study by Campino and others, 24 based in The Gambia and Malawi, studied the effect of TLR9 genetic variation on severe malaria.…”

Section: Introductionmentioning

confidence: 98%

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

Sam-Agudu

Greene

Opoka

et al. 2010

The American Journal of Tropical Medicine and Hygiene

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Abstract. Toll-like receptor (TLR) polymorphisms have been associated with disease severity in malaria infection, but mechanisms for this association have not been characterized. The TLR2, 4, and 9 single nucleotide polymorphism (SNP) frequencies and serum interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) levels were assessed in Ugandan children with cerebral malaria (CM, N = 65) and uncomplicated malaria (UM, N = 52). The TLR9 C allele at −1237 and G allele at 1174 were strongly linked, and among children with CM, those with the C allele at −1237 or the G allele at 1174 had higher levels of IFN-γ than those without these alleles ( P = 0.03 and 0.008, respectively). The TLR9 SNPs were not associated with altered IFN-γ levels in children with UM or altered TNF-α levels in either group. We present the first human data that TLR SNPs are associated with altered cytokine production in parasitic infection.

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Common Polymorphisms of Toll‐Like Receptors 4 and 9 Are Associated with the Clinical Manifestation of Malaria during Pregnancy

Cited by 120 publications

References 14 publications

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

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

Malaria Parasites Require TLR9 Signaling for Immune Evasion by Activating Regulatory T Cells

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

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