Toll-like receptor polymorphisms and cerebral malaria: TLR2 Δ22 polymorphism is associated with protection from cerebral malaria in a case control study

Article (PDF Available)inMalaria Journal 11(47):47 · February 2012with25 Reads
DOI: 10.1186/1475-2875-11-47 · Source: PubMed
Abstract
In malaria endemic areas, host genetics influence whether a Plasmodium falciparum-infected child develops uncomplicated or severe malaria. TLR2 has been identified as a receptor for P. falciparum-derived glycosylphosphatidylinositol (GPI), and polymorphisms within the TLR2 gene may affect disease pathogenesis. There are two common polymorphisms in the 5' un-translated region (UTR) of TLR2, a 22 base pair deletion in the first unstranslated exon (Δ22), and a GT dinucleotide repeat in the second intron (GTn). These polymorphisms were examined in a Ugandan case control study on children with either cerebral malaria or uncomplicated malaria. Serum cytokine levels were analysed by ELISA, according to genotype and disease status. In vitro TLR2 expression was measured according to genotype. Both Δ22 and GTn polymorphisms were highly frequent, but only Δ22 heterozygosity was associated with protection from cerebral malaria (OR 0.34, 95% confidence intervals 0.16, 0.73). In vitro, heterozygosity for Δ22 was associated with reduced pam3cys inducible TLR2 expression in human monocyte derived macrophages. In uncomplicated malaria patients, Δ22 homozygosity was associated with elevated serum IL-6 (p = 0.04), and long GT repeat alleles were associated with elevated TNF (p = 0.007). Reduced inducible TLR2 expression may lead to attenuated pro-inflammatory responses, a potential mechanism of protection from cerebral malaria present in individuals heterozygous for the TLR2 Δ22 polymorphism.

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    • "In a previous study, frequencies of TLR4 Asp299Gly and Thr399Ile polymorphism did not show any significant differences in the distribution of alleles or genotypes between patients with chagasic cardiomyopathy and asymptomatic subjects [17]. In another study, TLR2 196-174 del heterozygosity was associated with protection from cerebral malaria (OR 0.34, 95% confidence intervals 0.16, 0.73) [18]. A study reported comparison of distribution of TLR4 Asp299Gly and Thr399Ile polymorphism in patients with visceral leishmaniasis and ethnically matched controls; it did not show any difference both in case of alleles and genotypes (P > 0.05) [19]. "
    Full-text · Article · Jan 2016
    • "Surface staining was performed as described previously [44]. Cells were stained with PE-labeled CX3CL1 (R&D Systems, Minneapolis, MN), PE-labeled CD40 (BD Biosciences), PE-labeled ICAM-1 (BD Biosciences) or PE-labeled isotype control mAbs. "
    [Show abstract] [Hide abstract] ABSTRACT: CD40, CX3CL1 and TNF-α promote atheroma and neointima formation. CD40 and TNF-α are also central to the development of diabetic retinopathy while CX3CL1 may play a role in the pathogenesis of this retinopathy. The purpose of this study was to examine whether CD40 ligation increases CX3CL1 and TNF-α protein expression in human endothelial cells from the aorta and retina. CD154 (CD40 ligand) upregulated membrane-bound and soluble CX3CL1 in human aortic endothelial cells. CD154 triggered TNF-α production by human aortic endothelial cells. TNF Receptor Associated Factors (TRAF) are key mediators of CD40 signaling. Compared to human aortic endothelial cells that express wt CD40, cells that express CD40 with a mutation that prevents TRAF2,3 recruitment, or CD40 with a mutation that prevents TRAF6 recruitment exhibited a profound inhibition of CD154-driven upregulation of membrane bound and soluble CX3CL1 as well as of TNF-α secretion. While both CD154 and TNF-α upregulated CX3CL1 in human aortic endothelial cells, these stimuli could act independently of each other. In contrast to human aortic endothelial cells, human retinal endothelial cells did not increase membrane bound or soluble CX3CL1 expression or secrete TNF-α in response to CD154 even though CD40 ligation upregulated ICAM-1 and CCL2 in these cells. Moreover, TNF-α did not upregulate CX3CL1 in retinal endothelial cells. In conclusion, CD40 ligation increases CX3CL1 protein levels and induces TNF-α production in endothelial cells. However, endothelial cells are heterogeneous in regards to these responses. Human aortic but not retinal endothelial cells upregulated CX3CL1 and TNF-α in response to CD40 ligation, as well as upregulated CX3CL1 in response to TNF-α. These dissimilarities may contribute to differences in regulation of inflammation in large vessels versus the retina.
    Full-text · Article · Dec 2015
    • "Although, the early and robust inflammatory response is important for controlling acute blood-stage infection , superfluous or deregulated inflammation may have the consequence of severe malaria (Erdman et al., 2008). Consequently, association of genetic variations in TLR2 (5′UTR I/D), TLR4 (D299G and T399I) and TLR9 (T-1237C and T-1486C) (Greene et al., 2012; Gbédandé et al., 2013; Mockenhaupt et al., 2006b; Sawian et al., 2012), and change in their expression/responses with disease manifestation of malaria (Esposito et al., 2012; Franklin et al., 2009; Loharungsikul et al., 2008) emphasize the role of these TLRs in malaria pathogenesis. However, genetic association studies investigating the possible effect of these variants on severe malaria in different endemic regions are conflicting (Mockenhaupt et al., 2006b; Leoratti et al., 2008; Sam-Agudu et al., 2010; Zakeri et al., 2011; Esposito et al., 2012; Sawian et al., 2012). "
    [Show abstract] [Hide abstract] ABSTRACT: Background: In malaria, the toll-like receptors (TLRs) have recently emerged as major player of innate immunity. However, implication of TLR variants on clinical manifestations of malaria is conflicting. The present study aims to provide relevant information of growing interest in understanding the role of TLR4D299G, TLR9T-1237C and TLR9T-1486C polymorphisms on clinical outcomes of malaria. Methods: We genotyped TLR4D299G, TLR9T-1237C and TLR9T-1486C polymorphisms by PCR-RFLP methods and subsequently analysed in 200 uncomplicated patients and 200 severe patients. Further, the severe malaria was categorised into sub-clinical groups such as cerebral malaria (CM), non-cerebral severe malaria (NCSM), single organ dysfunction (SOD) and multi-organ dysfunctions (MODS) and analysed. Result: The TLR9-1237CC genotype was observed at significantly low frequency in MODS (p=0.0008), while in heterozygous state (TC) it was proportionately more frequent in SOD (p=0.087) as compared to mild malaria. The TLR9T-1486C heterozygote was more common in all categories of severe malaria. However, pair wise LD analysis revealed significant linkage between T-1237C and T-1486C, whereas haplotype analysis showed significantly low frequency of C-T haplotype in CM (P=0.005, Pc=0.02) and high frequency of T-C haplotype in NCSM as compared to mild malaria. Conclusion: Although TLR9-1237C could be a risk factor for severe malaria in heterozygous state, negative association of CC genotype with MODS warrants caution of segregating severe malaria into its sub-clinical groups while interpreting data. Further, clinical outcome in malaria was observed to be apparently modulated by LD between TLR9 promoter variants.
    Article · Oct 2015
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