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

Case Western Reserve University, Cleveland, Ohio, United States
The American journal of tropical medicine and hygiene (Impact Factor: 2.7). 04/2010; 82(4):548-55. DOI: 10.4269/ajtmh.2010.09-0467
Source: PubMed


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-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) 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-gamma than those without these alleles (P = 0.03 and 0.008, respectively). The TLR9 SNPs were not associated with altered IFN-gamma levels in children with UM or altered TNF-alpha 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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Available from: Nadia Sam-Agudu
    • "In Ghana, the minor allele has been associated with maternal anemia, low birth weight in infants and severe malaria in children (Mockenhaupt et al., 2006a,b). On the contrary, it was found to be protective (da Silva et al., 2012; Esposito et al., 2012) and can be attributed to its association with low parasitemia (Basu et al, 2010), whereas in other studies did not reveal any association either with the risk of susceptibility or resistance (Leoratti et al., 2008; Mockenhaupt et al., 2006b; May et al, 2010; Zakeri et al., 2011; Pirahmadi et al., 2013; Soares et al., 2008; Sam-Agudu et al., 2010). Although deficiency in TLR9 or inhibition of its activations by agonist have been shown to confer protection against cerebral malaria in mice (Coban et al., 2007; Franklin et al., 2011), mutations in the TLR9 promoter region (T-1237C and T-1486C) affecting cis-regulatory effect on TLR9 expression (Campino et al., 2009) have various consequences related to disease outcome or altered cytokine levels in different malaria endemic populations (Sam-Agudu et al., 2010). "
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    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.
    No preview · Article · Oct 2015 · Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases
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    • "The interaction between SNPs of TLR9 and IFNG further supports a potential role of TLR9/IFN-γ pathway in active PTB development. Previous studies provided intriguing information about TLR9 SNPs and Malaria severity [35,36], the association of TLR9 polymorphisms with altered IFN-γ levels has been suggested to be potential explanation to TLR9 mediated pathogenesis [37]. However, the association between TLR9/IFN-γ pathway and TB disease severity has not been studied. "
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    ABSTRACT: Association studies have been employed to investigate the relationships between host single nucleotide polymorphisms (SNPs) and susceptibility to pulmonary Tuberculosis (PTB). However, such candidate genetic markers have not been widely studied in Chinese population, especially with respect to the disease development from latent M. tuberculosis infection (LTBI). In this case--control study, 44 candidate SNPs were examined in a total of 600 participants (PTB patients, LTBI controls and healthy controls without M. tuberculosis infection) from Zhengzhou, China. The two groups of controls were frequency matched on gender and age with PTB patients. Genotyping was carried out by the Illumina Golden Gate assay. When comparing PTB patients with LTBI controls but not healthy controls without M. tuberculosis infection, significant associations with disease development were observed for TLR9 1174 A/G, TLR9 1635 A/G and IFNG 2109G/A. The two loci in TLR9 were in LD in our study population (r2=0.96, D'=1.00). A combined effect of the genotypes associated with increased risk of PTB (i.e. TLR9 1174G/G and IFNG 2109 A/A) was found when comparing PTB patients with LTBI controls (p=0.004) but not with healthy controls without infection (p=0.433). Potential associations between TLR9 and IFN-gamma genetic polymorphisms and PTB were observed in a Chinese population which supports further study of the roles played by TLR9/IFN-gamma pathway during the development of PTB.
    Full-text · Article · Oct 2013 · BMC Infectious Diseases
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    • "The primary focus in this model was on the local expression of IFN-γ, a pro-inflammatory cytokine that is generally accepted to be crucial in driving the pathogenesis of CM [13], [35], [36], [37] as well as being central to anti-malarial immunity [38]. Clinical studies have described a correlation between IFN-γ levels and the occurrence of CM in humans [39], [40], [41]. Based on animal studies, this IFN-γ appears to derive from immune cells that have accumulated within the brain vasculature prior to the terminal phases of pathology. "
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    ABSTRACT: We have established a novel in vitro co-culture system of human brain endothelial cells (HBEC), Plasmodium falciparum parasitised red blood cells (iRBC) and peripheral blood mononuclear cells (PBMC), in order to simulate the chief pathophysiological lesion in cerebral malaria (CM). This approach has revealed a previously unsuspected pro-inflammatory role of the endothelial cell through potentiating the production of interferon (IFN)-γ by PBMC and concurrent reduction of interleukin (IL)-10. The IFN-γ increased the expression of CXCL10 and intercellular adhesion molecule (ICAM)-1, both of which have been shown to be crucial in the pathogenesis of CM. There was a shift in the ratio of IL-10:IFN-γ protein from >1 to <1 in the presence of HBEC, associated with the pro-inflammatory process in this model. For this to occur, a direct contact between PBMC and HBEC, but not PBMC and iRBC, was necessary. These results support HBEC playing an active role in the pathogenesis of CM. Thus, if these findings reflect the pathogenesis of CM, inhibition of HBEC and PBMC interactions might reduce the occurrence, or improve the prognosis, of the condition.
    Full-text · Article · Jul 2013 · PLoS ONE
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