Toll-like receptors genes polymorphisms and the occurrence of HCMV infection among pregnant women

Abstract

BackgroundHuman cytomegalovirus (HCMV) is the most common cause of intrauterine infections worldwide. The toll-like receptors (TLRs) have been reported as important factors in immune response against HCMV. Particularly, TLR2, TLR4 and TLR9 have been shown to be involved in antiviral immunity. Evaluation of the role of single nucleotide polymorphisms (SNPs), located within TLR2, TLR4 and TLR9 genes, in the development of human cytomegalovirus (HCMV) infection in pregnant women and their fetuses and neonates, was performed.MethodsThe study was performed for 131 pregnant women, including 66 patients infected with HCMV during pregnancy, and 65 age-matched control pregnant individuals. The patients were selected to the study, based on serological status of anti-HCMV IgG and IgM antibodies and on the presence of viral DNA in their body fluids. Genotypes in TLR2 2258 A > G, TLR4 896 G > A and 1196 C > T and TLR9 2848 G > A SNPs were determined by self-designed nested PCR-RFLP assays. Randomly selected PCR products, representative for distinct genotypes in TLR SNPs, were confirmed by sequencing. A relationship between the genotypes, alleles, haplotypes and multiple variants in the studied polymorphisms, and the occurrence of HCMV infection in pregnant women and their offsprings, was determined, using a logistic regression model.ResultsGenotypes in all the analyzed polymorphisms preserved the Hardy-Weinberg equilibrium in pregnant women, both infected and uninfected with HCMV (P > 0.050). GG homozygotic and GA heterozygotic status in TLR9 2848 G > A SNP decreased significantly the occurrence of HCMV infection (OR 0.44 95% CI 0.21–0.94 in the dominant model, P ≤ 0.050). The G allele in TLR9 SNP was significantly more frequent among the uninfected pregnant women than among the infected ones (χ2 = 4.14, P ≤ 0.050). Considering other polymorphisms, similar frequencies of distinct genotypes, haplotypes and multiple-SNP variants were observed between the studied groups of patients.Conclusions TLR9 2848 G > A SNP may be associated with HCMV infection in pregnant women.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-017-0730-8) contains supplementary material, which is available to authorized users.

Essential role of HCMV deubiquitinase in promoting oncogenesis by targeting anti-viral innate immune signaling pathways

“…In addition, studies suggest that people having a particular SNP in TLR9 (2848GA) are more susceptible to HCMV infection and cancer development. 29 , 56 Here, we have found evidence for hypothetical dual role for HCMV-DUB, in defeating host anti-viral responses and also promoting an oncogenic state.…”

“…HCMV induces innate immunity through several PRRs, including endosome localized TLR9 and cytosolic DNA sensors (CDSs). 28 , 29 , 30 , 31 , 32 TLR9 and CDSs, relay their signals through Myeloid differentiation primary response gene88 (MyD88) and STING, respectively, for the synthesis of I-IFNs. 33 , 34 , 35 To understand the role of HCMV in I-IFN synthesis and its dependence on MyD88- or STING-pathway, these genes were knocked down in HFFs using short-hairpin RNA (shRNA), wherein myd88 and sting transcripts were significantly reduced compared with control shRNA for GFP ( Supplementary Figures S2a – S2b ).…”

‘From immunosenescence to immune modulation’: a re-appraisal of the role of cytomegalovirus as major regulator of human immune function

“…In relation to potential variables within the host, genetic polymorphism within our genome would certainly be predicted to impact on an individual's ability to either prevent primary infection or control established persistent infection. Indeed, a wide range of genetic analyses are starting to reveal important associations between genotype and both the risk of primary infection and clinical outcome (35)(36)(37)(38)(39)(40)(41)(42)(43)(44). This important consideration is likely to become even more apparent during the interrogation of very rich epidemiological cohorts that are now available.…”

Epidemiology of Cytomegalovirus among pregnant women in Africa

“…Variation in genes encoding human leukocyte antigen (HLA) and killer cell immunoglobulin like (KIR) receptors have also been widely implicated in susceptibility or resistance to infection and disease progression of various viruses due to their critical role in immune regulation [80]. Considering that CMV has an extensive repertoire of mechanisms for immune evasion, polymorphisms in genes encoding proteins involved in the immune cascade such as IL, IFN and TNFα may play a role CMV infection [81]. However, relatively little is known about genetic predisposition to CMV infection and transmission, particularly in the African setting, yet knowledge of such genetic determinants may yield novel therapeutic targets for CMV.…”