TLR7 and TLR8 Gene Variations and Susceptibility to Hepatitis C Virus Infection

Abstract

Toll-like receptors (TLRs) play pivotal roles in the innate immune system and control inflammatory responses and adaptive immunity. We previously evaluated associations between TLR7 and TLR8 gene SNPs and susceptibility to hepatitis C virus (HCV) infection. Our results suggested that TLR7IVS2-151G and TLR8-129G alleles were present at higher frequency in males of an HCV-infected group as compared to a control group (24.1% vs. 14.4%, p = 0.028; 17.6% vs. 6.8%, p = 0.004, respectively). Based upon their recognition of single stranded viral RNA, this suggested that TLR7 and TLR8 played a significant role in anti-HCV immune responses. Here, we studied the functional effects of these polymorphisms by analyzing the mRNA expressions of TLR7 and TLR8 and cytokine production induced ex vivo by TLR7- and TLR8-specific agonists using whole blood of subjects with different genotypes. The percentage of CD14+ cells from those with an AG haplotype that expressed TLR7 and TLR8 was significantly lower, but higher in intensity compared to cells from those with GG and AC haplotypes. Cells from those with an AG haplotype produced more IFN-α and less amounts of pro-inflammatory cytokines upon stimulation. This suggests that variations in TLR7 and TLR8 genes might impair immune responses during HCV infection.

Functional polymorphisms of the TLR7 and TLR8 genes contribute to Mycobacterium tuberculosis infection

“…It has been suggested that they play important roles in induction by IFN and inflammatory cytokines [14,15]. Based on data from our laboratory we have demonstrated that TLR7 and TLR8 polymorphisms influence TLR7 and TLR8 expression and signal transduction upon ligand stimulation [16,17]. We previously identified a single nucleotide polymorphism (SNP) at IVS2-151 in TLR7 (rs179009), and disequilibrium association of TLR8 with a SNP resulting in a Met/Val change at a start codon associated (G/C) SNP (rs3764879) at position -129 of the promoter [18].…”

“…The percentage of monocytes expressing TLR7 and TLR8 was significantly lower in subjects with the TLR7 IVS2-151A/TLR8-129G haplotype, but higher in intensity compared to cells from those with the TLR7 IVS2-151A/TLR8-129C haplotypes. Cells from MANUSCRIPT 4 subjects with the TLR7 IVS2-151A/TLR8 -129G haplotype produced more IFN-α and less pro-inflammatory cytokines upon stimulation [17]. A large number of studies have investigated the influence of TLR gene polymorphisms on MTB susceptibility [19][20][21].…”

Celiac Disease: An Immunological Jigsaw

“…TLR7 and TLR8 are innate receptors for single-stranded viral RNA. They have been associated with susceptibility to hepatitis C (Wang et al, 2011a), which may play a favoring role in CD (see below). The genetic link with innate antiviral responses seems however less strong in CD than in T1D, in which a combination of GWAS and eQTL data has revealed an association with a whole network of antiviral innate immune genes (Foxman and Iwasaki, 2011).…”

Toll-like receptor 8 (TLR8) polymorphisms are associated with non-progression of chronic hepatitis C in HIV/HCV coinfected patients

“…TLR8 gene is located on chromosome X, which is known to house the largest number of immune-related genes of the whole genome (Bianchi et al, 2012). Single nucleotide polymorphisms (SNPs) located within TLR8 have been related with an altered innate immune response, susceptibility to HCV infection (Wang et al, 2011;Wang et al, 2013), and progression of HIV disease (Mackelprang et al, 2014;Oh et al, 2008). HCV may also directly activate the innate immune system via TLR8, leading to chronic inflammation and hepatic fibrosis; and may impair TLR signaling in order to evade clearance and promote chronic infection (Howell et al, 2013).…”