TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

Abstract

A B S T R A C TTLR7 agonists are of high interest for the treatment of cancer, auto-immunity and chronic viral infections. They are known to activate plasmacytoid dendritic cells (pDCs) to produce high amounts of Type I Interferon (IFN) and to facilitate T and B cell responses, the latter with the help of maturation markers such as CD40, CD80 and CD86. The TLR7 single nucleotide polymorphism (SNP) rs179008 (GLn11Leu), sex and chronic viral infection have all been reported to influence pDC IFN production. It is unknown, however, whether these factors also influence pDC phenotypic maturation and thereby IFN-independent pDC functions. Furthermore, it is unclear whether SNP rs179008 influences HBV susceptibility and/or clearance.Here we investigated whether the SNP rs179008, sex and HBV infection affected phenotypic maturation of pDCs from 38 healthy individuals and 28 chronic HBV patients. In addition, we assessed SNP prevalence in a large cohort of healthy individuals (n = 231) and chronic HBV patients (n = 1054).Consistent with previous reports, the rs179008 variant allele was largely absent in Asians and more prevalent in Caucasians. Among Caucasians, the SNP was equally prevalent in healthy and chronically infected males. The SNP was, however, significantly more prevalent in healthy females than in those with chronic HBV infection (42 versus 28%), suggesting that in females it may offer protection from chronic infection. Ex vivo experiments demonstrated that induction of the co-stimulatory molecules CD40 and CD86 by TLR7 ligands, but not TLR9 ligands, was augmented in pDCs from healthy SNP-carrying females. Furthermore, CD80 and CD86 upregulation was more pronounced in females independent of the SNP. Lastly, our data suggested that chronic HBV infection impairs pDC maturation. These findings provide insight into factors determining TLR7 responses, which is important for further clinical development of TLR7-based therapies.

TLR7 Polymorphism (rs179008 and rs179009) in HIV-Infected Individual Naïve to ART

“…In our study, the prevalence of TLR7 rs179008 AA, AT, and TT genotypes in healthy controls was 81.0%, 16.5%, and 2.5%. This finding was unmatched with that of the other studies carried out by [12,13,29,14]. The occurrence of TLR7 rs179008A/T allelic frequency was comparable with the study carried out by Valverde-Villegas et al, 2017, [30,6,16] and dissimilar with the study reported by [6,12,13,29].…”

Genetic variation in toll like receptors 2, 7, 9 and interleukin-6 is associated with cytomegalovirus infection in late pregnancy

“…We also report an association between CMV DNA status and rs179008, a non-synonymous A > T (Gln11Leu) polymorphism within exon 3 of the TLR7 gene [43]. The resulting glycine to leucine change has been suggested to code for a functionally impaired TLR7 protein [44,45]. In the present study, the T allele was associated with significantly lower odds of CMV positivity.…”

HBx and c-MYC Cooperate to Induce URI1 Expression in HBV-Related Hepatocellular Carcinoma

“…It is suggested that estrogen has a suppressive effect on HCC because it is known that the prevalence of HCC is high in males, and low in premenopausal females [37]. It is also implied that there are sex differences in response to HBV infection [38]. It was demonstrated that URI1 inhibits NAD synthesis by suppressing the function of estrogen receptor in hepatocytes, leading to the development of HCC [10].…”