Sex-specific effects of TLR9 promoter variants on spontaneous clearance of HCV infection

Fischer, Janett; Weber, Alexander N.R.; Böhm, Stephan; Dickhöfer, Sabine; Maadidi, Souhayla El; Deichsel, D; Knop, Viola; Klinker, Hartwig; Möller, B.; Rasenack, J.; Wang, Lisa; Sharma, Manu; Hinrichsen, Holger; Spengler, Ulrich; Buggisch, Peter; Sarrazin, Christoph; Pawlita, Michael; Waterboer, Tim; Wiese, Manfred; Probst-Müller, Elsbeth; Malinverni, Raffaele; Bochud, Pierre–Yves; Gardiner, Clair M.; O’Farrelly, Cliona; Berg, Thomas

doi:10.1136/gutjnl-2015-310239

Cited by 30 publications

(28 citation statements)

References 48 publications

(44 reference statements)

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“…The minor C allele of rs187084 led to significantly lower expression of protective cytokines IFN- γ and TNF- α than the T allele [ 35 ]. In addition, rs187084 C allele increased the transcriptional activity of TLR9 and provoked a higher level of gene expression [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

The Associations between Toll-Like Receptor 9 Gene Polymorphisms and Cervical Cancer Susceptibility

Tian

Zhang

Yang

et al. 2018

Mediators of Inflammation

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This meta-analysis systematically reviews the association between Toll-like receptor 9 polymorphisms and the risk of cervical cancer. Case-control studies focused on the association were collected from the PubMed, Web of Science, Cochrane Library, Embase, MEDLINE, CNKI, VIP, and Wanfang databases from inception to July 2017. We screened the studies and assessed the methodological quality of the included studies and extracted data. A meta-analysis was performed using RevMan 5.3 and Stata 12.0 software. Pooled odds ratios and 95% confidence intervals were employed to evaluate the strength of the associations between Toll-like receptor 9 polymorphisms and cervical cancer risk. A total of 9 studies comprising 3331 cervical cancer patients and 4109 healthy controls met the inclusion criteria. Of these, 8 studies contained information about G2848A (rs352140) and 4 studies contained information about −1486T/C (rs187084). Our results revealed that the associations between rs187084 and cervical cancer risk in the dominant model (p = 0.002) and heterozygous model (p = 0.002) were significant, with 1.30- and 1.32-fold increases in susceptibility, respectively, compared to that in the wild-type model. However, rs352140 was not related to cervical cancer regardless of whether the subgroup analysis was conducted (p > 0.05). In conclusion, there is a significant correlation between rs187084 and cervical cancer risk with the minor C allele increasing the risk of occurrence of cervical cancer. However, rs352140 is not associated with the occurrence of cervical cancer.

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Section: Discussionmentioning

confidence: 99%

The Associations between Toll-Like Receptor 9 Gene Polymorphisms and Cervical Cancer Susceptibility

Tian

Zhang

Yang

et al. 2018

Mediators of Inflammation

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“…To confirm that rs179008 SNP is truly protective for CHB, our study needs to be repeated in a larger cohort. This cohort preferably should also contain patients spontaneously clearing the disease, similar to a recent study performed on TLR9 SNPs in HCV disease progression (Fischer et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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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.

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“…The T Ag locus of Merkel cell polyomavirus blocked the C/EBPb transactivator, which also regulated TLR9 transcription (29). Recently, Fischer et al (19) showed that TLR9 promoter SNPs associated with natural clearance of HCV infection showed higher transcriptional activities. We previously showed that TLR9 expression on pDCs, as well as TLR9-mediated secretion of IFN, was impaired by HBV (14).…”

Section: Discussionmentioning

confidence: 99%

“…Previous reports showed that oncoviruses such as HPV16, EBV, and hepatitis C virus (HCV) downregulate TLR9 transcription using NF-kB, which is a negative regulator of TLR9 transcription (12,13,19). We hypothesized that HBV used the same mechanism to block TLR9 transcription in human B cells.…”

Section: Hbv Uses Hbsag To Block Creb Phosphorylation and Binding To mentioning

confidence: 97%

Hepatitis B Virus Blocks the CRE/CREB Complex and Prevents TLR9 Transcription and Function in Human B Cells

Tout

Gomes

Ainouze

et al. 2018

The Journal of Immunology

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Effective B cell responses such as cytokine secretion, proliferation, and Ab-specific responses are essential to clear hepatitis B virus (HBV) infection. However, HBV alters numerous immune pathways to persist in the host. B cell activity depends on activation of the innate sensor TLR9 by viral or bacterial DNA motifs. How HBV can deregulate B cell functions remains unknown. In this study, we show that HBV can enter and decrease TLR9 expression in human primary B cells. Using PBMCs from human blood donors, we show that TLR9 expression was reduced in all peripheral B cells subsets exposed to HBV. B cell function mediated by TLR9, but not TLR7, such as proliferation and proinflammatory cytokines secretion, were abrogated in the presence of HBV; however, global Ig secretion was not downregulated. Mechanistically, we show, using human myeloma B cell line RPMI 8226, that the surface Ag hepatitis B surface Ag was responsible for TLR9 dysfunction. hepatitis B surface Ag suppressed the phosphorylation and thus the activation of the transcription factor CREB, preventing TLR9 promoter activity. Finally, we corroborated our in vitro findings in a cohort of chronic HBV carriers and found that TLR9 expression and function were significantly suppressed. The effect of HBV on TLR9 activity in B cells gives insights into oncoviral immune escape strategies, providing knowledge to develop novel immunotherapeutic approaches in chronic HBV-carrier patients.

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Sex-specific effects of TLR9 promoter variants on spontaneous clearance of HCV infection

Abstract: promoter SNPs are associated with the natural course of HCV infection and show higher transcriptional activities. Our results imply the DNA sensor TLR9 in natural immunity against the RNA virus, HCV.

Cited by 30 publications

References 48 publications

The Associations between Toll-Like Receptor 9 Gene Polymorphisms and Cervical Cancer Susceptibility

The Associations between Toll-Like Receptor 9 Gene Polymorphisms and Cervical Cancer Susceptibility

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

Hepatitis B Virus Blocks the CRE/CREB Complex and Prevents TLR9 Transcription and Function in Human B Cells

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