The Role Of B Cells And TLR9 Deregulation By Hepatitis B Virus During Innate Immune Response

Issam TOUT, International Center for Infectiology Research, France
GOMES M. 2 , AINOUZE M. 1 , ROBLOT G. 1 , MAROTEL M. 1 , DURANTEL D. 4 , ALAIN S. 2 , CHEMIN I. 3 , HASAN U. 1

1 Inserm U1111, International Center for Infectiology Research, Lyon, France
2 Inserm U1092, Laboratory of Virology, CHU Limoges, France
3 Inserm UMR1052, Cancer Research Centre of Lyon, France
4 Inserm U1052, CNRS UMR5286, Cancer Research Centre of Lyon, France

Chronic HBV infection affects more than 240 million people worldwide and is a major risk factor for developing cancer in which 10-30% of cases will progress towards liver cirrhosis and hepatocellular carcinoma. Infection outcome relies on the immune system maturity. TLR9 is a sensor of viral and bacterial DNA motifs and activates pDCs and B cells to generate effective immune responses against infection. Evidently, B cells play a major role in mediating humoral immune responses to clear the infection.
We have previously reported that TLR9 transcription was deregulated by HBV in pDCs. Moreover, we observed the loss of TLR9 expression in PBMCs, particularly B cells, which were derived from chronic HBV patients.
In this study, we aimed to determine if TLR9 expression and function is affected by HBV in human B cells. We also investigated the mechanism by which HBV can deregulate TLR9 pathway and which viral component is responsible for its suppression. TLR7 expression was also assessed as a control. Finally we corroborated the in vitro results using patients with chronic hepatitis B.
We found that HBV decreases TLR9 expression, at both mRNA and protein levels, in all B cells subsets and that TLR9 function, such as proliferation and pro-inflammatory cytokines secretion were abrogated in the presence of HBV; however Ig secretion was not affected. These results were confirmed, in CHB patients with variations between the different patients groups. Furthermore, we observed that HBV can downregulate TLR9 on a transcriptional level by deregulating its promoter. Moreover, we found that this downregulation is mediated by CRE/CREB pathway and that HBsAg participated majorly in this mechanism.
The effect of HBV on TLR9 activity in B cells should give insights into oncoviral immune escape strategies providing knowledge that will be essential to develop novel immunotherapeutic approaches.
This study was funded by ANRS.