Gene Discovery in CHB Patients to Identify Unknown Pathways That Lead to B and NK Cell Deregulation

Overview

Natural Killer (NK) and B cell immune responses occur during the early stages of infection and are essential to eradicate it. Yet, chronic hepatitis B (CHB) infection occurs because the antiviral immune response is insufficient. In both NK and B cell studies we will explore the genetic alterations that occur during the varied chronic stages of the disease. We believe that our findings will allow us to understand the molecular signature of NK and B cells in the context of HBV infection.

Thanks to past ANRS funding we showed that both B and NK cells are dysfunctional in Hepatitis B virus (HBV) in in vitro human models and validated in patients with chronic infection. We observed that B cells responses by Toll Like Receptor 9 (TLR9) were inhibited by the HBV viral protein HBsAg. We noted the loss of TLR9 expression on all B cell subsets by HBV was mediated by loss of its promoter activity by blocking the phosphorylation of the transcription factor CREB (pCREB). Furthermore, B cell-TLR9 mediated responses such as proliferation and cytokine production were abrogated in CHB patients. For NK cells we demonstrated several significant changes in their receptor expression, loss of cytokines IFN γ, MIP1a and cytotoxicity compared to healthy donors. However, for both NK and B cell dysfunction the molecular basis and signaling pathway of this phenomenon are poorly characterized and whether this state can be reversed, a question of therapeutic importance, is unknown. We hypothesize that several molecular changes occur in NK cells from CHB patients that depend on altering the mTOR pathway by HBV and more specifically by HBsAg. Together our results from this proposal should define the genetic signatures that lead to B and NK cell function and will contribute to our understanding on immune dysfunction by HBV. In both NK and B cell studies we will explore the genetic alterations that occur during the varied chronic stages of the disease. This can only be investigated in patients including all clinical stages of CHB.