Dissection of the molecular determinants and pathways involved in Hepatitis B virus (HBV) entry into hepatocytes
File(s)
Author(s)
Evripioti, Antonia Alexandra
Type
Thesis
Abstract
HBV entry into cells is mediated through a precisely orchestrated interaction of the pre-S1 glycoprotein domain of the virus principally with the sodium taurocholate cotransporting polypeptide (NTCP) receptor on the surface of hepatocytes. However, in vitro this typically relies on high multiplicities of infections, and even in this case a very small majority of the hepatocytes become infected with the virus. Here we describe a mechanism by which DMSO facilitates overexpression of human NTCP, resulting in the bulk trafficking of the receptor to the cell surface and hence enhancing susceptibility of these cells to HBV infection. This mechanism is an intricate network of intracellular interactions, with the main one being the inhibition of particular phosphodiesterases (PDEs), including PDE4, by DMSO. This outcome can hopefully now open the door for the study of new small molecule inhibitors to prevent HBV entry into hepatocytes by specifically targeting the levels of NTCP on the cells’ surface.
It is highly likely, however, that HBV entry into hepatocytes additionally relies on other, yet not fully characterised, cell surface receptors or host factors. Such an example may be the asialoglycoprotein receptor (ASGPR), which our data suggests may possibly be important and play a role during HBV entry. In particular, we found that the simultaneous presence of NTCP and ASGPR enhanced entry of HBV-mimicking particles into hepatocytes, more so than when only the NTCP receptor was overexpressed on those cells.
This is the first study to have established positive HBV infection of a mouse hepatic cell line overexpressing a chimeric form of the NTCP receptor. This outcome should hopefully now open the road towards further research and understanding of the HBV interspecies transmission barrier, as well as identification of those host factors vital for productive HBV infection in vitro and in vivo.
It is highly likely, however, that HBV entry into hepatocytes additionally relies on other, yet not fully characterised, cell surface receptors or host factors. Such an example may be the asialoglycoprotein receptor (ASGPR), which our data suggests may possibly be important and play a role during HBV entry. In particular, we found that the simultaneous presence of NTCP and ASGPR enhanced entry of HBV-mimicking particles into hepatocytes, more so than when only the NTCP receptor was overexpressed on those cells.
This is the first study to have established positive HBV infection of a mouse hepatic cell line overexpressing a chimeric form of the NTCP receptor. This outcome should hopefully now open the road towards further research and understanding of the HBV interspecies transmission barrier, as well as identification of those host factors vital for productive HBV infection in vitro and in vivo.
Version
Open Access
Date Issued
2017-07
Date Awarded
2017-10
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Dorner, Marcus
O'Hare, Peter
Thursz, Mark
Sponsor
Imperial College London
Publisher Department
Department of Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)