Abstract
Hepatitis A virus (HAV) replicates in the liver, and is excreted from the body in feces. However, the mechanisms of HAV transport from hepatocytes to the gastrointestinal tract are poorly understood, mainly due to lack of suitable in vitro models. Here, we use a polarized hepatic cell line and in vivo models to demonstrate vectorial transport of HAV from hepatocytes into bile via the apical cell membrane. Although this transport is specific for HAV, the rate of fecal excretion in inefficient, accounting for less than 1% of input virus from the bloodstream per hour. However, we also found that the rate of HAV excretion was enhanced in the presence of HAV-specific IgA. Using mice lacking the polymeric IgA receptor (pIgR−/−), we show that a proportion of HAV:IgA complexes are transported via the pIgR demonstrating a role for specific antibody in pathogen excretion.
Highlights
Hepatitis A virus (HAV) is an orally transmitted hepatotropic picornavirus that first infects the mucosa of the gastrointestinal tract
A fundamental question about HAV pathogenesis still remains: how does the virus reach the gastrointestinal tract for enteric excretion? In this paper we investigate a mechanism for HAV export using N6 cells as a model for polarized hepatocytes
To measure active transport of virus in the basolateral to apical direction, 106 focus-forming units (FFU) of HAV was added to the basolateral side of cultures and incubated at 37 °C or 4 °C for 2 h
Summary
Hepatitis A virus (HAV) is an orally transmitted hepatotropic picornavirus that first infects the mucosa of the gastrointestinal tract. There are several in vitro models of polarized tissue including MDCK and Caco-2 cells, both of which display simple, columnar orientation of polarity amenable to in vitro manipulations These non-hepatic models are not appropriate for studies with hepatotropic viruses, as hepatocytes have unique and complex mechanisms for polarized transport. It was shown that progeny HAV was almost exclusively exported via the basolateral membrane, suggesting that infected hepatocytes excrete virus into the blood rather than the bile as expected. Whilst these finding readily explain the viremia observed in the actuate phase of the disease, they do not account for high titer virus shed in feces. The aim of this study was to explore the mechanism for HAV export from hepatocytes, and to determine the role of specific IgA in this process using both in vitro and in vivo models
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