The mechanisms underlying the hepatotropism of hepatitis A virus (HAV) and the relapsing courses of HAV infections are unknown. In this report, we show for a mouse hepatocyte model that HAV-specific immunoglobulin A (IgA) mediates infection of hepatocytes with HAV via the asialoglycoprotein receptor, which binds and internalizes IgA molecules. Proof of HAV infection was obtained by detection of HAV minus-strand RNA, which is indicative for virus replication, and quantification of infectious virions. We demonstrate that human hepatocytes also ingest HAV-anti-HAV IgA complexes by the same mechanism, resulting in infection of the cells, by using the HepG2 cell line and primary hepatocytes. The relevance of this surrogate receptor mechanism in HAV pathogenesis lies in the fact that HAV, IgA, and antigen-IgA complexes use the same pathway within the organism, leading from the gastrointestinal tract to the liver via blood and back to the gastrointestinal tract via bile fluid. Therefore, HAV-specific IgA antibodies produced by gastrointestinal mucosaassociated lymphoid tissue may serve as carrier and targeting molecules, enabling and supporting HAV infection of IgA receptor-positive hepatocytes and, in the case of relapsing courses, allowing reinfection of the liver in the presence of otherwise neutralizing antibodies, resulting in exacerbation of liver disease.Hepatitis A virus (HAV), a hepatotropic picornavirus (for a review, see reference 15), causes acute viral hepatitis in humans by an immunopathogenetic mechanism (41). The HAV infection is characterized by a short, self-limited disease and does not lead to chronic cases. However, after initial improvement in symptoms and liver test values, one or more relapses of the disease are described for up to 20% of patients (14,40). These relapses occur between 30 and 90 days after the primary episode, when high titers of neutralizing antibodies are already detectable (12). HAV is transmitted by the fecal-oral route, but the mechanism by which the virus first enters the bloodstream and reaches the liver as well as the pathogenetic mechanism leading to a relapsing disease remains unclear. Kaplan et al. (17) reported that a mucin-like class I integral membrane glycoprotein which was identified on African green monkey kidney cells acts as an attachment molecule for HAV. It was demonstrated that the human homolog is a binding receptor for HAV; it has been suggested that it is also a functional receptor (10). Although cell lines originating from tissues other than liver, such as fibroblasts and kidney cells, are also susceptible to HAV infection (9, 11) and although HAV antigen and the putative receptor for HAV could be detected in different organs, such as kidney, spleen, and gastrointestinal tract (2, 6, 10, 18), no extrahepatic sites of HAV replication have been clearly identified. The data on the ubiquitous expression of a receptor for HAV and the ability of HAV to replicate in a number of nonliver cells in cell cultures, but obviously not in the organism, suggest that HAV...

Although Hepatitis A virus (HAV) is transmitted by the faecal–oral route, its target for replication is the liver. Little is known of its interactions with cells of the gastrointestinal tract, and it is not known by which mechanisms HAV crosses the intestinal epithelium. In this study, it is shown that HAV associated with IgA is translocated from the apical to the basolateral compartment of polarized epithelial cells via the polymeric immunoglobulin receptor by IgA-mediated reverse transcytosis. The relevance of this mechanism, by which HAV–IgA complexes may overcome the intestinal barrier and contribute to infections of the liver, results from the fact that HAV–IgA complexes are infectious for hepatocytes and that significant amounts of intestinal HAV–IgA are present during acute infections, which are also partly transmitted. Besides supporting the primary infection, this mechanism may play a role in relapsing infections by establishing an enterohepatic cycle for HAV.

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