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Journal of Virology, December 2000, p. 10950-10957, Vol. 74, No. 23
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Hepatitis A Virus-Specific Immunoglobulin A Mediates Infection of Hepatocytes with Hepatitis A Virus via the Asialoglycoprotein Receptor

Andreas Dotzauer,1,* Ulrike Gebhardt,1 Karen Bieback,1 Ulrich Göttke,1 Anja Kracke,1 Jörg Mages,1 Stanley M. Lemon,2 and Angelika Vallbracht1

Department of Virology, University of Bremen, D-28359 Bremen, Germany,1 and Department of Microbiology and Immunology, The University of Texas Medical Branch at Galveston, Galveston, Texas 77555-10192

Received 25 May 2000/Accepted 30 August 2000

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 mucosa-associated 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.

* Corresponding author. Mailing address: Department of Virology, University of Bremen, Leobener Strasse/UFT, D-28359 Bremen, Germany. Phone: 49 421 218 4354. Fax: 49 421 218 4266. E-mail: dotzauer{at}uni-bremen.de.

Journal of Virology, December 2000, p. 10950-10957, Vol. 74, No. 23
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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