Morphogenesis of hepatitis B and hepatitis D virus particles: Strategies, mechanisms and host factors
Parasitology and Biology of Tropical Infectious Disease Pathogens
Final Report Abstract
Hepatitis B virus (HBV) infections are still a leading cause of liver disease. The extremely successful spread of this pathogen among the human population is explained by its effective transmission strategies and its manifold particle types, including virions (VPs), naked capsids, and subviral empty envelope particles (SVPs). SVPs constitute the bulk of circulating viral particles in infected patients and are a major obstacle to raise effective immune responses and subsequently virus clearance. Due to its tiny genome, HBV depends on cellular machineries to thrive in infected hepatocytes. The hepatitis delta virus (HDV) is a cousin of HBV, as it takes over the HBV envelope during propagation. Accordingly, overlaps in host cell dependency, cellular trafficking pathways and export routes of both pathogens are conceivable. The HBV/HDV envelope was the focus of our investigations. A detailed siRNA screen, targeting most of the mammalian components of the coat protein complex II (COPII)-coated vesicle machinery, revealed that both, the HBV subviral and viral envelope, are entirely dependent on the functioning COPII network. Mammals harbor multiple copies of several Sec protein genes, including two copies of Sec23 and four copies of Sec24 that form the inner coat of the COPII vesicle and play a key role in recruiting the appropriate protein cargos to the transport vesicle. To our surprise, we found that the HBV envelope is a specific client of the Sec24A and Sec23B paralogs, a novel finding in COPII biology. We succeeded to map the HBV/Sec24A interaction points and suspect that an interference with the COPII/HBV crosstalk may help to design therapeutic approaches targeting the egress of HBV/HDV particles types. As a completely unexpected result, we identified ERGIC-53, a high-mannose specific lectin as novel host factor guiding HBV trafficking and egress out of the cell. Quite surprisingly, we found that ERGIC-53 is essential for HBV viral particle propagation, but dispensable for HBV subviral particle secretion, implicating that it may serve as a device to segregate intracellular trafficking routes of HBV particle types. Our observation that “a lectin goes viral” provides an explanation for the long-lasting phenomenon why HBV viral, but not subviral particles require N-glycans to exit cells. Moreover, our cell imaging studies pointed to novel, ER-derived, subcellular compartments where HBV assembly and budding initiates. As the loss of ERGIC-53 is well tolerated in humans, this protein may be an attractive cellular target for therapeutic antiviral intervention. Our team (A. Christ, T. Döring, T. Heimann, L. Zeyen) has succeeded to publish these results in four papers in peer-reviewed journals. Worth mentioning, our pilot “Sec24A-paper” draw particular attention of the editor of the journal.
Publications
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„Morphogenese der Hepatitis-B- und Hepatitis-D-Virus-Partikel: Funktionelle Analyse intrazellulärer Transportmechanismen“. 2019, Dissertationsschrift
Lisa Maria Zeyen
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„Morphogenese der Hepatitis-B- und Hepatitis-D-Virus-Partikel: Funktionelle Analyse intrazellulärer Transportmechanismen“. 2019, Dissertationsschrift, Fachbereich Biologie, Johannes Gutenberg-Universität Mainz.
Lisa Maria Zeyen
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Hepatitis B subviral envelope particles use the COPII machinery for intracellular transport via selective exploitation of Sec24A and Sec23B. Cellular Microbiology, 22(6).
Zeyen, Lisa; Döring, Tatjana; Stieler, Jens T. & Prange, Reinhild
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Hepatitis B Virus Exploits ERGIC-53 in Conjunction with COPII to Exit Cells. Cells, 9(8), 1889.
Zeyen, Lisa; Döring, Tatjana & Prange, Reinhild
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Hepatitis B virus movement through the hepatocyte: An update. Biology of the Cell, 114(12), 325-348.
Prange, Reinhild
