Hepatitis E Virus Infects Neurons and Brains

Xinying Zhou, Fen Huang, Lei Xu, Zhanmin Lin, Femke M. S. de Vrij, Ane C. Ayo-Martin, Mark van der Kroeg, Manzhi Zhao, Yuebang Yin, Wenshi Wang, Wanlu Cao, Yijin Wang, Steven A. Kushner, Jean Marie Peron, Laurent Alric, Robert A. de Man, Bart C. Jacobs, Jeroen J. van Eijk, Eleonora M. A. Aronica, Dave SprengersHerold J. Metselaar, Chris I. de Zeeuw, Harry R. Dalton, Nassim Kamar, Maikel P. Peppelenbosch, Qiuwei Pan

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Hepatitis E virus (HEV), as a hepatotropic virus, is supposed to exclusively infect the liver and only cause hepatitis. However, a broad range of extrahepatic manifestations (in particular, idiopathic neurological disorders) have been recently reported in association with its infection. In this study, we have demonstrated that various human neural cell lines (embryonic stem cell-derived neural lineage cells) induced pluripotent stem cell-derived human neurons and primary mouse neurons are highly susceptible to HEV infection. Treatment with interferon-α or ribavirin, the off-label antiviral drugs for chronic hepatitis E, exerted potent antiviral activities against HEV infection in neural cells. More importantly, in mice and monkey peripherally inoculated with HEV particles, viral RNA and protein were detected in brain tissues. Finally, patients with HEV-associated neurological disorders shed the virus into cerebrospinal fluid, indicating a direct infection of their nervous system. Thus, HEV is neurotropic in vitro, and in mice, monkeys, and possibly humans. These results challenge the dogma of HEV as a pure hepatotropic virus and suggest that HEV infection should be considered in the differential diagnosis of idiopathic neurological disorders
Original languageEnglish
Pages (from-to)1197-1206
JournalJournal of Infectious Diseases
Issue number8
Early online date2017
Publication statusPublished - 2017

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