Hepatitis E Virus Infects Neurons and Brains

Abstract

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.

Updates in Hepatitis E virus (HEV) field; lessons learned from human liver chimeric mice

“…Several extrahepatic manifestations have been associated with HEV infection such as neurological disorders, glomerulonephritis, cryoglobulinemia, thrombocytopenia, acute pancreatitis and hemolytic anemia . HEV seems to replicate in the kidney and brain; HEV RNA and/or ORF2 Ag were detected in urine, cerebrospinal fluid and kidney and brain tissues of HEV infected patients . NHPs have been used for studying HEV EHMs.…”

“…In addition, liver enzymes were elevated and anti‐HEV IgG was generated in these mice . Moreover, extrahepatic replication was recorded in the brain of these mice . The mouse tropism of gt4 HEV is somewhat surprising since mice were previously shown to be resistant to infection by the other HEV genotypes that are capable of infecting humans .…”

Hepatitis E virus – key points for the clinical haematologist

“…Hepatitis E is more than just a hepatotropic virus, and has been demonstrated to infect neurons and brain tissue (Zhou et al , ). The clinical association between hepatitis E and neurological conditions, including Guillain–Barré Syndrome, neuralgic amyotrophy and encephalitis/myelitis, has been widely reported (Dalton et al , ).…”

Hepatitis E: New Clinical and Public Health Problem on the Western World? Review

“…neurological [6,[30][31][32][33][34], including cases of S. GuillainBarrè, neurologic pain amyotrophic, encephalitis, peripheral neuropathy, vestibular neuritis), confi rming that HEV in addition to hepatotropic is also neurotropic.…”