Hepatitis E virus infects brain microvascular endothelial cells, crosses the blood–brain barrier, and invades the central nervous system

Abstract

Hepatitis E virus (HEV) is an important but understudied zoonotic virus causing both acute and chronic viral hepatitis. A proportion of HEV-infected individuals also developed neurological diseases such as Guillain–Barré syndrome, neuralgic amyotrophy, encephalitis, and myelitis, although the mechanism remains unknown. In this study, by using an in vitro blood–brain barrier (BBB) model, we first investigated whether HEV can cross the BBB and whether the quasi-enveloped HEV virions are more permissible to the BBB than the nonenveloped virions. We found that both quasi-enveloped and nonenveloped HEVs can similarly cross the BBB and that addition of proinflammatory cytokine tumor necrosis factor alpha (TNF-α) has no significant effect on the ability of HEV to cross the BBB in vitro. To explore the possible mechanism of HEV entry across the BBB, we tested the susceptibility of human brain microvascular endothelial cells lining the BBB to HEV infection and showed that brain microvascular endothelial cells support productive HEV infection. To further confirm the in vitro observation, we conducted an experimental HEV infection study in pigs and showed that both quasi-enveloped and nonenveloped HEVs invade the central nervous system (CNS) in pigs, as HEV RNA was detected in the brain and spinal cord of infected pigs. The HEV-infected pigs with detectable viral RNA in CNS tissues had histological lesions in brain and spinal cord and significantly higher levels of proinflammatory cytokines TNF-α and interleukin 18 than the HEV-infected pigs without detectable viral RNA in CNS tissues. The findings suggest a potential mechanism of HEV-associated neuroinvasion.

Relevance of Tacrolimus Trough Concentration and Hepatitis E virus Genetic Changes in Kidney Transplant Recipients With Chronic Hepatitis E

“…This hypothesis is supported by the association between a high level of intrahost HEV diversity (in ORF1 and ORF2 regions) and evolution toward chronic hepatitis E. 18 , 25 In addition, a compartmentalization of HEV quasi-species was observed between the blood and cerebrospinal fluid in patients with chronic hepatitis E. 26 , 27 Such compartmentalization argue for extrahepatic HEV replication in the central nervous system, in line with other clinical and in vitro studies. 28 , 29 , 30 Recent studies suggested that HEV could also replicate in human intestines. Indeed, HEV can replicate in enterocytes in vitro and be detected in intestinal tissue samples from patients with chronic HEV infection.…”

Hepatitis E virus infects human testicular tissue and Sertoli cells

“…Notably, the virus strains we used here are all wild-type HEVs isolated from stool samples of hepatitis E patients or infected animals, and wild-type strains are known to be extremely difficult to culture in cells. Previous studies frequently used the Kernow-C1 p6 cloned virus for in vitro replication/infection [ 10 , 14 ]. It seems that this strain has a more favorable in vitro growth efficiency in hepatic cells or extrahepatic cells than wild-type HEVs.…”

“…During chronic HEV infection, HEV replicates more efficiently under immunosuppressant treatment and extrahepatic replication and manifestations can frequently occur [ 4 , 5 ]. HEV replication outside of the liver and hepatocytes has been reported in cell culture models, including neuronal [ 6 ], renal [ 7 ] and placental cell lines [ 8 ], as well as in tissues of hepatitis E patients or experimentally infected animals such as kidney [ 9 ], brain [ 10 ], cerebrospinal fluid [ 11 ], urine [ 12 ], placenta [ 13 ] and intestine [ 14 ]. In recent years, the presence of HEV in human semen samples has aroused broad interest in the field.…”

Isolation and characterization of a novel rodent hepevirus in long-tailed dwarf hamsters (Cricetulus longicaudatus) in China

“…It was reported that some individuals infected with HEV also experience neurological complications such as Guillain-Barré syndrome, neuralgic amyotrophy, encephalitis, and myelitis [63][64][65][66][67]. As CI-2018QH was detected in the brain tissue of a Cricetulus longicaudatus, to confirm the probable neurologic tropism, we had attempted isolation of the virus by intracranial inoculation of 3-day-old ICR suckling mice with WL30G and WL48G specimens.…”