Evidence of Hepatitis E virus breaking through the blood–brain barrier and replicating in the central nervous system

Abstract

Neurologic dysfunctions such as Guillain-Barre' syndrome, encephalitis, meningitis and transverse myelitis occur frequently in patients with hepatitis E virus (HEV) infection, and this study was conducted to better characterize the role of HEV in the pathogenesis of neurologic disorders. Genotype 4 strain of swine HEV was used to inoculate Mongolian gerbils. Reverse transcription-nested polymerase chain reaction (RT-nPCR), ELISA, histopathology, ultrastructural pathology and enzyme immunohistochemistry method were conducted to investigate the replication and localization of HEV in the central nervous system (CNS) and the consequent pathological changes. Both positive- and negative-strand HEV RNA was detectable in brain and spinal cord from 7 to 28 dpi (days postinoculation) via RT-nPCR. Various pathological changes such as perineural invasion, neuron necrosis, microglia nodule, lymphocyte infiltration, perivascular cuff and myelin degeneration were observed in HEV-positive brains and spinal cords. Immunohistochemical (IHC) staining targeting on HEV ORF2 protein revealed positive signals concentrated mainly in the cytoplasm of neuron, ependymal epithelium and choroid plexus area. Positive area density of ZO-1 (zonula occludens-1) in brain of HEV-positive gerbils decreased, while the GFAP (glial fibrillary acidic protein) expression was upregulated compared with control groups. These results provide strong evidence that HEV is able to damage the blood-brain barrier (BBB), replicate in brain and spinal cord, and hammer the causative role of HEV in the pathogenesis of neurologic disorders.

Zoonotic Hepatitis E Virus: Classification, Animal Reservoirs and Transmission Routes

“…Finally, HEV RNA was detected in the liver from seven to 42 days post infection, which is consistent with the last days of HEV RNA detection in the swine model [110], suggesting that HEV RNA replication in the Mongolian gerbil is similar to its replication in the swine model. Using this model, a study has also shown that swine HEV-4 is able to cross the blood–brain barrier and replicate in the brain and the spinal cord after experimental infection [111]. Mongolian gerbils could then be useful to study the neurological disorders associated with HEV infection.…”

Acute hepatitis E infection as a cause of unexplained neurological symptoms

“…It has been argued that neural damage is immune mediated (supported by reports of delays between infection and neuropathological presentation),14 that it may result from HEV-evoked autoimmunity (substantiated by links between HEV and autoimmune thyroiditis),15 16 and that HEV can act as a neurotropic agent, directly affecting the central nervous system. The latter is supported by evidence that HEV genotype 4 can cross the blood–brain barrier,17 and the discovery of different HEV quasispecies in the serum and cerebrospinal fluid of a kidney transplant patient 18. Regardless of the pathophysiology, a clear temporal link is demonstrated between HEV infection and neurological disease in case reports, such as this one, throughout the literature.…”

Hepatitis E Virus–Associated Meningoencephalitis in a Lung Transplant Recipient Diagnosed by Clinical Metagenomic Sequencing

“…The timing of neurological manifestations after HEV infection has not been well described, but ranged from 12–60 months in 1 review of 6 cases in immunosuppressed patients. In animal models, HEV is able to cross the blood–brain barrier, replicate in the central nervous system, and cause neuronal necrosis and myelin degeneration [10]. …”