Thursday, April 10, 2025
4/10/2025
A gerbil model to delineate the mechanism of hepatitis E virus extrahepatic pathogenesis - Summary: Hepatitis E virus (HEV) is an important but extremely understudied human pathogen, causing acute and chronic hepatitis E, high mortality during pregnancy, neurological sequelae, and foodborne hepatitis. According to WHO, estimated 20 million HEV infections occur each year, leading to >3.3 million cases and >44,000 deaths annually. HEV infection is associated with numerous extrahepatic manifestations including a range of neurological sequelae, which is associated with HEV-3 (mainly) and HEV-4 (lesser extent) infection and occur in ~5.5% of HEV-infected patients. HEV-associated neurological sequelae is an emerging clinical problem, but the underlying mechanism(s) of HEV-associated extrahepatic pathogenesis is unknown. In preliminary studies, we showed that HEV infects cells in the neurovascular unit (NVU) including brain microvascular endothelial cells, microglia, and astrocyte, and that HEV causes pathological lesions in CNS in infected pigs with significantly higher levels of proinflammatory cytokines IL-18 and TNF-ɑ in pigs with detectable HEV RNA in brains than in pigs with no detectable HEV RNA in brains. Our pilot study showed that gerbils are highly susceptible to infection by HEV-1, HEV-3 and HEV-4. Our long-term goal is to delineate the mechanisms of HEV-associated extrahepatic pathogenesis. In aim 1, we hypothesize that HEV induces extrahepatic neurological injuries via induction of pyroptosis by infecting NVU cells to release proinflammatory cytokines leading to neuroinflammation and neurological injuries. We aim to: (1) determine the effect of HEV-3-induced pyroptosis in NVU cells; (2) identify the mechanisms of HEV-induced pyroptosis in NVU cells particularly via caspase 1-mediated canonical pathway; (3) identify HEV-specific pyroptosis-associated proinflammatory cytokines in NVU cells; (4) determine whether HEV-induced pyroptosis in NVU cells is HEV genotype-specific. We anticipate that HEV induces pyroptosis in microglia, astrocyte, and neuronal cells; that HEV induces pyroptosis through caspase 1-mediated canonical pathway to produce proinflammatory cytokines to cause acute cell death; that only HEV-3/HEV-4, but not HEV-1, induce pyroptosis in NVU cells. In aim 2, we hypothesize that HEV induces neurological sequelae through injuries of neural cells via induction of pyroptosis in brain and spinal cord tissues. We aim to: (1) infect gerbils with HEV-1, HEV-3 and HEV-4, respectively, to delineate the mechanism of neuroinflammation and neurological injuries attributable to each HEV genotype; (2) define HEV-specific neurological lesions in CNS and correlate neurological lesions with hepatic lesions; (3) identify the mechanism(s) of HEV-induced pyroptosis via the caspase-1–mediated pyroptosis in brain by using a caspase 1 inhibitor (VX-765) in HEV-infected gerbils. We expect that we will identify HEV-specific neuroinflammation and neurological lesions and types of neural cells involved in pyroptosis, that HEV-induced neurological lesions in brain occur mainly in HEV-3/HEV-4, but not in HEV-1, infected gerbils, that HEV induces pyroptosis in brains via the caspase 1-mediated canonical pathway which will involve in activation of inflammasome to release proinflammatory cytokines IL-1β, IL-18, and TNF-ɑ, and that treatment of HEV-infected gerbils with caspase 1 inhibitor VX-765 will reduce the amounts of neuroinflammation and lesions in CNS tissues compared to controls. The information will inform potential therapeutic targets of HEV-related neurological sequelae.
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