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Conserved replication strategies facilitate the cross-species

ABSTRACT: A significant number of pandemics, endemics and even sporadic outbreaks trace back to zoonotic spillovers of emerging RNA viruses. Especially, zoonotic infections with the distantly related hepatitis E virus (HEV, species Paslahepevirus balayani) from various animal origins, such as pigs, deer, wild boar, rabbits and camelids, are well-documented and account for 20 million acute hepatitis cases each year. The detection of HEV RNA in rats surrounding pig farms suggest that they serve as an additional reservoir and source of zoonotic HEV infection. Moreover, the rising number of zoonotic spillover events with the distantly related rat hepatitis E virus (ratHEV, species Rocahepevirus ratti) underscores the urgent need to elucidate the role of rats as a reservoir for HEV infection and in the transmission dynamics of viruses within the family Hepeviridae. Herein, we introduce a novel HEV reverse zoonosis model based on the infection of rat liver cells, which supports completion of the entire HEV replication cycle. RNA sequencing analyses unraveled distinct host responses to HEV infection characterized by minimal activation of innate immune responses. Importantly, host-directed antivirals targeting entry factors previously identified in human host cells effectively restricted HEV infection in rat liver cells. Furthermore, human-specific genomic rearrangements conferred increased fitness across human and rat hepatoma cells. In conclusion, our study indicates conserved viral replication mechanisms of HEV between rats and humans, providing valuable insights into the molecular mechanisms of zoonotic spillover across species.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE329031 | GEO | 2026/05/01

REPOSITORIES: GEO

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Project description:The hepatitis E virus (HEV; species Paslahepevirus balayani) is a common human pathogenic and zoonotic virus that can cause both acute fulminant and chronic hepatitis. Despite its reputation as a hepatotropic virus, HEV infection is also associated with a number of extrahepatic diseases, including kidney disorders. However, the extent to which HEV replicates in kidney cells remains unclear. The present study aims to investigate the capacity of HEV to propagate in kidney cells in vitro and to assess whether HEV displays mutational signatures that correlate with compartmentalisation in vivo. We use HEV cell culture models to study the replication cycle and the effect of antivirals in human kidney cell lines and primary cells. In addition, we identified patients with chronic HEV infection (n = 9) from which we then sequenced viral RNA of urine, stools and plasma to analyse the viral sequence composition, to assessintra-host diversity and compartmentalisation(n = 2). A wide range of human kidney cell lines as well as primary cells supports viral entry, replication and propagation of HEV in vitro. Interestingly, the broad-spectrum antiviral ribavirin was less effective in inhibiting HEV replication in some kidney cells. Sequencing of HEV RNA-directed RNA polymerase coding region from plasma, stool and urine and subsequent phylogenetic analysis revealed diversification of HEV into tissue-specific viral subpopulations. In particular, the viruses derived from urine were found to be distinct from those derived from plasma and stool. In conclusion, kidney cells support the propagation of HEV in vitro and exhibit reduced sensitivity to antiviral treatment. Furthermore, HEV patient-derived sequences demonstrated compartmentalisation into distinct clusters that correlated with sample source. Collectively, these data indicate the potential for extrahepatic replication of HEV, which may result in clinically significant disease or serve as a reservoir for patient relapse.

Project description:Background & Aims: Other than hepatitis B or C virus infection, Hepatitis E virus (HEV) infection is generally asymptomatic or leads to acute and self-limiting hepatitis. However, the mechanism of host cell defense against HEV is unclear. Viruses are known to perturb host cellular metabolism to enable their replication and spread. AMP-activated protein kinase (AMPK) activation is crucial for the regulation of cell homeostasis. We thus investigated the role of AMPK in HEV infection. Methods: Huh7, THP1 and HepG2 cells inoculated with infectious HEV viral particle or Huh7 and organoids transfected with in vitro generated subgenomic or full-length GT3 (Kernow-C1 p6 strain) HEV RNA, namely, p6Luc or p6 were used to model HEV infection. Viral replication and genes expression were quantified. Activation of AMPK, innate immune response and autophagy process were assessed. Results: We found HEV infection can trigger AMPK activation by phosphorylation of AMPK at threonine 172 by transfecting HEV viral RNA into host cells or inoculating host cells with infectious HEV viral particle. The activation of AMPK is associated with HEV induced mitochondrial damage and ATP deficiency. Pharmacological activation of AMPK using 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) attenuated HEV replication, which was reversed by an AMPK inhibitor (compound C). Lentivirus-mediated knockdown of AMPK provided further evidence that AMPK has an antiviral effect on HEV replication. These results suggested that AMPK activation is a potent strategy of host cells for HEV clearance. Consistent with its antiviral effect, AMPK activation potentiated the expression of genes with antiviral properties (e.g., IFNs, ISG15, and IRF9) and inhibited inflammatory response (e.g., NF-KB NLRP3 and IL-1β). Meanwhile, HEV and activated AMPK also decreased autophagosome accumulation by decreasing induction of autophagy and autophagic degradation. Consistently, we found inhibition of AMPK efficiently augmented HEV induced autophagosome accumulation, evidenced by a marked increase in LC3II. Our previous study showed that rapamycin, an activator of autophagic induction by inhibiting mTOR, and Bafilomycin A1, an inhibitor of autophagic degradation, has a potent pro-HEV effect under AICAR treatment. Moreover, Wortmannin inhibiting autophagic induction recover AMPK inhibitor induced HEV replication. Together, these results suggested that HEV induced AMPK activation can serve to protect HEV infected cells from HEV infection by attenuating autophagosome and promoting innate immunity. Conclusions: Here we show that HEV infection can activate AMPK phosphorylation, which attenuates autophagosome accumulation and increases innate immune signaling. Thus, the AMPK activation in response to HEV infection is critical in host cells for rapid viral clearance by coordinating autophagic process and establishing persistent antiviral immunity.

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Conserved replication strategies facilitate the cross-species

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