Dataset Information

Structure and antigenicity of divergent Henipavirus fusion glycoproteins

ABSTRACT: A novel henipavirus (HNV) named Langya virus (LayV) was isolated in human patients in China in August 2022. It is closely related to Mòjiāng virus (MojV) and represents the first instance of HNV zoonosis to humans outside of Nipah virus (NiV) and Hendra viruses (HeV). Within this work, mass spectrometry glycoproteomic analysis revealed that although the LayV F protein has reduced glycosylation compared to its NiV and HeV counterparts, a unique glycan was identified positioned at the DIII apex, shielding a previously identified site of vulnerability in NiV F.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Cricetulus Griseus (chinese Hamster) (cricetulus Barabensis Griseus)

SUBMITTER: Kyle Macauslane

LAB HEAD: Benjamin L. Schulz

PROVIDER: PXD039898 | Pride | 2023-05-03

REPOSITORIES: Pride

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Structure and antigenicity of divergent Henipavirus fusion glycoproteins.

Isaacs Ariel A Low Yu Shang YS Macauslane Kyle L KL Seitanidou Joy J Pegg Cassandra L CL Cheung Stacey T M STM Liang Benjamin B Scott Connor A P CAP Landsberg Michael J MJ Schulz Benjamin L BL Chappell Keith J KJ Modhiran Naphak N Watterson Daniel D

Nature communications 20230616 1

In August 2022, a novel henipavirus (HNV) named Langya virus (LayV) was isolated from patients with severe pneumonic disease in China. This virus is closely related to Mòjiāng virus (MojV), and both are divergent from the bat-borne HNV members, Nipah (NiV) and Hendra (HeV) viruses. The spillover of LayV is the first instance of a HNV zoonosis to humans outside of NiV and HeV, highlighting the continuing threat this genus poses to human health. In this work, we determine the prefusion structures ...[more]

PMID: 37328468

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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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