Increased Cleavage of Japanese Encephalitis Virus prM Protein Promotes Viral Replication but Attenuates Virulence

Xiong, Junyao; Yan, Ming; Zhu, Shuo; Zheng, Bohan; Wei, Ning; Yang, Lingen; Si, Youhui; Cao, Shengbo; Ye, Jing

doi:10.1128/spectrum.01417-22

Cited by 6 publications

(4 citation statements)

References 45 publications

(48 reference statements)

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“…The Pre-membrane protein (PrM) is important for viral maturation, and mutant variants of PrM have shown increased rates of replication [ 69 ], however the selective impacts of the mutation observed in this study (143 (Gly > Arg)) is unknown.…”

Section: Resultsmentioning

confidence: 99%

Comparative genomics of Japanese encephalitis virus shows low rates of recombination and a small subset of codon positions under episodic diversifying selection

Sistrom,

Andrews,

Edwards

2024

PLoS Negl Trop Dis

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Orthoflavivirus japonicum (JEV) is the dominant cause of viral encephalitis in the Asian region with 100,000 cases and 25,000 deaths reported annually. The genome is comprised of a single polyprotein that encodes three structural and seven non-structural proteins. We collated a dataset of 349 complete genomes from a number of public databases, and analysed the data for recombination, evolutionary selection and phylogenetic structure. There are low rates of recombination in JEV, subsequently recombination is not a major evolutionary force shaping JEV. We found a strong overall signal of purifying selection in the genome, which is the main force affecting the evolutionary dynamics in JEV. There are also a small number of genomic sites under episodic diversifying selection, especially in the envelope protein and non-structural proteins 3 and 5. Overall, these results support previous analyses of JEV evolutionary genomics and provide additional insight into the evolutionary processes shaping the distribution and adaptation of this important pathogenic arbovirus.

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Section: Resultsmentioning

confidence: 99%

Comparative genomics of Japanese encephalitis virus shows low rates of recombination and a small subset of codon positions under episodic diversifying selection

Sistrom,

Andrews,

Edwards

2024

PLoS Negl Trop Dis

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“…The T492I mutation conferred an enhancement on viral infectivity, replication and immune resistance, but attenuated the pathogenicity. Similarly, mutation of S78R-K79R-S81R in Japanese Encephalitis Virus increased the cleavage of prM Protein, promoting viral replication but attenuating virulence [56]. These indicate that T492I may be the mutation that contributes to the attenuation of virulence in Omicron sub-variants.…”

Section: Discussionmentioning

confidence: 99%

T492I mutation alters SARS-CoV-2 properties via modulating viral non-structural proteins

Lin

Sha

Trimpert

et al. 2023

Preprint

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The historically dominant SARS-CoV-2 Delta variants and the currently dominant Omicron variants carry a T492I substitution within the non-structural protein 4 (NSP4). Based on a combination of in silico analyses, we predicted that the T492I mutation increases the transmissibility and adaptability of the virus. We confirmed this hypothesis by performing competition experiments in hamsters and in human airway tissue culture models. Furthermore, we show that the T492I mutation also increases the replication capacity and infectiveness of the virus, and improves its ability to evade antibody neutralization induced by previous variants. Mechanistically, the T492I mutation increases cleavage efficiency of the viral main protease NSP5 by enhancing enzyme-substrate binding, resulting in increased production of nearly all non-structural proteins processed by NSP5. Importantly, T492I mutation suppresses the viral RNA associated chemokines in monocytic macrophages, which may contribute to the attenuated pathogenicity of Omicron variants. Our results highlight the importance of the NSP4 mutation in the evolutionary dynamics of SARS-CoV-2 and identify a novel target for the development of broad-spectrum antiviral agents.

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“…Mutants lacking the furin cleavage site or exhibiting altered cleavage specificity have encountered substantial evolutionary pressure, promoting restoration of the wild-type variant 45 . Recent investigations of JEV and ZIKV with mutations in or near the furin cleavage site have demonstrated notable changes in replication and virulence 48,50 . The outcomes of the present study are consistent with existing literature, highlighting that residues within and near the cleavage site play critical roles in modulating specific interactions with furin protease 51 .…”

Section: Tbev Amino Acid Residue Mutations Elucidate the Intermediate...mentioning

confidence: 99%

Divergent pathogenic dynamics of immature tick-borne and mosquito-borne flaviviruses: a paradigm shift in prM-containing particle infectivity

Ruzek,

Holoubek,

Salat

et al. 2024

Preprint

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Maturing flaviviruses undergo pH-dependent conformational changes, transitioning from trimeric pre-membrane protein prM and envelope protein E (prM-E) complexes to dimeric E with cleaved prM. However, little is known about the intermediate maturation stages and whether immature virions contribute to infection. Here we demonstrated that immature prM-containing particles of tick-borne flaviviruses—tick-borne encephalitis virus (TBEV), Langat virus, and louping ill virus—exhibited infectivity in mammalian cells under physiological conditions. This finding challenges the long-standing assumption that prM-containing flavivirus particles are non-infectious, as is the case for immature mosquito-borne flaviviruses, including Usutu virus, Zika virus, and West Nile virus (WNV). In a mouse model, prM-TBEV exhibited high pathogenicity, contrasting with the reduced pathogenicity of prM-WNV. Structural modelling, functional validation, and site-directed mutagenesis revealed interactions within the prM-E complex that influence pH sensitivity, furin cleavage site accessibility, and virus infectivity. This study, therefore, elucidates the distinctive dynamics of infectivity of tick- and mosquito-borne flaviviruses.

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Increased Cleavage of Japanese Encephalitis Virus prM Protein Promotes Viral Replication but Attenuates Virulence

Cited by 6 publications

References 45 publications

Comparative genomics of Japanese encephalitis virus shows low rates of recombination and a small subset of codon positions under episodic diversifying selection

Comparative genomics of Japanese encephalitis virus shows low rates of recombination and a small subset of codon positions under episodic diversifying selection

T492I mutation alters SARS-CoV-2 properties via modulating viral non-structural proteins

Divergent pathogenic dynamics of immature tick-borne and mosquito-borne flaviviruses: a paradigm shift in prM-containing particle infectivity

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