Virulence and Cross-Protection Conferred by an Attenuated Genotype I-Based Chimeric Japanese Encephalitis Virus Strain Harboring the E Protein of Genotype V in Mice

Xia, Qiqi; Zhang, Yan; Yang, Yang; Ma, Xiaochun; Guan, Zhixin; Zhang, Junjie; Li, Zongjie; Liu, Ke; Li, Beibei; Shao, Donghua; Qiu, Yafeng; Wei, Jianchao; Ma, Zhiyong

doi:10.1128/spectrum.01990-22

Cited by 5 publications

(2 citation statements)

References 62 publications

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“…JEV NSW/22 retains E at position 138, and this amino acid has been identified by several studies as a principal neurovirulence determinant (90)(91)(92)(93)(94), with a role in neuronal cell binding hypothesized (37). YFV 17D has a valine (V) at this residue, possibly contributing to reduced neurovirulence (95). NS1 and NS2A have been implicated in neuroinvasion, but not neurovirulence (88).…”

Section: Discussionmentioning

confidence: 99%

Neurovirulence of the Australian outbreak Japanese Encephalitis virus genotype 4 is lower compared to genotypes 2 and 3 in mice and human cortical brain organoids

Nguyen

Stewart

Tang

et al. 2023

Preprint

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Human infections with Japanese encephalitis virus (JEV) are a leading cause of viral encephalitis, with ≈70,000 symptomatic cases (≈40% with long-term neurological sequelae) and ≈20,000 deaths reported annually, primarily in Asia and the Western Pacific. An outbreak of JEV genotype 4 was also recently reported in Australia, with an isolate (JEVNSW/22) obtained from a stillborn piglet. Herein we characterize the neuropathology of JEVNSW/22, JEVFU (genotype 2) and JEVNakayama (genotype 3) in adult C57BL/6J wild-type mice, mice deficient in interferon regulatory factor 7 (IRF7-/-), and mice deficient in the type I interferon receptor (IFNAR-/-). In C57BL/6J and IRF7-/- mice with lethal outcomes, viral antigen was detected by immunohistochemistry in inter alia the cortex, thalamus and hippocampus. In these mice, histological lesions included neuronal degeneration, neuronal vacuolation, perivascular cuffing, leukocyte infiltrates, hemorrhage, and microgliosis, with apoptosis and astrocyte activation detected by immunohistochemistry. Microgliosis and hemorrhage persisted in some surviving mice ≈3-4 weeks post infection. JEV was universally lethal in IFNAR-/ mice by day 3 with histological signs of brain hemorrhage, but produced no other detectable brain infection or lesions, with NS1 readily detected in blood vessels, but not neurons, by immunohistochemistry. All JEV isolates showed robust productive cytopathic infection of human cortical brain organoids (hBOs), as well as a human neural progenitor cell line (RENcell VM). We thus describe a new IRF7-/-mouse model for JEV, which shows increased penetrance of lethal neuroinvasiveness and recapitulates many aspects human disease. Although less virulent in IRF7-/- mice, JEVNSW/22 retained the capacity to cause lethal encephalitis and to replicate and destroy human neuronal cells.

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Section: Discussionmentioning

confidence: 99%

Neurovirulence of the Australian outbreak Japanese Encephalitis virus genotype 4 is lower compared to genotypes 2 and 3 in mice and human cortical brain organoids

Nguyen

Stewart

Tang

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…JEV NSW/22 retains E at position 138, and this amino acid has been identified by several studies as a principal virulence determinant [94][95][96][97][98] , with a role in neuronal cell binding hypothesized 42 . YFV 17D has a valine (V) at this residue, possibly contributing to reduced virulence 99 . NS1 and NS2A have been implicated in JEV virulence 92 .…”

Section: Data Availabilitymentioning

confidence: 99%

Characterisation of a Japanese Encephalitis virus genotype 4 isolate from the 2022 Australian outbreak

Nguyen,

Gyawali,

Stewart

et al. 2024

npj Viruses

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Human infections with the Japanese encephalitis virus (JEV) are a leading cause of viral encephalitis. An unprecedented outbreak of JEV genotype 4 was recently reported in Australia, with an isolate (JEVNSW/22) obtained from a stillborn piglet brain. Herein we conduct a thorough characterization of JEVNSW/22 in three different mouse strains and in human cortical brain organoids (hBOs), and determined the ability of JEVNSW/22 to be neutralized by sera from humans vaccinated with IMOJEV. JEVNSW/22 was less virulent than JEVFU (genotype 2) and JEVNakayama (genotype 3) in C57BL/6J mice and in interferon regulatory factor 7 deficient (Irf7−/−) mice, with infection of wild-type and knockout murine embryonic fibroblasts indicating JEVNSW/22 is more sensitive to type I interferon responses. Irf7−/− mice provide a new model for JEVNSW/22, showing higher viremia levels compared to C57BL/6J mice, and allowing for lethal neuroinvasive infection. All JEV strains were universally lethal in Ifnar−/− mice by day 3, with histological signs of brain hemorrhage, but no other lesions. There were no indications of brain infection in Ifnar−/− mice, with viral protein detected in blood vessels, but not neurons. All JEV isolates showed robust cytopathic infection of human cortical brain organoids, albeit lower for JEVNSW/22. IMOJEV vaccination in humans induced antibodies capable of neutralizing JEVNSW/22, although, for all JEV strains, cross-neutralization titers declined with increasing divergence from IMOJEV in the envelope amino acid sequences. Overall, our study establishes JEVNSW/22 mouse and hBO models of infection, allowing for possible lethal neuroinvasive infection in mice that was rarer than for other JEV genotypes. JEV vaccination regimens may afford protection against this newly emerged JEV genotype 4 strain, although neutralizing antibody responses are sub-optimal.

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Isolation and identification of a duck-derived Japanese encephalitis virus and evaluation of its virulence in mice

Li,

Zhang,

Tang

et al. 2024

Veterinary Microbiology

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Virulence and Cross-Protection Conferred by an Attenuated Genotype I-Based Chimeric Japanese Encephalitis Virus Strain Harboring the E Protein of Genotype V in Mice

Abstract: The GV JEV showed an increase in epidemic areas, which exhibited higher pathogenicity in mice than the prevalent GI and GIII strains. We replaced a recombinant chimeric GI-GV JEV (JEV-GI/V) strain to determine the role of the structural proteins in virulence and cross-protection.

Cited by 5 publications

References 62 publications

Neurovirulence of the Australian outbreak Japanese Encephalitis virus genotype 4 is lower compared to genotypes 2 and 3 in mice and human cortical brain organoids

Neurovirulence of the Australian outbreak Japanese Encephalitis virus genotype 4 is lower compared to genotypes 2 and 3 in mice and human cortical brain organoids

Characterisation of a Japanese Encephalitis virus genotype 4 isolate from the 2022 Australian outbreak

Isolation and identification of a duck-derived Japanese encephalitis virus and evaluation of its virulence in mice

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