New Detection of Locally Acquired Japanese Encephalitis Virus Using Clinical Metagenomics, New South Wales, Australia

Maamary, Joel; Maddocks, Susan; Barnett, Yael; Wong, Stephen T.C.; Rodríguez, Michael; Hueston, Linda; Jeoffreys, Neisha; Eden, John-Sebastian; Dwyer, Dominic E.; Floyd, Tony; Plit, M.; Kok, Jen; Brew, Bruce J.

doi:10.3201/eid2903.220632

Cited by 7 publications

(7 citation statements)

References 14 publications

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“…Overall, the lesions in C57BL/6J and Irf7 -/- mouse brains are consistent with H&E detectable lesions in post-mortem human JEV infected brains (6, 45, 56–58). To provide additional potential insights into the nature of the cellular infiltrates (e.g.…”

Section: Resultssupporting

confidence: 75%

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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: Resultssupporting

confidence: 75%

“…Overall, the lesions in C57BL/6J and IRF7 -/mouse brains are consistent with H&E detectable lesions in post-mortem human JEV infected brains 6,38,[49][50][51] .…”

Section: Jev Causes Severe Histological Lesions In C57bl/6j and Irf7 ...supporting

confidence: 62%

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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“…To overcome this problem, increasing efforts have been directed in recent years to identify the causes of encephalitis using metagenomic next-generation sequencing. 12 13 14 In particular, Wilson, et al 15 reported in a prospective study that an additional infectious aetiology could be identified in 22% (13/58) of 208 encephalitis patients that could not be detected by conventional methods. Therefore, the future introduction of such diagnostic methods can greatly contribute to the exploration of the causes of encephalitis in Korean children.…”

Section: Discussionmentioning

confidence: 99%

Aetiology and Prognosis of Encephalitis in Korean Children: A Retrospective Single-Centre Study, 2005–2020

Kim,

Baek

et al. 2024

Yonsei Med J

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Purpose Encephalitis is a heterogeneous syndrome that occurs in childhood and is not rare. However, epidemiological studies of encephalitis based on the International Encephalitis Consortium (ICS) and expert recommendations are lacking. We investigated the aetiology and prognosis of encephalitis in Korean children. Materials and Methods This retrospective study included children aged <19 years hospitalised for encephalitis at Severance Children’s Hospital between 2005 and 2020. The 2013 ICS criteria were used to diagnose encephalitis, and causality was classified according to the site from which the specimen was obtained. Neurological sequelae were categorised using the modified Rankin Scale (mRS) score. Results In total, 551 children were included, with 7% classified as possible, 77% as probable, and 15% as proven cases. A cause was identified in 42% of the cases (n=222), with viruses being the most common (42%), followed by bacteria (38%) and autoimmune encephalitis (12%). In cases of proven/probable encephalitis (n=65), bacteria accounted for 52%, followed by viruses (25%) and autoimmune encephalitis (22%). In cases with a single pathogen, the anti-N-methyl-D-aspartate receptor autoantibody (n=14) was the most common, followed by Group B streptococcus (n=13), herpes simplex virus (n=11), enterovirus (n=4), and others. Approximately 37% of patients had severe sequelae (mRS score ≥3) at discharge, which decreased to 31% 6 months after discharge. Conclusion This large-scale study showed that autoimmune and infectious causes accounted for a significant proportion of encephalitis in Korean children. Further studies are needed to determine whether early targeted treatment following early diagnosis leads to a favourable prognosis in these populations.

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“…The RAPIDprep assay was designed specifically as a rapid response tool, and it has proven to be effective in novel disease investigations, including identifying the first cases of the emergent Japanese encephalitis virus during the 2021-22 outbreak in south-eastern Australia [44][45][46] and characterizing the first cases of COVID-19 in NSW [35]. The assay has also been used to investigate non-human diseases, and it was critical to the genome recovery of a novel Hendra virus variant detected initially from a fatal equine infection by pan-paramyxovirus RT-PCR [2].…”

Section: Discussionmentioning

confidence: 99%

RAPIDprep: A Simple, Fast Protocol for RNA Metagenomic Sequencing of Clinical Samples

Tulloch

Kim

Sikazwe

et al. 2023

Viruses

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Emerging infectious disease threats require rapid response tools to inform diagnostics, treatment, and outbreak control. RNA-based metagenomics offers this; however, most approaches are time-consuming and laborious. Here, we present a simple and fast protocol, the RAPIDprep assay, with the aim of providing a cause-agnostic laboratory diagnosis of infection within 24 h of sample collection by sequencing ribosomal RNA-depleted total RNA. The method is based on the synthesis and amplification of double-stranded cDNA followed by short-read sequencing, with minimal handling and clean-up steps to improve processing time. The approach was optimized and applied to a range of clinical respiratory samples to demonstrate diagnostic and quantitative performance. Our results showed robust depletion of both human and microbial rRNA, and library amplification across different sample types, qualities, and extraction kits using a single workflow without input nucleic-acid quantification or quality assessment. Furthermore, we demonstrated the genomic yield of both known and undiagnosed pathogens with complete genomes recovered in most cases to inform molecular epidemiological investigations and vaccine design. The RAPIDprep assay is a simple and effective tool, and representative of an important shift toward the integration of modern genomic techniques with infectious disease investigations.

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New Detection of Locally Acquired Japanese Encephalitis Virus Using Clinical Metagenomics, New South Wales, Australia

Cited by 7 publications

References 14 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

Aetiology and Prognosis of Encephalitis in Korean Children: A Retrospective Single-Centre Study, 2005–2020

RAPIDprep: A Simple, Fast Protocol for RNA Metagenomic Sequencing of Clinical Samples

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