Novel transcription and replication-competent virus-like particles system modelling the Nipah virus life cycle

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ABSTRACT

Nipah virus (NiV), a highly pathogenic Henipavirus in humans, has been responsible for annual outbreaks in recent years. Experiments involving live NiV are highly restricted to biosafety level 4 (BSL-4) laboratories, which impedes NiV research. In this study, we developed transcription and replication-competent NiV-like particles (trVLP-NiV) lacking N, P, and L genes. This trVLP-NiV exhibited the ability to infect and continuously passage in cells ectopically expressing N, P, and L proteins while maintaining stable genetic characteristics. Moreover, the trVLP-NiV displayed a favourable safety profile in hamsters. Using the system, we found the NiV nucleoprotein residues interacting with viral RNA backbone affected viral replication in opposite patterns. This engineered system was sensitive to well-established antiviral drugs, innate host antiviral factors, and neutralizing antibodies. We then established a high-throughput screening platform utilizing the trVLP-NiV, leading to the identification of tunicamycin as a potential anti-NiV compound. Evidence showed that tunicamycin inhibited NiV replication by decreasing the infectivity of progeny virions. In conclusion, this trVLP-NiV system provided a convenient and versatile molecular tool for investigating NiV molecular biology and conducting antiviral drug screening under BSL-2 conditions. Its application will contribute to the development of medical countermeasures against NiV infections.

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A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays.

Zhang, Chung, Oldenburg (1999)

The ability to identify active compounds (³hits²) from large chemical libraries accurately and rapidly has been the ultimate goal in developing high-throughput screening (HTS) assays. The ability to identify hits from a particular HTS assay depends largely on the suitability or quality of the assay used in the screening. The criteria or parameters for evaluating the ³suitability² of an HTS assay for hit identification are not well defined and hence it still remains difficult to compare the quality of assays directly. In this report, a screening window coefficient, called ³Z-factor,² is defined. This coefficient is reflective of both the assay signal dynamic range and the data variation associated with the signal measurements, and therefore is suitable for assay quality assessment. The Z-factor is a dimensionless, simple statistical characteristic for each HTS assay. The Z-factor provides a useful tool for comparison and evaluation of the quality of assays, and can be utilized in assay optimization and validation.

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Analysis of in vivo dynamics of influenza virus infection in mice using a GFP reporter virus.

Balaji Manicassamy, Santhakumar Manicassamy, Alan Belicha-Villanueva … (2010)

Influenza A virus is being extensively studied because of its major impact on human and animal health. However, the dynamics of influenza virus infection and the cell types infected in vivo are poorly understood. These characteristics are challenging to determine, partly because there is no efficient replication-competent virus expressing an easily traceable reporter gene. Here, we report the generation of a recombinant influenza virus carrying a GFP reporter gene in the NS segment (NS1-GFP virus). Although attenuated when compared with wild-type virus, the NS1-GFP virus replicates efficiently in murine lungs and shows pathogenicity in mice. Using whole-organ imaging and flow cytometry, we have tracked the dynamics of influenza virus infection progression in mice. Imaging of murine lungs shows that infection starts in the respiratory tract in areas close to large conducting airways and later spreads to deeper sections of the lungs. In addition to epithelial cells, we found GFP-positive antigen-presenting cells, such as CD11b(+)CD11c(-), CD11b(-)CD11c(+), and CD11b(+)CD11c(+), as early as 24 h after intranasal infection. In addition, a significant proportion of NK and B cells were GFP positive, suggesting active infection of these cells. We next tested the effects of the influenza virus inhibitors oseltamivir and amantadine on the kinetics of in vivo infection progression. Treatment with oseltamivir dramatically reduced influenza infection in all cell types, whereas, surprisingly, amantadine treatment more efficiently blocked infection in B and NK cells. Our results demonstrate high levels of immune cells harboring influenza virus antigen during viral infection and cell-type-specific effects upon treatment with antiviral agents, opening additional avenues of research in the influenza virus field.

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EphrinB2 is the entry receptor for Nipah virus, an emergent deadly paramyxovirus.

Oscar Negrete, Ernest Levroney, Hector Aguilar … (2005)

Nipah virus (NiV) is an emergent paramyxovirus that causes fatal encephalitis in up to 70 percent of infected patients, and there is evidence of human-to-human transmission. Endothelial syncytia, comprised of multinucleated giant-endothelial cells, are frequently found in NiV infections, and are mediated by the fusion (F) and attachment (G) envelope glycoproteins. Identification of the receptor for this virus will shed light on the pathobiology of NiV infection, and spur the rational development of effective therapeutics. Here we report that ephrinB2, the membrane-bound ligand for the EphB class of receptor tyrosine kinases (RTKs), specifically binds to the attachment (G) glycoprotein of NiV. Soluble Fc-fusion proteins of ephrinB2, but not ephrinB1, effectively block NiV fusion and entry into permissive cell types. Moreover, transfection of ephrinB2 into non-permissive cells renders them permissive for NiV fusion and entry. EphrinB2 is expressed on endothelial cells and neurons, which is consistent with the known cellular tropism for NiV. Significantly, we find that NiV-envelope-mediated infection of microvascular endothelial cells and primary cortical rat neurons is inhibited by soluble ephrinB2, but not by the related ephrinB1 protein. Cumulatively, our data show that ephrinB2 is a functional receptor for NiV.

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Author and article information

Journal

Journal ID (nlm-ta): Emerg Microbes Infect

Journal ID (iso-abbrev): Emerg Microbes Infect

Title: Emerging Microbes & Infections

Publisher: Taylor & Francis

ISSN (Electronic): 2222-1751

Publication date (Electronic, pub): 12 June 2024

Publication date (Electronic, collection): 2024

Publication date PMC-release: 12 June 2024

Volume: 13

Issue: 1

Electronic Location Identifier: 2368217

Affiliations

[a ]Zhongshan School of Medicine, Sun Yat-sen University , Guangzhou, People’s Republic of China

[b ]Institute of Infectious Diseases, Guangzhou Eighth people’s Hospital, Guangzhou Medical University , Guangzhou, People’s Republic of China

[c ]School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University , Shenzhen, People’s Republic of China

[d ]Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences , Guangzhou, People’s Republic of China

[e ]Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety , Shenzhen, People’s Republic of China

[f ]Guangdong Provincial Highly Pathogenic Microorganism Science Data Centre , Guangzhou, People’s Republic of China

Author notes

[CONTACT ] Linna Liu liulinna7@ 123456126.com Institute of Infectious Diseases, Guangzhou Eighth people’s Hospital, Guangzhou Medical University , Guangzhou, People’s Republic of China

Jun Qian qianj9@ 123456mail.sysu.edu.cn Zhongshan School of Medicine, Sun Yat-sen University , Guangzhou, People’s Republic of China; School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, People’s Republic of China; Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen, People’s Republic of China; Guangdong Provincial Highly Pathogenic Microorganism Science Data Centre, Guangzhou, People’s Republic of China

Supplemental data for this article can be accessed online at https://doi.org/10.1080/22221751.2024.2368217

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Quan Liu https://orcid.org/0000-0003-3411-3196

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Publisher ID: 2368217

DOI: 10.1080/22221751.2024.2368217

PMC ID: 11229746

PubMed ID: 38865205

SO-VID: 08c359f4-907b-42c0-a651-07d75d5e3650

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This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

Novel transcription and replication-competent virus-like particles system modelling the Nipah virus life cycle

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Drug Repurposing

Most cited references 60

A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays.

Analysis of in vivo dynamics of influenza virus infection in mice using a GFP reporter virus.

EphrinB2 is the entry receptor for Nipah virus, an emergent deadly paramyxovirus.

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