Expanding the tolerance of segmented Influenza A Virus genome using a balance compensation strategy

Xiujuan Zhao; Xiaojing Lin; Ping Li; Zinuo Chen; Chengcheng Zhang; Balaji Manicassamy; Lijun Rong; Qinghua Cui; Ruikun Du

doi:10.1371/journal.ppat.1010756

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Expanding the tolerance of segmented Influenza A Virus genome using a balance compensation strategy

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Expanding the tolerance of segmented Influenza A Virus genome using a balance compensation strategy

Xiujuan Zhao, Xiaojing Lin, Ping Li, Zinuo Chen, Chengcheng Zhang, Balaji Manicassamy, Lijun Rong, Qinghua Cui and Ruikun Du

PLoS pathogens, Vol.18(8), pp.e1010756-e1010756

08/01/2022

DOI: 10.1371/journal.ppat.1010756

PMCID: PMC9380948

PMID: 35926068

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Abstract

Reporter viruses provide powerful tools for both basic and applied virology studies, however, the creation and exploitation of reporter influenza A viruses (IAVs) have been hindered by the limited tolerance of the segmented genome to exogenous modifications. Interestingly, our previous study has demonstrated the underlying mechanism that foreign insertions reduce the replication/transcription capacity of the modified segment, impairing the delicate balance among the multiple segments during IAV infection. In the present study, we developed a “balance compensation” strategy by incorporating additional compensatory mutations during initial construction of recombinant IAVs to expand the tolerance of IAV genome. As a proof of concept, promoter-enhancing mutations were introduced within the modified segment to rectify the segments imbalance of a reporter influenza PR8-NS-Gluc virus, while directed optimization of the recombinant IAV was successfully achieved. Further, we generated recombinant IAVs expressing a much larger firefly luciferase (Fluc) by coupling with a much stronger compensatory enhancement, and established robust Fluc-based live-imaging mouse models of IAV infection. Our strategy feasibly expands the tolerance for foreign gene insertions in the segmented IAV genome, which opens up better opportunities to develop more versatile reporter IAVs as well as live attenuated influenza virus-based vaccines for other important human pathogens.

Details

Title: Subtitle: Expanding the tolerance of segmented Influenza A Virus genome using a balance compensation strategy
Creators: Xiujuan Zhao - Shandong University of Traditional Chinese Medicine
Xiaojing Lin
Ping Li
Zinuo Chen
Chengcheng Zhang
Balaji Manicassamy
Lijun Rong
Qinghua Cui
Ruikun Du
Resource Type: Journal article
Publication Details: PLoS pathogens, Vol.18(8), pp.e1010756-e1010756
DOI: 10.1371/journal.ppat.1010756
PMID: 35926068
PMCID: PMC9380948
NLM abbreviation: PLoS Pathog
ISSN: 1553-7366
eISSN: 1553-7374
Publisher: Public Library of Science
Grant note: DOI: 10.13039/501100001809, name: National Natural Science Foundation of China, award: 82104134; DOI: 10.13039/100014103, name: Key Technology Research and Development Program of Shandong, award: 2020CXGC010505
Language: English
Date published: 08/01/2022
Academic Unit: Microbiology and Immunology
Record Identifier: 9984297436802771

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