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Published on: November 2, 2020
A CRISPR knockout mouse library for functional genomics in influenza research
Hiroshi Ueki1, Yuriko Tomita2, Calvin Duong3
1The University of Tokyo, Pandemic Preparedness, Infection and Advanced Research Center, Tokyo 108-8639, Japan; International Virus Infectious Disease Research Center, National Institute of Global Health and Medicine, Japan Institute for Health Security (JIHS), Tokyo 162-8655, Japan; Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Abstract:
Functional validation of host factors in whole-animal models is a major bottleneck in virology; it hinders the translation of data from in vitro studies into a deeper understanding of the viral life cycle and pathogenesis. To address this challenge, we developed a systematic in vivo screening platform for influenza A virus. This platform comprises a library of 84 CRISPR-Cas9-generated gene-modified mouse lines targeting host factors prioritized from the literature and in vitro small interfering RNA (siRNA) screening studies. Using this resource, we identified 17 host factors whose genetic ablation conferred resistance to influenza A virus infection. Further studies of two of these factors, Arhgef28 and Lasp1, revealed distinct protective mechanisms against influenza A virus. We offer this mouse library to the research community as a powerful platform for studying virus-host interactions in a physiologically relevant context.
Insights
Researchers developed a mouse model system to identify host factors influencing influenza A virus infection. This study identified 17 new host factors that, when removed, make mice resistant to the flu virus.
Area of Science:
- Virology
- Genetics
- Immunology
Background:
- Validating host factors for viral diseases in animal models is challenging.
- This limits understanding of viral life cycles and disease development.
Purpose of the Study:
- To create a screening platform for identifying host factors in influenza A virus infection.
- To overcome limitations in translating in vitro findings to whole-animal models.
Main Methods:
- Developed a screening platform using 84 CRISPR-Cas9 gene-modified mouse lines.
- Targeted host factors identified from literature and in vitro studies.
- Screened for resistance to influenza A virus infection.
Main Results:
- Identified 17 host factors conferring resistance to influenza A virus upon genetic ablation.
- Detailed studies on Arhgef28 and Lasp1 revealed distinct protective mechanisms.
- Established a valuable resource for studying virus-host interactions.
Conclusions:
- The developed mouse library is a powerful platform for in vivo host factor screening.
- Provides a physiologically relevant context for understanding influenza A virus pathogenesis.
- Facilitates the discovery of novel antiviral targets.
