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Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy
Published on: April 3, 2018
Genome-wide CRISPR screening identifies LRP1 as an entry factor for SFTSV
Chen Xing1,2, Cong Zhang1,3, Zhihao Xu4
1Department of Microbiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
Abstract:
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease caused by the SFTS virus (SFTSV), which has high mortality rates and poses a significant threat to public health. To identify potential therapeutic targets against SFTSV, we conduct genome-wide knockout screening, which identifies the previously known host factor CCR2, and reveals prolow-density lipoprotein receptor-related protein 1 (LRP1) as an entry factor for SFTSV. Knockdown or knockout of LRP1 significantly attenuate SFTSV infection in mouse embryonic fibroblasts (MEFs). Additionally, inhibition of LRP1 suppresses SFTSV pseudovirus infection in MEFs, suggesting its role in viral entry. The interaction between the SFTSV glycoprotein Gn and LRP1 via the CLI and CLII domains is revealed by co-IP and surface plasmon resonance (SPR). Moreover, LRP1 antagonists and neutralizing antibodies effectively attenuate SFTSV infection in MEFs. Administration of an LRP1-neutralizing antibody in a lethal male mouse model reduces the viral load, mitigates tissue damage, and improves survival. This study identifies LRP1 as a host entry receptor for SFTSV, providing a target for therapeutic strategy development.
Insights
Severe fever with thrombocytopenia syndrome (SFTS) is a dangerous tick-borne illness. Researchers found that low-density lipoprotein receptor-related protein 1 (LRP1) is crucial for SFTS virus entry, identifying it as a potential therapeutic target.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne viral disease with high mortality.
- SFTS virus (SFTSV) poses a significant public health threat, necessitating the identification of therapeutic targets.
Purpose of the Study:
- To identify host factors involved in SFTSV infection and explore potential therapeutic strategies.
- To elucidate the role of low-density lipoprotein receptor-related protein 1 (LRP1) in SFTSV entry and pathogenesis.
Main Methods:
- Genome-wide knockout screening to identify host factors.
- Knockdown and knockout experiments in mouse embryonic fibroblasts (MEFs).
- Co-immunoprecipitation (co-IP) and surface plasmon resonance (SPR) to analyze protein interactions.
- In vivo studies using a lethal mouse model.
Main Results:
- Genome-wide screening identified LRP1 as a critical host entry factor for SFTSV.
- LRP1 knockdown or knockout significantly attenuated SFTSV infection in MEFs.
- LRP1 antagonists and neutralizing antibodies effectively inhibited SFTSV infection.
- Administration of an LRP1-neutralizing antibody improved survival in a lethal mouse model by reducing viral load and tissue damage.
Conclusions:
- Low-density lipoprotein receptor-related protein 1 (LRP1) is identified as a host entry receptor for SFTSV.
- LRP1 presents a promising target for the development of novel therapeutic strategies against SFTSV infection.
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