Genome-wide CRISPR screening identifies LRP1 as an entry factor for SFTSV

Chen Xing, Cong Zhang, Zhihao Xu, Yajie Wang, Wanqing Lu, Xiaohan Liu, Yingying Zhang, Jingyuan Ma, Shuqi Yang, Yinan Du, Gang Xu () and Yan Liu ()
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Chen Xing: Anhui Medical University
Cong Zhang: Anhui Medical University
Zhihao Xu: Anhui Medical University
Yajie Wang: Anhui Medical University
Wanqing Lu: Anhui Medical University
Xiaohan Liu: Anhui Medical University
Yingying Zhang: Anhui Medical University
Jingyuan Ma: Anhui Medical University
Shuqi Yang: Anhui Medical University
Yinan Du: Anhui Medical University
Gang Xu: Anhui Medical University
Yan Liu: Anhui Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59305-0

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