Engineering antiviral immune-like systems for autonomous virus detection and inhibition in mice

Yidan Wang, Ying Xu, Chee Wah Tan, Longliang Qiao, Wan Ni Chia, Hongyi Zhang, Qin Huang, Zhenqiang Deng, Ziwei Wang, Xi Wang, Xurui Shen, Canyu Liu, Rongjuan Pei, Yuanxiao Liu, Shuai Xue, Deqiang Kong, Danielle E. Anderson, Fengfeng Cai, Peng Zhou, Lin-Fa Wang () and Haifeng Ye ()
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Yidan Wang: East China Normal University
Ying Xu: East China Normal University
Chee Wah Tan: Duke-NUS Medical School
Longliang Qiao: East China Normal University
Wan Ni Chia: Duke-NUS Medical School
Hongyi Zhang: Tongji University
Qin Huang: East China Normal University
Zhenqiang Deng: East China Normal University
Ziwei Wang: East China Normal University
Xi Wang: Chinese Academy of Sciences
Xurui Shen: Chinese Academy of Sciences
Canyu Liu: University of Chinese Academy of Sciences
Rongjuan Pei: Chinese Academy of Sciences
Yuanxiao Liu: East China Normal University
Shuai Xue: East China Normal University
Deqiang Kong: East China Normal University
Danielle E. Anderson: Duke-NUS Medical School
Fengfeng Cai: Tongji University
Peng Zhou: Chinese Academy of Sciences
Lin-Fa Wang: Duke-NUS Medical School
Haifeng Ye: East China Normal University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract The ongoing COVID-19 pandemic has demonstrated that viral diseases represent an enormous public health and economic threat to mankind and that individuals with compromised immune systems are at greater risk of complications and death from viral diseases. The development of broad-spectrum antivirals is an important part of pandemic preparedness. Here, we have engineer a series of designer cells which we term autonomous, intelligent, virus-inducible immune-like (ALICE) cells as sense-and-destroy antiviral system. After developing a destabilized STING-based sensor to detect viruses from seven different genera, we have used a synthetic signal transduction system to link viral detection to the expression of multiple antiviral effector molecules, including antiviral cytokines, a CRISPR-Cas9 module for viral degradation and the secretion of a neutralizing antibody. We perform a proof-of-concept study using multiple iterations of our ALICE system in vitro, followed by in vivo functionality testing in mice. We show that dual output ALICESaCas9+Ab system delivered by an AAV-vector inhibited viral infection in herpetic simplex keratitis (HSK) mouse model. Our work demonstrates that viral detection and antiviral countermeasures can be paired for intelligent sense-and-destroy applications as a flexible and innovative method against virus infection.

Date: 2022
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DOI: 10.1038/s41467-022-35425-9

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