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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Engineering antiviral immune-like systems for autonomous virus detection and inhibition in mice
Yidan Wang1,2, Ying Xu1, Chee Wah Tan3
1Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Centre, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai, 200241, China.
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.
Insights
Scientists engineered autonomous, intelligent, virus-inducible immune-like (ALICE) cells to detect and destroy viruses. This novel sense-and-destroy system shows promise for broad-spectrum antiviral therapies and pandemic preparedness.
Area of Science:
- Synthetic biology
- Immunology
- Virology
Background:
- Viral diseases pose significant public health and economic threats, exacerbated in immunocompromised individuals.
- The COVID-19 pandemic highlighted the need for robust pandemic preparedness and broad-spectrum antiviral strategies.
- Current antiviral approaches may lack the specificity and adaptability required for emerging viral threats.
Purpose of the Study:
- To engineer a novel "sense-and-destroy" antiviral system using designer cells.
- To develop a versatile platform for detecting diverse viral genera and initiating targeted antiviral responses.
- To evaluate the in vitro and in vivo efficacy of these engineered cells against viral infections.
Main Methods:
- Designed autonomous, intelligent, virus-inducible immune-like (ALICE) cells incorporating a destabilized STING-based viral sensor.
- Utilized a synthetic signal transduction system to link viral detection to effector molecule expression.
- Incorporated antiviral cytokines, CRISPR-Cas9 for viral degradation, and neutralizing antibodies as effector functions.
- Performed in vitro testing and in vivo validation in a herpetic simplex keratitis (HSK) mouse model using AAV-vector delivery.
Main Results:
- Successfully developed ALICE cells capable of detecting viruses from seven different genera.
- Demonstrated that the dual-output ALICE system (ALICESaCas9+Ab) effectively inhibited viral infection in vitro.
- Confirmed in vivo functionality, showing inhibition of viral infection in the HSK mouse model.
- Validated the AAV-vector delivery system for ALICE cells in a mammalian model.
Conclusions:
- Engineered ALICE cells represent a flexible and innovative approach for intelligent antiviral countermeasures.
- The "sense-and-destroy" strategy effectively pairs viral detection with targeted antiviral effectors.
- This platform holds potential for future pandemic preparedness and broad-spectrum antiviral therapeutic development.
