NSF/MCB-BSF: Sentinels: Viral First Responder Cells (VFRCs) for COVID-19 and Future Rapidly Emerging Infectious Diseases

COVID-19 necessitates new approaches to artificial immunity for people at-risk, recently exposed, or in early stages of viral infection, for which there are limited treatment options. Rapid onset of lung inflammation caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the respiratory illness responsible for the coronavirus pandemic, can in principle be overcome with immunomodulatory gene therapy, but achieving this goal faces long-standing challenges. Further, there is a need for anti-viral therapies across other viral families such as H1N1 (flu), West Nile, Zika, Yellow Fever Virus, and emerging variants. To address these challenges, this project will create Viral First Responder Cells (VFRCs), a new type of sentinel/therapeutic cell. VFRCs are genetically engineered patient cells programmed to mount a first line defense against highly contagious viral diseases with long incubation periods, vector-borne diseases, and future viral diseases. Upon viral detection, VFRCs produce a cocktail of outputs to stop viral replication and activate an appropriately modulated immune response. The project's scientific output will focus on equitable distribution (e.g. genetically diverse target responses) and will broadly disseminate research-focused training material in novel media, including new grant-specific virtual lab training modules for remote and at-home learning. The project will provide inclusive viral therapy and COVID-related learning opportunities for underrepresented minority students, integrate with MIT's efforts to address systemic racism, and increase retention of women and minorities via an outreach portal. This project will create a new synthetic immune system to overcome limitations in traditional artificial immunity (e.g. immunization or antibody therapy) by genetically engineering patient cells (e.g. a small subset of lung epithelial cells) with broad-range and virus specific sensors of infection (VFRC sentinels). VFRCs rapidly detect viral entry using precise multi-input sensors that monitor for changes to cellular transcriptional signatures and genetic logic that responds by activating both pathways that lead to eradication of the virus, including appropriate activation of innate and adaptive host immune responses. Creating the capability to both sense immune state changes / viral entry and trigger powerful immunomodulatory responses in a controlled fashion will define a radically new approach for anti-viral therapies, define a new area of immunomodulatory biological design, and lead to new therapies for emergent viral threats. VFRC circuits limit side effects to cells already compromised by the virus and provide a more effective and tuned response based on the both the stage of infection and the degree of patient immunocompetence. An important element of VFRC safety is restricting intracellular response to occur only during active infection. When the virus is not present, genetic circuits introduced into the VFRCs remain in a vigilant but inactive "monitor" state. In this state, VFRCs monitor for signs of infection but do not alter the transcriptome. VFRCs also include a physician regulated genetic safety switch to deactivate any undesired response. Once proven safe and effective for one virus, this approach, which already includes broad viral entry sensors, can be customized for new viruses. This research will also answer fundamental scientific questions about viral immune responses and immunomodulatory therapy optimization.