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

新冠肺炎需要对高危人群、最近暴露的人群或病毒感染早期阶段的人采取新的人工免疫方法，这些人的治疗选择有限。由严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)引起的肺部炎症迅速发作，原则上可以通过免疫调节基因疗法来克服，但实现这一目标面临长期挑战。此外，还需要在H1N1(流感)、西尼罗河病毒、寨卡病毒、黄热病病毒和新出现的变种等其他病毒家族中进行抗病毒治疗。为了应对这些挑战，该项目将创造病毒第一反应细胞(VFRC)，这是一种新型的哨兵/治疗细胞。VFRC是经过基因工程的患者细胞，编程为对潜伏期长的高传染性病毒疾病、媒介传播疾病和未来的病毒疾病建立一线防御。一旦检测到病毒，VFRC就会产生一系列的输出，以阻止病毒复制并激活适当调节的免疫反应。该项目的科学成果将侧重于公平分配(例如基因多样化的目标反应)，并将通过新的媒体广泛传播注重研究的培训材料，包括用于远程和在家学习的新的赠款专用虚拟实验室培训模块。该项目将为未被充分代表的少数族裔学生提供包容性病毒疗法和与COVID相关的学习机会，与麻省理工学院解决系统性种族主义的努力相结合，并通过外展门户增加妇女和少数群体的留存。该项目将创建一种新的合成免疫系统，通过对患者细胞(例如，一小部分肺上皮细胞)进行基因工程，使其具有大范围和病毒特异性感染传感器(VFRC哨兵)，以克服传统人工免疫(例如免疫或抗体疗法)中的局限性。VFRC使用精确的多输入传感器快速检测病毒进入，这些传感器监测细胞转录特征和遗传逻辑的变化，遗传逻辑通过激活导致病毒根除的两条途径做出反应，包括适当激活先天和适应性宿主免疫反应。建立以受控方式感知免疫状态变化/病毒进入并触发强大的免疫调节反应的能力将定义一种全新的抗病毒治疗方法，定义免疫调节生物学设计的新领域，并导致针对紧急病毒威胁的新疗法。VFRC电路将副作用限制在已被病毒损害的细胞上，并根据感染阶段和患者免疫活性的程度提供更有效和可调的反应。VFRC安全性的一个重要因素是限制细胞内反应仅在活动性感染期间发生。当病毒不存在时，引入VFRC的基因电路保持警惕但不活跃的“监控”状态。在这种状态下，VFRC监测感染的迹象，但不改变转录组。VFRC还包括一个由医生控制的基因安全开关，以停用任何不希望看到的反应。一旦被证明对一种病毒安全有效，这种方法已经包括了广泛的病毒进入传感器，可以为新病毒定制。这项研究还将回答有关病毒免疫反应和免疫调节治疗优化的基本科学问题。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.