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

NSF/MCB-BSF：哨兵：针对 COVID-19 和未来快速出现的传染病的病毒第一反应细胞 (VFRC)

• 批准号: 2116037
• 负责人: Ron Weiss
• 金额: $ 119.58万
• 依托单位: Massachusetts Institute of Technology
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2116037&HistoricalAwards=false
• 关键词: NSF; MCB; BSF; Sentinels; Viral

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.

COVID-19需要新的方法来为处于风险中的人，最近暴露的人或处于病毒感染早期阶段的人提供人工免疫，这些人的治疗选择有限。严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）是导致冠状病毒大流行的呼吸系统疾病，原则上可以通过免疫调节基因治疗来克服，但实现这一目标面临着长期的挑战。此外，还需要跨其他病毒家族的抗病毒疗法，如H1N1（流感）、西尼罗河病毒、寨卡病毒、黄热病病毒和新出现的变体。为了应对这些挑战，该项目将创建病毒第一反应细胞（VFRC），一种新型的哨兵/治疗细胞。VFRC是基因工程患者细胞，被编程为针对具有长潜伏期的高度传染性病毒性疾病、媒介传播疾病和未来病毒性疾病建立第一线防御。在病毒检测时，VFRC产生输出的混合物以停止病毒复制并激活适当调节的免疫应答。该项目的科学产出将侧重于公平分配（例如，遗传多样性目标反应），并将以新媒体广泛传播以研究为重点的培训材料，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。该项目将为代表性不足的少数民族学生提供包容性病毒治疗和与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，该项目将创建一个新的合成免疫系统，以克服传统人工免疫的局限性，本发明涉及通过基因工程改造患者细胞（例如，肺上皮细胞的小子集）与广泛的和病毒特异性的感染传感器（VFRC哨兵）的组合（例如，免疫或抗体疗法）。VFRC使用精确的多输入传感器快速检测病毒进入，该传感器监测细胞转录特征和遗传逻辑的变化，该变化通过激活导致病毒根除的两种途径来响应，包括先天性和适应性宿主免疫应答的适当激活。创造以受控方式感知免疫状态变化/病毒进入并触发强大免疫调节反应的能力将定义抗病毒疗法的全新方法，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经被病毒损害的细胞上，并根据感染阶段和患者免疫能力的程度提供更有效和更协调的反应。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的遗传电路保持警惕但不活跃的“监视”状态。在这种状态下，VFRC监测感染的迹象，但不改变转录组。VFRC还包括医生调节的遗传安全开关，以灭活任何不期望的反应。一旦证明对一种病毒是安全有效的，这种方法已经包括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知识价值和更广泛的影响审查标准进行评估，被认为值得支持。