Innate Control of Adaptive Immunity to SARS-CoV-2

项目概要/摘要 到目前为止，严重急性呼吸系统综合征冠状病毒2（SARS-Cov-2）已造成超过3200万人死亡， 冠状病毒病（COVID-19）病例，约100万人死亡。多项疫苗试验 开始努力阻止这一流行病，但病毒清除和免疫保护的相关性， SARS-CoV-2仍然未知。事实上，目前还没有针对任何人类冠状病毒的许可疫苗， 尚未发现成功的冠状病毒疫苗的免疫学相关性。在他短暂的任期内， 岩崎实验室的Goldman-Israelow博士已经开发出一种适应性很强的SARS-CoV-2小鼠模型 感染，可以应用于任何基因型的小鼠。他以第一作者的身份发表了这项工作， 实验医学他还表明，先天免疫激活驱动急性病理。但 先天免疫信号驱动适应性免疫的程度仍有待探索。这项建议会 解决如何：（1）I型干扰素信号传导和（2）cGAS信号传导控制SARS抗体的发展- 二型冠状病毒这项工作对于描述控制SARS适应性免疫的基本规则至关重要- CoV-2，这将促进高效疫苗的开发。 这份提案描述了本杰明·戈德曼（Benjamin Goldman）为期五年的严格职业发展培训计划， Israelow，医学博士，哲学博士、目标是为他作为一名学者的独立研究生涯做好准备 物理学家兼科学家主要研究者是一位完成医学博士学位的医生科学家。和博士 在西奈山伊坎医学院接受生物医学科学培训， 病毒学Goldman-Israelow博士继续他的培训，加入了医生科学家研究途径， 耶鲁纽黑文医院，一个联合住院医师和奖学金计划，目前是一个传染病 疾病研究员他已经开始了一项强化培训计划，以扩大他在病毒方面的专业知识 免疫学博士指导下，Akiko岩崎，一个先驱和世界领导者在破译复杂 病毒之间的相互作用，先天免疫识别和适应性免疫。岩崎博士不仅是一个世界- 一流的科学家，但也是一个世界级的导师与一个非常富有成效的跟踪记录指导医生- 科学家除了高曼博士提供的智力培养和实际的实验室培训外， Israelow将继续接收在岩崎博士的实验室，他已经制定了一个培训计划建立在高产 教学课程他还精心打造了一个由翻译科学家组成的咨询委员会 拥有与此提案相关的广泛的科学专业知识和令人印象深刻的指导记录。耶鲁 医学院，沿着其内科和免疫生物学系，将提供 资源，支持和基础设施，以协助戈德曼博士Israelow在实现本文件所述的目标， 他的长期目标是成为一名独立的物理学家，科学家，研究 控制病毒感染和疫苗接种的抗体产生。

Project Summary/Abstract To date, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) has caused over 32 million cases of coronavirus disease (COVID-19), with ~1 million associated deaths. Multiple vaccine trials have begun in an effort to stop this pandemic, yet the correlates of viral clearance and immune protection from SARS-CoV-2 remain unknown. In fact, there are no licensed vaccines to any human coronavirus, as we have not yet discovered the immunologic correlates of a successful coronavirus vaccine. In his brief tenure in the Iwasaki lab, Dr. Goldman-Israelow has already developed a highly adaptable mouse model of SARS-CoV-2 infection that can be applied to mice of any genotype. He published this work as co-first author in the Journal of Experimental Medicine. He also showed that innate immune activation drives acute pathology. However, the extent to which innate immune signals drive adaptive immunity remains to be explored. This proposal will address how: (1) type I interferon signaling and (2) cGAS signaling control antibody development to SARS- CoV-2. This work is critical for characterizing the fundamental rules that govern adaptive immunity to SARS- CoV-2, which will promote the development of highly effective vaccines. This proposal describes a rigorous five-year career development training program for Benjamin Goldman- Israelow, M.D., Ph.D., with the goal of preparing him for an independent research career as an academic physician-scientist. The principal investigator is a physician scientist who completed his M.D. and Ph.D. training in Biomedical Sciences at the Icahn School of Medicine at Mount Sinai, where he studied molecular virology. Dr. Goldman-Israelow continued his training by joining the Physician Scientist Research Pathway at Yale New Haven Hospital, a combined residency and fellowship program, and is currently an infectious diseases fellow. He has embarked on an intensive training program to broaden his expertise in viral immunology under the mentorship of Dr. Akiko Iwasaki, a pioneer and world leader in deciphering the complex interplay among viruses, innate immune recognition, and adaptive immunity. Dr. Iwasaki is not only a world- class scientist, but also a world-class mentor with a very productive track record of mentoring physician- scientists. In addition to the intellectual grooming and practical laboratory-based training that Dr. Goldman- Israelow will continue to receive in Dr. Iwasaki’s lab, he has developed a training program built on high-yield didactic coursework. He has also carefully crafted an advisory committee comprising translational scientists with a broad range of scientific expertise relevant to this proposal and impressive records of mentorship. Yale School of Medicine, along with its Departments of Internal Medicine and Immunobiology, will provide the resources, support, and infrastructure to assist Dr. Goldman-Israelow in achieving the aims described in this proposal and his long-term goal of developing into an independent physician-scientist studying the rules that govern antibody development to both viral infection and vaccination.