Innate Control of Adaptive Immunity to SARS-CoV-2

项目摘要/摘要 迄今为止，严重急性呼吸综合征冠状病毒2(SARS-CoV-2)已造成3200多万人死亡 冠状病毒病(新冠肺炎)病例，相关死亡约100万人。多项疫苗试验已经 开始努力阻止这种大流行，然而病毒清除和免疫保护的相关性 SARS-CoV-2病毒仍不清楚。事实上，没有任何人类冠状病毒的许可疫苗，就像我们有的那样。 还没有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 岩崎实验室的戈德曼-伊斯雷洛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的小鼠。他作为第一作者之一发表了这项研究。 实验医学。他还表明，先天免疫激活会导致急性病理改变。然而， 先天免疫信号在多大程度上驱动适应性免疫仍有待探索。这项提议将 阐述如何：(1)I型干扰素信号和(2)cGAS信号控制SARS抗体的产生- CoV-2。这项工作对于描述管理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·高盛严格的五年职业发展培训计划- 伊斯雷洛，医学博士，博士，目标是为他作为一名学者的独立研究生涯做准备 医生兼科学家。首席研究员是一位完成医学博士和博士学位的内科科学家。 在西奈山伊坎医学院接受生物医学培训，在那里他学习分子 病毒学。戈德曼-伊斯雷洛博士继续他的培训，加入了内科科学家研究路径，网址为 耶鲁纽黑文医院，一个结合住院医生和奖学金的项目，目前是一个传染性的 疾病专家。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 在岩崎明子博士的指导下的免疫学，岩崎明子是破译该复合体的先驱和世界领先者 病毒、先天免疫识别和适应性免疫之间的相互作用。岩崎博士不仅是一个世界- 一流的科学家，也是一位世界级的导师，在指导医生方面有着非常富有成效的记录- 科学家。除了戈德曼博士的智力培养和基于实验室的实际培训外- 伊斯雷洛将继续在岩崎博士的实验室接受培训，他已经开发了一个建立在高产基础上的培训计划 说教式的课程作业他还精心组建了一个由翻译科学家组成的顾问委员会 拥有与这项提议相关的广泛科学专业知识和令人印象深刻的指导记录。耶鲁大学 医学院及其内科和免疫生物学系将提供 资源、支持和基础设施，以帮助戈德曼-以色列博士实现本文件中描述的目标 他的提议和他的长期目标是发展成为一名独立的内科科学家，研究 管理针对病毒感染和疫苗接种的抗体开发。

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.