INTESTINAL MICROBIAL REGULATION OF ANTIVIRAL IMMUNITY

项目总结 这项提议的目标是描述一个为阿什利·斯蒂德，医学博士，博士，为独立做准备的5年计划 研究微生物群在抗病毒免疫中的作用的内科科学家。她以优异的成绩毕业 毕业于杜克大学，获得生物学学位，并从哈佛大学获得医学和研究研究生学位 华盛顿大学医学院医学科学家培训计划。在完成以下操作后 在她的儿科重症监护研究员期间，她加入了撒迪厄斯·斯塔彭贝克医生的实验室， 她已经证明了升高的基础干扰素I型信号对宿主在 流感感染。这一发现解决了流感领域的一个争议。她延长了这些研究的时间 研究肠道微生物群在推动全身干扰素水平中的作用及其对 病毒感染。这些发现是这项提案中目标的基础。 华盛顿大学医学院是斯蒂德博士开展研究的典范 平台凭借其在NIH的悠久历史和资源的广度和深度为研究提供资金。的确有 正如斯蒂德博士的指导委员会和合作者所证明的那样，各部门之间频繁的串扰， 结合微生物学、免疫学、儿科和医学系的专业知识。Dr。 斯塔彭贝克是粘膜表面宿主-微生物相互作用领域的领导者；因此，他是一个理想的 斯蒂德博士的导师，因为他有能力破译发病机制和他强有力的轨迹 在培养青年科学家方面的记录。他的实验室是一个智力能量的训练中心，有不同的群体 致力于广泛而有创意的项目。斯蒂德博士将有多个机会在当地展示她的研究成果 在更大的科学界。她将参加研究生级别的课程，以增强她在 微生物学和基因组学，并与她的合作者一起培养关键的技术技能。 斯蒂德博士的近期目标是实现这项提案中概述的目标。虽然很明显肠道中的 微生物组对流感的抗性发病机制有重要作用，分子上了解这种相互作用 仍然鲜为人知。她最近发现了一种微生物相关的代谢物，脱氨基酪氨酸， 增强I型干扰素信号。这一发现表明，一种特定的微生物代谢物可能介导了 微生物组的保护作用。通过完成提出的目标，斯蒂德博士将检验以下假设： 去氨基酪氨酸通过增强全身干扰素信号保护流感发病机制，2)定义 去氨基酪氨酸增强干扰素信号的机制，以及3)识别干扰素的成分 产生脱氨基酪氨酸的微生物群。她的实验室最初的重点将是进一步描述这些 从她的研究中获得的洞察力将转化为旨在提高对 病毒致病机制和增强抗病毒免疫。

PROJECT SUMMARY The goal of this proposal is to describe a 5-year plan to prepare Ashley Steed, MD, PhD, for independence as a physician-scientist studying the role of the microbiome in antiviral immunity. She graduated with distinction from Duke University with a degree in Biology and obtained her medical and research graduate degree from Washington University School of Medicine's Medical Scientist Training Program. After completing her residency and during her pediatric critical care fellowship, she joined Dr. Thaddeus Stappenbeck's laboratory, where she has demonstrated that elevated basal interferon type I signaling is protective to the host during influenza infection. This finding resolves a controversy in the influenza field. She has extended these studies to investigate the role of the enteric microbiome in driving systemic interferon levels and the consequences for viral infection. These findings serve as the basis for the aims in this proposal. Washington University School of Medicine is an exemplary location for Dr. Steed to develop her research platform with its longstanding history of NIH funded research and breadth and depth of resources. There is frequent crosstalk among departments, as Dr. Steed's mentoring committee and collaborators demonstrate, combining the expertise from the departments of Microbiology, Immunology, Pediatrics, and Medicine. Dr. Stappenbeck is a leader in the field of host-microbial interactions at mucosal surfaces; thus he is an ideal mentor for Dr. Steed because of his ability to decipher mechanisms of pathogenesis and his strong track record in training young scientists. His laboratory is a training hub of intellectual energy with a diverse group working on broad and creative projects. Dr. Steed will have multiple opportunities to present her work locally and in the larger scientific community. She will take graduate level classes to enhance her knowledge in microbiology and genomics and develop key technical skills with her collaborators. Dr. Steed's immediate goal is to fulfill the aims outlined in this proposal. While it is clear that the enteric microbiome is important for resistance to influenza pathogenesis, molecular understanding of this interaction remains obscure. She recently discovered a microbially-associated metabolite, desaminotyrosine, that enhances type I interferon signaling. This finding suggests that a specific microbial metabolite may mediate the protective effect of the microbiome. By completing the proposed aims, Dr. Steed will 1) test the hypothesis that desaminotyrosine protects from influenza pathogenesis by enhancing systemic interferon signaling, 2) define the mechanism by which desaminotyrosine augments interferon signaling, and 3) identify components of the microbiome that produce desaminotyrosine. Her laboratory's initial focus will be to further delineate these mechanisms such that insight from her research will translate to strategies aimed at improving resistance to viral pathogenesis and enhancing antiviral immunity.