Intestinal Microbial Regulation of Antiviral Immunity

PROJECT SUMMARYThe goal of this proposal is to describe a 5-year plan to prepare Ashley Steed, MD, PhD, for independence asa physician-scientist studying the role of the microbiome in antiviral immunity. She graduated with distinctionfrom Duke University with a degree in Biology and obtained her medical and research graduate degree fromWashington University School of Medicine's Medical Scientist Training Program. After completing herresidency 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 duringinfluenza infection. This finding resolves a controversy in the influenza field. She has extended these studiesto investigate the role of the enteric microbiome in driving systemic interferon levels and the consequences forviral 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 researchplatform with its longstanding history of NIH funded research and breadth and depth of resources. There isfrequent 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 idealmentor for Dr. Steed because of his ability to decipher mechanisms of pathogenesis and his strong trackrecord in training young scientists. His laboratory is a training hub of intellectual energy with a diverse groupworking on broad and creative projects. Dr. Steed will have multiple opportunities to present her work locallyand in the larger scientific community. She will take graduate level classes to enhance her knowledge inmicrobiology 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 entericmicrobiome is important for resistance to influenza pathogenesis, molecular understanding of this interactionremains obscure. She recently discovered a microbially-associated metabolite, desaminotyrosine, thatenhances type I interferon signaling. This finding suggests that a specific microbial metabolite may mediate theprotective effect of the microbiome. By completing the proposed aims, Dr. Steed will 1) test the hypothesis thatdesaminotyrosine protects from influenza pathogenesis by enhancing systemic interferon signaling, 2) definethe mechanism by which desaminotyrosine augments interferon signaling, and 3) identify components of themicrobiome that produce desaminotyrosine. Her laboratory's initial focus will be to further delineate thesemechanisms such that insight from her research will translate to strategies aimed at improving resistance toviral pathogenesis and enhancing antiviral immunity.