Emerging viral pathogens represent an ongoing, unpredictable threat to human health. This proposal presents a career development research and training program that seeks to understand the emergence of Powassan virus, a tick-borne flavivirus that causes severe neurological infection. Powassan virus is transmitted by Ixodes scapularis ticks and has been increasingly detected in New England and other Lyme-endemic areas. However, very little is known about the frequency of Powassan virus infection, the spectrum of illness it causes, and the viral strains that cause human infection. The candidate will use a viral genomic approach to understand the evolution of Powassan virus in ticks, and will characterize the frequency, clinical manifestations, and viral genomics of Powassan virus in humans, in the most comprehensive investigation of this virus to date. To provide context for understanding the increasing detection of human infections, the candidate will first investigate the molecular epidemiology of Powassan virus in ticks collected throughout New England. The candidate will sequence Powassan virus genomes directly from tick samples and perform phylogenetic analyses to assess whether there has been growth of the viral population that could contribute to increasing human infection. To comprehensively characterize Powassan virus infection in humans, the candidate will screen samples from established cohorts of patients who are at risk for this infection. This study will define the frequency of Powassan virus infection in both neurological and non-neurological infection, and will sequence Powassan virus genomes from human infection to guide studies of pathogenesis. Altogether, this work will provide a critical step in understanding the emergence and impact of Powassan virus infection, with the goal of guiding for further efforts towards prevention and treatment. The proposal aligns with the NIAID priority objective to understand and prevent tick-borne infections. This K08 Mentored Clinical Scientist Research Career Development Award proposes training for the candidate in both laboratory and computational techniques in virology. The candidate's background includes doctoral research training in virology and clinical specialization in Infectious Disease. In the current proposal, she will learn new skills in serology, viral genome sequencing, bioinformatics, and phylogenetics through both formal training and practical application. The stimulating environment of Massachusetts General Hospital, the Broad Institute, and Harvard University are extremely well suited to the proposed training plan, including coursework in computational biology, clinical and research seminars, and career development workshops. The candidate will be guided by a mentorship advisory committee comprised of experts in viral genomics and translational research. Through this research and training, she will become very well positioned to launch her career as an independent physician scientist studying emerging viruses of public health importance.