Title: Interferon-Mediated Control of Neuropathogenic Flaviviruses Abstract: The primary research goals of this Mentored Clinical Scientist Research Career Development Award proposal are to study mechanisms by which antiviral interferons suppress neuropathogenic Flaviviruses. Flaviviruses, including Zika virus (ZIKV) and West Nile virus (WNV), can cause severe neurological complications, including brain disruption sequence and encephalitis. These manifestations are the net result of both virus-induced effects and host immune responses. The type I interferon (IFN) response establishes a cellular antiviral state through the induction of hundreds of IFN-stimulated genes (ISGs), many of which have direct antiviral effects. Through a cell-based screen to identify novel antiviral ISGs, the candidate uncovered C19orf66 as a potent inhibitor of multiple RNA viruses, including WNV, ZIKV, and Venezuelan equine encephalitis virus (VEEV). The candidate has shown that C19orf66 is required for an optimal IFN response and targets the viral life cycle at the stage of genome replication. Additionally, C19orf66 is basally expressed in primary human neural progenitor cells (hNPs), a useful model to study Zika virus-host interaction. Here, the candidate proposes to further characterize the mechanism of C19orf66 inhibition of Flaviviruses. A combination of molecular virological, cell biological, and biochemical approaches will be used to study: 1) the precise viral life cycle step inhibited by C19orf66, 2) the contribution of C19orf66 to antiviral immunity in hNP cell culture models and 3) the in vivo relevance in a mouse model of ZIKV infection. This research plan, complemented by a comprehensive career development plan that capitalizes on the candidate’s strong clinical interest in central nervous system infections, will lead to an independent research career laid on the foundation of strong education and sound technical skills. The research component of this award will be conducted in the laboratory of Dr. John Schoggins at UT Southwestern, who has significant expertise in basic virology and innate immunity, with additional oversight by co-mentor, Dr. Beth Levine, an expert in virus-host interactions with a strong history of successful mentorship. Critical to the candidate’s career development are attendance and presentations at professional conferences, regular meetings with her advisory committee, courses in fundamentals of neuroscience and immunology, mentorship and career development, research ethics, and hands-on training in the neuroscience lab of Dr. Genevieve Konopka. In summary, this training plan will satisfy the candidate’s short-term goals to strengthen her neuroscience and immunology fund of knowledge and expand her experience in basic science, providing for her long-term goal of independent research in the innate immune control of neuropathogenic Flaviviruses.