The candidate is a physician-scientist with an interest in host-pathogen interactions whose long-term career goal is to develop into an independent investigator. Through recent training in viral immunology and clinical pathology, the candidate has developed the scientific framework necessary to address significant gaps in our understanding of innate host-pathogen interactions relevant to human health. While continuing to foster his development as an independent scientist, the candidate's immediate goals are to successfully complete the proposed studies, obtain non-scientific skills necessary to lead a research team, and transition to an independent environment. The mentorship of Dr. Wayne Yokoyama, an accomplished immunologist and physician-scientist, has guided the candidate in developing a plan to achieve his short-term and long-term career goals. The Department of Pathology and Immunology at Washington University School of Medicine in St. Louis, where the candidate will pursue his scientific and career development activities, has an established track-record for fostering the growth of highly productive and innovative scientists. This community of clinical and basic science researchers provides the ideal collaborative environment essential for supporting new investigators. The research project described in this application addresses a fundamental aspect of the innate immune response to viral infection. Natural killer (NK) cells are essential for the genetic resistance of certain mice strains to murine cytomegalovirus (MCMV) infection. Significant progress has been made in the mentor's laboratory describing the association of Ly49H-mediated NK cell receptor signaling and recognition of the virally-encoded m157 molecule. However, previous attempts at discriminating between specific NK-dependent and non-specific innate antiviral immune responses have been limited. The candidate has developed a research plan incorporating several distinct approaches to directly address these limitations. Preliminary results indicate that NK cell activity is governed by a discrete set of requirements, kinetics, and organ-specific factors. Based on this work, the candidate's research plan consists of three specific aims to identify mechanisms governing antiviral NK cell activity: 1 investigate the role of innate cytokines on antiviral NK cell activity; 2) define the contribution f T cells in modulating NK cell effector function; and 3) examine the trafficking of NK cells during cytotoxic killing of virally infected host cells. Using a recently developed co- infection system, he candidate will discriminate between NK cell-specific and non-specific requirements for viral clearance. Leveraging two-photon imaging techniques and a new NK cell reporter mouse, the candidate will further obtain direct visual evidence for the trafficking and targeting of NK cells o sites of MCMV infection. These innovative approaches will uniquely inform us of the requirements and kinetics underlying NK cell activity. The significance of the research lies is its potential to impact studies investigating the role of NK cells in other host-pathogen interactions, especially in clinically important human diseases.