The impact of dietary zinc deficiency on innate immunity to lung infection

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PROJECT SUMMARY Candidate: My postdoctoral research thus far focused on the effects of host dietary zinc on bacterial pathogenesis during Acinetobacter baumannii pneumonia in Dr. Eric P. Skaar's laboratory at Vanderbilt University Medical Center. I earned my PhD in Microbiology with Dr. Diana Downs studying thiamine (vitamin B1) biosynthesis in Salmonella enterica at the University of Wisconsin-Madison and the University of Georgia. Career Goals and Objectives: My career goal is to be a tenure-track faculty member at a top-tier research institution working with trainees at all levels to understand how metabolism affects the host-pathogen interface. In order to achieve this goal, I need additional mentored training in host inflammation and immunology. Career Development and Training Activities: My mentoring committee will be led by Dr. Skaar and include Dr. R. Stokes Peebles, Dr. C. Henrique Serezani, and Dr. Dawn C. Newcomb, experts in metals at the host-pathogen interface, infection imaging, type 2 lung immunity, innate inflammation, and respiratory epithelial biology. My mentoring committee will continue to meet biannually and support my practical, didactic, and career development training to aid my transition to independence. Research Strategy: The World Health Organization estimated that zinc deficiency contributes to 16% of lower respiratory infections globally. Our exciting preliminary data show that zinc deficiency significantly increases mortality from A. baumannii pneumonia by 24 h post infection, and that neutralization of the type 2 cytokine IL-13 protects mice from mortality. The central hypothesis of this proposal is that dietary Zn deficiency promotes type 2 inflammation during lung infection, preventing A. baumannii killing. Significance and Innovation: The research plan will identify molecular mechanisms underlying the link between zinc deficiency and pneumonia. The proposed experiments will uncover potential therapeutic targets to promote lung innate immunity. Aim 1 (K99): Determine the effect of Zn deficiency on leukocyte-mediated bacterial killing. We will test the effect of zinc deficiency on leukocyte function ex vivo and in vivo using sophisticated animal models and an engineered suite of fluorescent A. baumannii to image the host-pathogen interface in real time. Aim 2 (R00): Identify the mechanism by which Zn deficiency promotes type 2 immunity in response to bacterial lung infection. We will identify the cellular source of IL-13 and upstream cytokine signaling by the airway epithelium to investigate the effect of Zn deficiency on human airway epithelial cell initial inflammatory response to infection that drives lung mucosal immunity. Transition to independence: These aims were developed independently of Dr. Skaar and my co-mentors, and they will not pursue overlapping research plans. During the K99, I will apply for faculty positions nationally.