Population Dynamics of Rotavirus: A Combined Theoretical, Bioinformatic and Laboratory Based Approach

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DESCRIPTION (provided by applicant): Rotavirus, a leading cause of childhood death globally, exhibits extensive genetic diversity and complex epidemiological dynamics. The possibility of short-term or long-term evolutionary response to the recently introduced vaccines is not well understood. Genome reassortment is the major mechanisms of genetic change in this segmented RNA virus. The research in this proposal will evaluate the role of reassortment as a potential mode of escape from vaccination pressure, either through zoonotic introduction of genes, or reshuffling of existing genetic variation. This award will play a critical role in helpin me achieve my long-term career goals, which include: (1) becoming and expert in the evolution of infectious diseases, combining bioinformatics, epidemiological modeling, and laboratory based evolution experiments, (2) establishing a career as an independent physician investigator in a leading medical research institution, (3) becoming an effective mentor to trainees at multiple levels. The goals will be achieved through a combination of a mentoring form a diverse mentorship committee, and formal didactic training, focusing on specific career and scientific development goals. Candidate: I am currently a Clinical Lecturer in the Division of Infectious Diseases at the University of Michigan, and will be appointed Assistant Professor in Jan 2016. I maintain an outpatient clinic of one half day a week and one month of inpatient service per year. I received a PhD studying bacterial evolution using experimental evolution. During my fellowship research period, I have been mentored by Dr. Mercedes Pascual, an expert in the theoretical aspects of infectious disease ecology and evolution. In her lab I received training in the use of modeling of evolutionary processes using phylogenetic data. I am seeking to add significant additional training by combining this evolutionary perspective with formal epidemiological modeling, as well as developing laboratory based experimental evolution system to further test our hypotheses. This will be achieved by through continued mentorship by Dr. Pascual with additional training in laboratory virology with Dr. Adam Lauring and Dr. David Markovitz, experts in virology and viral evolution. Additionally, I will receive career guidance and expert mentorship in bioinformatics analyses by Dr. Gilbert Omenn. Environment: My scientific goals include: (1) modeling of infectious disease dynamics by including both epidemiological and evolutionary processes (2) applying Bayesian phylogenetic methods to test ecological models, (3) Developing laboratory skills in the growth, propagation and manipulation of rotavirus in cell culture in order to carry out evolution experiments in the lab. These scientific goals will be achieved by a combination of mentoring and formal coarse work through several centers at the University of Michigan including the Michigan Institute for Clinical & Health Research, Center for Statistical Consultation and Research, and the Center for Complex systems, Center for Computational Biology and Medicine. Of equal importance, my career development goals, which include: (1) Develop leadership skills for managing an interdisciplinary project. (2) Writing effective institutional review board (IRB) proposals, including the responsible conduct of research. (3) Improve my written and oral communication skills. Specific instructional programs and courses will be utilized including the Michigan Institute for Clinical and Health Research, IRBMED, and the Program for Education and Evaluation in Responsible Research and Scholarship. Research: The goal of the proposed research is to identify the role of reassortment in the response of rotavirus to vaccination. I plan to test the hypothesis that both epistatic molecular interactions and the patterns of immunity among the human population limit the ability of reassorted viruses to spread in the population, and that vaccination will change the population-wide patterns of host immunity, resulting in spread of reassortant viruses. Aim 1 will identify historical patterns of reassortment using a Bayesian phylogenetic analysis of two large sets of whole genome sequences. Aim 2 will measure reassortment rates between laboratory strains of rotavirus, and map accessible mutational pathway to respond to the molecular barriers to reassortment using experimental evolution. Aim 3 will use a simulation model of rotavirus dynamics that integrates the evolutionary and epidemiological dynamics to explore how the findings form Aim 1 and Aim 2 affect the expected response to vaccination.