Identifying Intermolecular Constraints on Influenza Virus Evolution

PROJECT SUMMARY/ABSTRACT The long-term goals of the candidate are to establish an independent research laboratory investigating host adaptation of zoonotic viruses. This proposal outlines a set of aims that will provide a foundation for a career as a professor at an academic institution. The candidate has established a training plan comprising five main areas: coursework in computational biology, mentorship under a diverse and supportive network of University of Pittsburgh faculty, publication of research in peer-reviewed articles, networking at seminars and conferences, and application for transitional funding and faculty positions. The candidate has assembled a diverse mentoring committee to achieve these goals: Dr. Seema Lakdawala, the primary sponsor; Dr. Vaughn Cooper, co-sponsor of this application; Dr. Erik Wright, collaborator; and a formal mentoring committee including Drs. John Williams, Neal DeLuca, Matthew Nicotra, and Anne-Ruxandra Carvunis. See co-sponsor statement and letters of support. The research objectives proposed in this application include the investigation of the role of complex interactions on influenza virus evolution. Protein-protein interactions determine whether polymerase subunits are compatible, and recently described RNA-RNA interactions are theorized to drive genomic assembly of viral RNA segments into daughter viruses. However, the impact of such complex interactions on viral evolution are not well understood. Such knowledge will ultimately aid in the prediction of how genetic reassortment of genomic segments occurs between two influenza virus strains, a process that leads to emerging pandemic and zoonotic strains. These objectives are in accordance with the mission of the NIAID to better understand and prevent infectious diseases. We hypothesize that evolutionary relationships predict complex interactions among viral RNA and protein that constrain reassortment. We present the following aims to address this hypothesis: Aim 1. To define the mechanism of evolutionary constraints on RNA-RNA interactions in seasonal human IAV. We will identify nucleotide residues underlying our initial observation that parallel evolution occurs between viral RNA and examine their roles in genomic packaging. Aim 2. To examine parallel evolution between protein subunits of avian polymerase complexes. We will test whether complex protein-protein interactions similarly constrain avian influenza virus evolution. These aims will provide a basis for the candidate to launch an independent laboratory distinct from that of her advisor investigating evolutionary constraints on host adaptation of zoonotic viruses. The sponsor, co-sponsor collaborator and mentoring committee are all present at the University of Pittsburgh and can provide the support necessary for this candidate to succeed.