Functional Convergence at the Host-Virus Interface

Project summary
Viruses and the organisms they infect impose strong reciprocal selective pressure on each other. This is
particularly pronounced at protein-protein interfaces between viruses and their hosts, such as in the case of
antiviral proteins and the virus-encoded proteins that they target. Studying the biology of infection therefore
provides insight into infectious disease as well as into the underlying mechanisms of protein evolution. Host-
virus interactions have been extensively studied in mammals and to a lesser extent other vertebrates, yet
protein-based immunity has been studied less in other metazoans. Studying protein-based immunity in
divergent species will provide an important comparative point to better understand how antiviral proteins
evolve. It additionally presents an opportunity to characterize unique ways by which other species combat
viral infection, with potential implications for our own struggles with viral diseases. This Pathway to
Independence proposal will support the development of a research program focused on the use of structural
homology as a means of uncovering and studying independently evolved effector proteins, both in
understudied, biodiverse species and in the viruses that infect them. Throughout the proposal, structural
modeling is used to close the gap in our understanding of the structural and functional diversity present in
the proteomes of model organisms and viruses and those that have been less studied. In Aim 1, I will perform
extensive structural homology searches for viruses and diverse animals. The goals of these searches will
be to 1) define patterns of gene capture in diverse viruses, with focus on unique domain organizations, and
2) define structural homologs of antiviral proteins in diverse metazoans. Aim 2 investigates the apparent
independent evolution of an antiviral zinc finger-containing protein in mollusks and vertebrates. This aim will
provide insight into how domains adapt to serve unique functions. It integrates virological and biochemical
approaches to understand the relationship between RNA binding properties and antiviral potential of proteins
that include this domain. Aim 3 involves the use of yeast as a heterologous system to study the functional
plasticity of antiviral EIF2a kinases and virus-encoded proteins that inhibit them. This aim will provide insight
into the rules of pathogen sensing by kinases and expand the study of translational shutoff during viral
infection beyond vertebrates and model organisms. Aims 2 and 3 of this proposal will establish a foundation
for the future study of other independently evolved effector proteins, such as those found in the searches
proposed in Aim 1. This proposal will provide me with extensive training to attain my career goals. I already
have robust experience in molecular biology and virology techniques, as well as a developing skillset in
computational biology. By completing the Aims of this proposal, I will learn new techniques in computational
biology, biochemistry, and yeast genetics from my outstanding mentor and advisory committee that will
supplement my skillset and diversify the research paradigms in my future independent career.

Grant Number: 5K99GM155323-02
NIH Institute/Center: NIH
Principal Investigator: Ian Boys