Defining the Influence of Host Cell Proteostasis Networks and Temperature on Influenza Evolution

Abstract

Viruses accumulate mutations and evolve more rapidly than any domain of life. Not only does the random acquisition of mutations drive this high evolutionary rate, but constant pressure from the host also contributes. As minimalistic pathogens, viruses rely on host machineries to synthesize, fold, and degrade their proteins. These proteostasis machineries can influence the accessible sequence landscape of viral proteins, and thus shape their evolution. Furthermore, the entire viral replication cycle takes place within the host cell. Therefore, the environment of the host, including factors such as temperature, can influence the evolutionary trajectory of viral proteins. The overarching goal of my thesis work is to better understand the influence of the host cell environment, with a particular focus on the proteostasis networks and the temperature of the cell. My first project uses deep mutational scanning to elucidate the roles of the host proteostasis networks in defining influenza hemagglutinin’s evolutionary ability. My second project takes a similar approach to investigate how high or low temperature impact the accessible sequence space of HA. My third project combines both proteostasis network and temperature perturbations to investigate how the host cell environment can impact HA’s ability to escape neutralizing antibodies. My final project leverages the high mutation rate of influenza to study the phenomenon of error catastrophe, and the impact of altered proteostasis network environments on buffering the effect of mutations. Together, these studies clearly define a role for both the host proteostasis networks as well as temperature environment in determining influenza’s accessible sequence space, currently underappreciated factors in predicting how viruses evolve to evade selection pressures and a critical component to consider for successful vaccine and drug development as well as pandemic preparedness.