Evolution, persistence, and spread of endemic viruses

There is a huge diversity of human endemic viruses - and most of us are infected by many of them each year - yet so much of our research focuses on only a few 'headline' pathogens. Though our deeper understanding of viruses like HIV and influenza has been critical to combatting them, it only scratches the surface of a broader understanding of how human viruses evolve and the interplay with human immunity. As the pandemic has highlighted, our ability to understand, anticipate, and respond to new viral threats is limited by what we've previously discovered in other viruses. With high-throughput sequencing and characterization of SARS-CoV-2 now common place, I believe we have an unprecedented opportunity to gain a much more comprehensive understanding of viral diversity and variation by embarking on a comprehensive, phylogenetic approach to study endemic human viruses.Focusing on the Enterovirus family, with Enterovirus D68 (EV-D68) as my starting point, I aim to exploit both publicly available sequence and serological data to explore (i) phylogeography: the seasonal patterns and geographic connections between outbreaks; (ii) genetic bottlenecks and diversity: how lineages diversify and persist between outbreaks; and (iii) antigenic evolution: how immunity is shaped by initial and subsequent exposures and whether viruses evolve to evade this immunity.Aim 1: Create phylogenetic analyses, starting with EV-D68 but expanding to other non-polio Enteroviruses (NP-EVs), to explore geographic connections, antigenic evolution, and genetic diversity. By including available demographic information, I can describe the geographical spread and mixing both within and between outbreaks and the patterns observed in countries exchanging viruses, as well as investigate associations with clinical data. Additionally, the COVID-19 pandemic created an unprecedented reduction in viral respiratory viruses, resulting in a unique opportunity to study persistence, genetic bottlenecks, and characteristics of successful lineages.Aim 2: In this collaborative aim, I will investigate the role of antigenic evolution and the contribution of asymptomatic infection to circulation and persistence. We will measure titres of multiple serum samples against a panel of antigens and integrate them with viral phylogenies in time and space. I will infer the likely exposure profiles for individuals of different ages from different places and construct an optimal set of antigen samples that span viral diversity. Using cross-sectional and longitudinal sera, I will quantify cross-reactivity across clades and time (looking for signs of 'original antigenic sin'), and investigate the impact of reinfection. Aim 3: Integrate epidemiological, phylodynamic, and serological data into models to explore hypotheses about transmission and immunity. Using models that incorporate naïve children, variable immunity in adults, and travel data prior to and during outbreak periods, I can explore what parameters allow us to replicate the periodic outbreaks observed in children, whether adults serve as a reservoir between outbreaks, and how variants mix during and between outbreaks regionally and globally.Through metagenomics, we are gaining an ever more detailed descriptive picture of what viruses live with us; my aim is to complement these efforts through a comprehensive understanding of how these individual virus species spread and change. Through phylogenetic and serological study of Enteroviruses, we can better comprehend the long-standing interplay of human immunity and the evolution of the endemic viruses that we encounter throughout our lives. In my proposed project, I will start to create the framework for exploring the evolution, dynamics, and transmission of the common endemic viruses that we live with every day.