Sierra and Andrea working in a biosafety cabinet in the BL3

Research

Research

We study mechanisms by which RNA viruses overcome evolutionary barriers to emerge, be transmitted, and cause disease. Our overarching goal is to use our understanding of viral evolution and disease mechanisms to contribute to controlling and preventing viral pandemics.

RNA viruses like influenza, HIV, and Zika frequently have high mutation rates and fast generation times. They can also reach very large population sizes in infected hosts. For these and other reasons, RNA viruses can rapidly adapt to changing environments and selective pressures. But this evolutionary capacity is not unlimited — it’s tempered by various constraints on viral fitness and population sizes. Currently our work focuses on answering 3 big questions about RNA virus evolution, pathogenesis, and immunity.

  1. How do transmission bottlenecks impact influenza virus evolution?

Influenza viruses cause seasonal epidemics and occasional pandemics. Viral evolution plays a key role in both these processes. Severe influenza seasons can occur when circulating seasonal viruses acquire mutations that allow them to escape from human immunity. Pandemics occur when novel influenza viruses emerge from animal reservoirs and are transmitted in humans. We want to know more about the evolutionary pathways influenza viruses can take within and between hosts to result in disease in human populations. 

Previous work by our lab and others showed that airborne transmission of influenza viruses involves a genetic bottleneck. That is, viral genetic diversity present in one infected host is mostly lost after transmission to a new host, probably because new infections are initiated with a very small number of individual flu viruses. The genotype of viruses passing through this bottleneck forms the basis for onward evolution in the next host, so defining what factors determine which viruses survive the transmission bottleneck will give us important information about the evolutionary potential of influenza viruses. We want to understand how transmission bottlenecks impact evolutionary processes including adaptation of avian influenza viruses to humans (host switching) and antigenic variation in seasonal influenza. We hope this work will help inform the design of surveillance measures as well as influenza vaccines.

  1. What evolutionary processes govern the emergence and host adaptation of arboviruses like Zika and dengue?

We have been studying the pathogenesis of Zika virus (ZIKV) since its emergence in the Americas in late 2015. As part of this work we want to find out how viruses like ZIKV overcome evolutionary barriers to emergence to cause large-scale outbreaks. How does this process affect viruses’ ability to cause disease, evade host immunity, and get transmitted? To address these questions, we use animal models of arbovirus infection coupled with deep sequencing to study how virus populations evolve within and between hosts in different situations. Through this work we hope to uncover mechanisms by which viruses emerge and cause disease. We hope this work will inform responses to existing outbreaks and help prepare faster, more targeted responses to newly emerging disease threats. 

  1. How does pre-existing immunity shape the outcome of infections with antigenically variable viruses?

Most vaccines are designed to protect naive individuals — people who have not yet been exposed to the targeted pathogen. However, designing vaccines against antigenically variable pathogens like influenza or dengue virus (DENV) incurs a special challenge. Most people we vaccinate have already been exposed to the pathogen. We are becoming increasingly interested in how pre-existing immunity can shape the immune response to vaccination or infection with antigenically related pathogens. Ongoing projects in the laboratory are examining how pre-existing immunity to DENV affects the outcome of ZIKV infection in pregnancy. This work will have implications for the safety of DENV and ZIKV vaccines and, we hope, will enhance our understanding of how these viruses interact antigenically.