Research

RNA arbovirus evolution: 

Arthropod-borne viruses (arboviruses), can emerge from epidemiologically silent periods to cause outbreaks as well as sporadic pandemics. To achieve this, they need to navigate distinct host environments and barriers to infection and transmission. The balance between transmission and virulence influences ongoing spread, the pathogenicity of disease, and even the potential to establish a pandemic outbreak. Therefore, ongoing viral evolution may generate important phenotypic variants, including strains that differ in host range, transmission mechanisms and efficiency, tissue tropism, antigenicity, and/or virulence. Although these novel biological functions often require multiple concerted genomic changes, how such combinations of mutations can arise and be favored by natural selection is unclear. Understanding the links between viral genetic variability and host specialization will provide fundamental insight into arbovirus population-level genetics and is critically important for revealing strengths and weaknesses of the virus that could be targeted for intervention.  Therefore, we combine experimental evolution with our well-established methods for deep sequencing data to identify patterns of viral evolution, and assess how viral genetic variability, pathogenesis, and transmission are linked. Understanding the processes that govern arbovirus evolution may allow us to predict and prevent future pandemics.  

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

Exposure to one flavivirus can elicit immune responses that cross-react with genetically related viruses in complex relationships, with a variety of impacts on subsequent flavivirus infections. The best-characterized example of this is within the dengue virus (DENV) serocomplex. Pre-existing immunity to one of the 4 DENV serotypes (DENV1-4) can increase the risk of severe disease upon infection with a different serotype in what is termed antibody-dependent enhancement (ADE). Emerging evidence suggests that immunological cross-reactivity among flaviviruses is not always reciprocal—that is, pre-existing immunity to virus A may protect against disease associated with virus B, while pre-existing immunity to virus B may increase the risk of disease upon infection with virus A. Thus, the degree to which pre-existing flavivirus immunity is cross-protective, enhancing, or neutral may depend on the order in which the host has encountered different flaviviruses. We are therefore integrating studies of flavivirus immunological cross-reactivity in nonhuman primate models and human cohorts to evaluate the impact of flavivirus exposure on virus replication dynamics, antibody repertoire diversity, neutralization titer, and Fc effector function. The goal is to examine how the order of exposure to DENV serotypes and to Zika virus (ZIKV) shapes cross-reactive antibody profiles in humans and macaques with matched exposure histories. We will then extend these studies to ask how exposure histories impact the capacity to respond to a novel antigenically related flavivirus, using Spondweni virus as a prototype. Our findings will have broad implications for assessing the risk of emerging viruses and disease in flavivirus-exposed populations and designing next-generation flavivirus vaccines.  

Powassan virus evolution, fitness, and pathogenesis

Tick-borne Powassan virus (POWV) is an emerging public health threat, but has been understudied to date. Since its discovery in 1958, human cases of POWV have been reported in the United States, Canada, and Russia. Starting in 2006, confirmed cases of POWV have increased in both frequency and scope in New England and the Upper Midwest. Notably, POWV is now considered an emerging public health threat because it has been frequently associated with the aggressive, human-biting blacklegged tick vector, Ixodes scapularis. The future spread of POWV is unpredictable, but it will be important to understand the potential for more widespread emergence. The goals of this project are to evaluate whether there are regional, local, and even hyperlocal differences in the genetic structure of tick and POWV populations that affect patterns of POWV host/vector competence, virulence, and evolution.  We seek to understand the phenotypic and genotypic underpinnings of virus–host dynamics for POWV using mouse and tick experimental systems. These studies are critically important because POWV likely will continue to emerge in the future. Therefore, understanding how POWV overcomes evolutionary barriers to emerge and cause disease in humans will be critical for prediction, prevention, and control of this arboviral disease.

Drivers of virus emergence:  

In addition to the laboratory-based components of my research program, I also maintain an active field-based research program. We aim to provide a deeper understanding of the complex determinants of arboviral disease by understanding entomological, social, and virological drivers of emerging infectious disease events. Currently,  we have been working in collaboration with the Minnesota and Wisconsin Departments of Health to better understand the changing epidemiology of tick-borne Powassan virus in these states. We are also evaluating the utility of metagenomic sequencing for pathogen surveillance and detection in Jos, Plateau State, Nigeria.

We are sequencing SARS-CoV-2 genomes to understand patterns of virus transmission and evolution, and are working with academic and public health partners in Wisconsin and Minnesota to implement genomic surveillance for SARS-CoV-2 in the Upper Midwest. In addition, we  are trying to sequence SARS-CoV-2 variants from air (see Detection of respiratory viruses in air samples). To accomplish this, we are using the  AerosolSense™ in-air surveillance system to determine how well these samplers detect SARS-CoV-2 and other respiratory pathogens in real-world congregate settings where there is complex ventilation and traffic patterns. Finally, we are testing for the presence of SARS-CoV-2 in MN wildlife species (especially cervids like moose) to better understand the changing landscape of zoonotic SARS-CoV-2 in the Upper Midwest.