Immunity-guided virus discovery
We created zebrafish that turn green when antiviral immunity is activated. We use these fish as sentinels to illuminate asymptomatic and pre-symptomatic virus infections that are otherwise invisible, leading to discoveries of diverse naturally occurring viruses in laboratory settings and other environments. These co-evolving viruses provide versatile new tools for investigating infection biology in vertebrates.
Infection biology from cells to systems
The relatively small size of zebrafish provides an opportunity to dissect antiviral activities in all cell types at once. We are integrating multiple single cell modalities (sequencing, imaging, etc.) with infected zebrafish to comprehensively chart the genetic and cellular networks that process and produce antiviral immunity in vertebrates.
Patterning of antiviral immunity
Immune responses to virus infections must be tuned to provide adequate defense while limiting the risk of excessive inflammatory damage. How do vertebrates compartmentalize antiviral activities to effectively manage the balance of defense and disease? We are using zebrafish to decode the organismal addressing system of antiviral signaling during infection by viruses that replicate in different tissues.
Quantifying impacts of virus infection
Disease-causing infections draw our attention for good reasons. However, the high frequency at which viruses are discovered in asymptomatic hosts suggests that overt disease results from only a small fraction of virus-host interactions. Are asymptomatic and disease-causing infections immunologically distinguishable? If the vast majority of infections can be categorized as asymptomatic, do they play a meaningful role in host and virus evolution? Addressing these questions requires new quantitative definitions of infection that can account for the full spectrum of disease states caused by viruses.
Antiviral origins and innovations
Interferons emerged in early gnathostomes and serve as the main antiviral alarm signals in all jawed vertebrates. Due to its central importance, the IFN system is also a primary target for disruption by viruses. How has the IFN system diversified over hundreds of millions of years of co-evolutionary conflict with viruses? We are investigating IFN signaling conservation and diversity across vertebrates (images on tree are scaled by number of species in each group), using zebrafish to test hypotheses about antiviral gene evolution and function.
Evolution of virus host range
Host switching is the primary catalyst for infectious disease outbreaks, which pose perpetual threats to human health and agriculture. Understanding how viruses switch host specificities is critical for preventing or managing new viral outbreaks. We are using zebrafish (Danio rerio) and its relatives as a model clade for virus discovery and for experimentally identifying host and viral determinants of virus host range and switching.
Viruses of other research organisms
We are collaborating with Ryan Langlois's lab at the University of Minnesota to develop new platforms for virus discovery and experimentation in mice and other rodents. These approaches involve sequencing of tissues from laboratory mice that were co-housed with rodents from other environments to discover viruses and immune barriers to transmission within and between host species.