CAREER: Museomic approach for exploring the evolution of past, persistent, and emerging orthopoxvirus outbreaks

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Determining which animals a virus can infect remains a major obstacle for understanding how pathogens are maintained in natural populations and their potential spillover threat to humans. This is especially true for the group of viruses that includes smallpox, one of the deadliest pathogens in human history. A major unanswered question tied to this deadly pandemic is why some species of pox viruses are able to infect multiple animals while others only infect one. In light of the recent outbreak of monkeypox, a pox virus capable of infecting multiple species, the need to better understand host-pox virus diversity and evolution is of particular importance. This project will use novel technologies combined with historic and modern samples of animals housed in natural history museums to expand our understanding of pox virus infection across the tree of life. Additionally, this project advances the goals of the NSF by increasing diversity in STEM and creating a diverse workforce by placing underrepresented minorities at the center of cutting-edge research. Specifically, this work involves linking a primarily undergraduate, minority-serving institution with partnerships at several premier research institutions in Chicago and beyond, creating a network of opportunities for students engaged in the project. This project will leverage a large series of historical museum specimens from regions and time periods when pox outbreaks were known to occur, and advance genomic techniques to expand our knowledge of pox-virus evolution and host diversity. The proposed work will focus on three museum collections, targeting: a past outbreak (smallpox); a current outbreak (monkeypox); and finally, an emerging threat (Alaskapox). Viral genomes will be generated from pox-positive samples using a combination of high throughput sequencing and targeted enrichment approaches, allowing researchers to elucidate the evolutionary history of these complex but little-studied pathogens. Such data will be used to answer a suite of questions related to the evolution of Orthopoxvirus including: 1) How does genome architecture influence host range for different species of pox viruses? 2) Do intermediate hosts or distantly related hosts play a role in Orthopoxvirus diversification or transmission? and 3) Does increasing the known diversity of Orthopoxvirus in mammals help resolve the phylogenetic position and origin of human smallpox?This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.