Zoonotic diseases arise from spillover pathogen transmission from wildlife to human populations. Zoonotic pathogens can have catastrophic impacts on society, and their emergence is increasing amid global change. Prior to infecting humans, zoonotic pathogens circulate in wildlife hosts across complex ecological and evolutionary contexts that shape their potential for spillover transmission. Understanding host-pathogen relationships in natural environments is therefore critical for mitigating zoonotic spillover and disease emergence. Orthohantavirus is a globally distributed genus of viruses that circulate primarily in rodents and other small mammals. Human infection with orthohantavirus occurs through contact with infected rodents or inhalation of viral particles from rodent excreta and can manifest as disease, with mortality ranging from <0.1% to 60% depending on the orthohantavirus lineage. The biological theory of orthohantavirus originally held that each orthohantavirus has a single rodent host species. This dissertation reassesses orthohantavirus-host relationships in light of findings showing that many orthohantaviruses can infect multiple host species. Across three chapters, this dissertation investigates how orthohantavirus-host relationships unfold at global, community, and species scales using network analysis, geographic and environmental data, and evolutionary modeling. Through this multi-scale approach, this research shows that host community structure, geographic range, and evolutionary history jointly shape orthohantavirus host relationships and spillover risk across scales. Collectively, these findings indicate that orthohantaviruses are better understood as existing within broader host communities shaped by environment, geography, and evolutionary history. This conceptual shift in orthohantavirus-host theory from a one-host one-virus to a multi-host system has important implications for evaluating and mitigating spillover risk.

Zoonotic diseases are caused by pathogens that originate from wildlife but can spill over to infect humans, resulting in a new disease. The emergence of zoonotic diseases is increasing and represents one of the most pressing challenges in public health. Hantavirus is a zoonotic virus that generally comes from rodents but can infect humans, posing a severe public health challenge. Hantavirus spreads to humans through contact with infected wildlife hosts, which are primarily rodents, or by inhaling virus from their droppings. In humans, infection can cause severe lung or kidney disease and can sometimes be fatal. Hantaviruses have been found worldwide in a variety of wildlife hosts and are associated with different diseases in humans. For many years, scientists believed that each hantavirus was associated with only one specific rodent species. This dissertation challenges that theory by drawing on recent findings showing many hantaviruses can infect multiple wildlife hosts. This dissertation approached the problem from three scales: a single host species, multi-host communities, and the global host-virus system. To investigate hantavirus-host relationships at these three scales, this research utilized environmental, geographic, and evolutionary methods and data. Together, these studies demonstrated that hantaviruses do not exist in isolation within one rodent species, they circulate in communities of wildlife hosts. The host communities that carry hantaviruses are shaped by long-term relationships influenced by global hantavirus evolution and the environment.

Doctor of Philosophy