Host-Focused Approaches to Investigating Virus Emergence

Zooanthroponosis is a major threat to global human and animal health. Zooanthroponotic transmission of SARS-CoV-2 has occurred multiple times throughout the pandemic in numerous animal species that are susceptible to infection. SARS-CoV-2 likely originated from zoonotic spillover associated with live animal sales at the Huanan Seafood Market in Wuhan, China. In addition, there have been global reports of SARS-CoV-2 “spillback” into and subsequent transmission among wild, captive, and domesticated nonhuman animal species, including farmed mink, companion animals, captive animals, and wildlife. However, these discoveries have typically been incidental and there has been no systematic study of species-specific susceptibility to SARS-CoV-2. Thus, there are likely additional animal species that serve as incidental hosts for SARS-CoV-2 and present a risk for establishment of new animal reservoirs in North America, as well as the emergence of new potential variants. We have identified candidate species at the Huanan market that may have been intermediate hosts involved in initial zoonotic spillover and North American animal species that present a high risk for SARS-CoV-2 zooanthroponosis. We generated expression constructs of these species’ ACE2 orthologs for testing susceptibility to infection with different SARS-CoV-2 variants, including the ancestral Wuhan-1 strain, D614G, and the five variants of concern (VOCs). We have further developed an analytical pipeline for assessing host susceptibility based on host transcriptomic data, using environmental sequence data obtained from the Huanan market to identify cross-species host signatures of infection. Susceptible species will be prioritized for downstream permissivity, surveillance, evolution, and pathogenesis studies, with the ultimate goal of assessing risk and deploying countermeasures such as vaccination at the human-animal interface. This work is also being expanded to study potential reservoirs for other emerging viruses such as MERS-CoV and mpox (monkeypox) virus, including in field studies and pathogenesis models to assess zoonotic risk and pandemic potential.