The zoonotic origin of the COVID-19 pandemic virus highlights the need to fill the vast gaps in our knowledge of SARS-CoV-2 ecology and evolution in non-human hosts. Here, we detected that SARS-CoV-2 was introduced from humans into white-tailed deer more than 30 times in Ohio, USA during November 2021-March 2022. Subsequently, deer-to-deer transmission persisted for 2–8 months, disseminating across hundreds of kilometers. Newly developed Bayesian phylogenetic methods quantified how SARS-CoV-2 evolution is not only three-times faster in white-tailed deer compared to the rate observed in humans but also driven by different mutational biases and selection pressures. The long-term effect of this accelerated evolutionary rate remains to be seen as no critical phenotypic changes were observed in our animal models using white-tailed deer origin viruses. Still, SARS-CoV-2 has transmitted in white-tailed deer populations for a relatively short duration, and the risk of future changes may have serious consequences for humans and livestock.

In 2010, H14 influenza A viruses were recovered from clinically normal sea ducks in the United States. These are the first H14 isolates recovered in the Western Hemisphere and represent the only documented H14 influenza A viruses isolated since the original isolates were recovered from near the Caspian Sea during 1982.

In late 2021, Eurasian-lineage highly pathogenic avian influenza (HPAI) A(H5N1) viruses from HA clade 2.3.4.4b were first detected in the United States. These viruses have caused severe morbidity and mortality in poultry and have been detected in numerous wild and domestic animals, including cows and humans. Notably, infected cows transmitted the virus to cats, causing extreme pathogenicity and death. While human-to-human spread of the virus has not been recorded, efficient transmission of the bovine-origin virus has also led to extreme pathogenicity and death in ferret models. Recently, markers in PB2 (E627K) and HA (E186D, Q222H), indicating mammalian adaptation mutations, were detected in an H5N1-infected patient manifesting critical illness in Canada. These, combined with instances of interspecies spread of the virus, have raised global public health concerns. This could highlight the potential for the virus to successfully adapt to mammals, posing a serious risk of a global outbreak. A One Health approach is, thereby, necessary to monitor and control the outbreak. This review aims to analyze the epidemiology, transmission, and ecological impacts of HPAI A(H5N1) clade 2.3.4.4b in the U.S., identify knowledge gaps, and inform strategies for effective outbreak management and mitigation.