SARS-CoV-2 within-host population expansion, diversification and adaptation in zoo tigers, lions and hyenas

Abstract

Abstract SARS-CoV-2 rapidly adapts to new hosts following cross-species transmission; this is highly relevant as unique within-host variants have emerged following infection of susceptible wild and domestic animal species. Furthermore, SARS-CoV-2 transmission from animals (e.g., white-tailed deer, mink, domestic cats, and others) back to humans has been observed, documenting the potential of animal-derived variants to infect humans. Here, we investigate SARS-CoV-2 evolution and host-specific adaptation during an outbreak in Amur tigers ( Panthera tigris altaica ), African lions ( Panthera leo ), and spotted hyenas ( Crocuta crocuta ) at Denver Zoo in 2021. SARS-CoV-2 genomes from longitudinal samples from 16 individuals are evaluated for within-host variation and genomic signatures of selection, and we determine that the outbreak was likely initiated by a single spillover of a rare Delta sublineage. Within-host virus populations rapidly expand and diversify, and we detect signatures of purifying and positive selection, including strong positive selection in hyenas and in the nucleocapsid ( N ) gene in all animals. Four candidate species-specific adaptive mutations are identified: N A254V in lions and hyenas, and ORF1a E1724D, spike T274I, and N P326L in hyenas. These results reveal accelerated SARS-CoV-2 adaptation following host shifts in three non-domestic species in daily contact with humans.