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TitleSpecies- and variant-specific ACE2 compatibility shapes SARS-CoV-2 spillover potential in North American cervids.
Journal, issue, pagesNat Commun, Year 2026
Publish dateApr 9, 2026
AuthorsConstanza Espada / Kai Ye / Yingyi Long / Kritika Pasai / Thomas J DeLiberto / Jonathon Heale / Riley Wiese / Qiongying Yang / Mingyi Zhou / Sean Streich / Yizhi Jane Tao / Jeffrey C Chandler / Xiu-Feng Wan /
PubMed AbstractFree-ranging white-tailed deer (WTD) are established SARS-CoV-2 reservoirs, but the susceptibility of other cervid species remains unclear. Here we integrate receptor analysis, structural modeling, ...Free-ranging white-tailed deer (WTD) are established SARS-CoV-2 reservoirs, but the susceptibility of other cervid species remains unclear. Here we integrate receptor analysis, structural modeling, and field surveillance to assess SARS-CoV-2 susceptibility across North American cervids. We identify species- and variant-specific differences in ACE2-spike compatibility. Elk ACE2 exhibits weak binding to the ancestral strain (Wuhan-Hu-1) and Delta spike receptor-binding domains (RBDs), likely due to a unique K31N substitution. In contrast, it shows stronger binding to Alpha, Beta, Gamma, and Omicron RBDs containing N501Y. Biophysical assays, gel filtration chromatography, and cryo-EM confirm stable complex formation between elk ACE2 and Alpha RBD, but not RBD from the ancestral strain. Despite weak binding, elk ACE2 supports viral entry and replication in vitro. However, surveillance revealed limited evidence of infection in the United States, contrasting with widespread WTD transmissions. These findings demonstrate that ACE2 compatibility alone is insufficient to predict reservoir potential and provide a framework for assessing species susceptibility to emerging coronaviruses.
External linksNat Commun / PubMed:41957014
MethodsEM (single particle)
Resolution3.3 - 3.37 Å
Structure data

72207

9q3u

EMDB-72207, PDB-9q3u:
Cryo EM structure of elk ACE2 in complex with SARS-CoV-2 spike trimer
Method: EM (single particle) / Resolution: 3.37 Å

72208

9q3v

EMDB-72208, PDB-9q3v:
Cryo EM structure of elk ACE2 in complex with XBB 1.5 spike RBD
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • severe acute respiratory syndrome coronavirus 2
  • cervus canadensis (elk)
  • Severe acute respiratory syndrome coronavirus
KeywordsVIRAL PROTEIN / SARS-CoV-2 / Cervidae / ACE2 receptor / viral host interaction / host susceptibility

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