Unlocking the molecular secrets of cross-species transmission through ACE2 receptor analysis
What do tigers, minks, and deer have in common with humans? They've all fallen victim to COVID-19.
As the world grappled with the SARS-CoV-2 pandemic, scientists noticed something concerning—the virus wasn't just spreading among humans. Reports emerged from zoos, farms, and even wild environments of animals testing positive for the coronavirus. This discovery raised urgent questions: Which other species might be vulnerable? Could animals become reservoirs for the virus, potentially undermining our control efforts? 2
The answer lies in a tiny molecular handshake between the virus and a protein on our cells called ACE2.
Animal Species Confirmed Infected
Critical Amino Acid Sites
Species Analyzed
Families Studied
Angiotensin-converting enzyme 2 (ACE2) plays a vital role in our bodies far beyond its involvement in COVID-19. Normally, this protein helps regulate blood pressure and other physiological functions. But when SARS-CoV-2 emerged, scientists discovered the virus had evolved to use ACE2 as its primary entry point into cells 1 6 .
The now-infamous spike protein on the coronavirus surface acts like a key, and the ACE2 receptor serves as the lock. When the spike protein binds to ACE2, it opens the doorway for the virus to invade the cell. This molecular key-and-lock mechanism explains why the virus can jump between species—any animal with a similar enough ACE2 "lock" could potentially be infected 9 .
Through detailed structural analysis, researchers have identified specific regions on the ACE2 receptor that are crucial for binding to the SARS-CoV-2 spike protein. These key binding sites are located primarily on two domains: the α-helix 1 and β-sheet 5 regions 9 .
What makes this discovery so important is that while the overall ACE2 protein might differ considerably between species, the similarity at these specific binding sites often determines susceptibility.
This explains puzzling early observations—why some animals closely related to humans showed resistance to infection, while more distantly related species proved vulnerable. The critical factor wasn't overall genetic similarity, but rather the precise molecular structure at these handful of key positions where the virus makes contact 9 .
SARS-CoV-2 spike protein approaches the ACE2 receptor on host cell surface
Specific amino acids in the receptor-binding domain interact with ACE2 binding sites
Binding triggers structural changes in the spike protein
Viral and host cell membranes fuse, allowing viral entry
Traditional methods of predicting disease susceptibility often rely on phylogenetic relationships—how closely species are related on the evolutionary tree. But when it comes to SARS-CoV-2 susceptibility, this approach falls short. Bats, which are evolutionary distant from humans, are believed to be the natural reservoir for SARS-like coronaviruses, while some close primate relatives show lower susceptibility based on their ACE2 characteristics 9 .
The LCAS method begins by analyzing ACE2 sequences from species confirmed to be susceptible to SARS-CoV-2. By comparing these sequences, researchers identify the specific amino acid positions within key binding domains that are identical across all susceptible hosts. This creates a molecular fingerprint of susceptibility 2 .
Once this fingerprint is established, scientists can screen other species by checking whether their ACE2 receptors match this pattern at these critical sites. If there's a perfect match, that species is predicted to be vulnerable to infection. This method has proven to be a rapid, efficient screening tool that can prioritize species for further monitoring and research 2 5 .
| Species | Common Name | Evidence Level | Risk Category |
|---|---|---|---|
| Neovison vison | American mink | Natural infections documented worldwide 1 | High Risk |
| Felis catus | Domestic cat | Natural and experimental infections | Medium Risk |
| Odocoileus virginianus | White-tailed deer | Widespread infection in wild populations 1 | High Risk |
| Numida meleagris | Helmeted guineafowl | First avian species predicted susceptible 1 | Potential Risk |
| Rhinolophus sinicus | Chinese rufous horseshoe bat | Natural reservoir for related coronaviruses 1 | Medium Risk |
Modern bioinformatics research relies on a sophisticated array of computational tools and databases. The study of ACE2 receptors and their interaction with SARS-CoV-2 combines structural biology, phylogenetics, and molecular modeling to create a comprehensive picture of cross-species vulnerability 1 2 .
| Research Tool | Function and Application | Example Sources |
|---|---|---|
| ACE2 Receptor Sequences | Provide genetic blueprints for comparison across species | NCBI Protein Database, UniProt 2 5 |
| Homology Modeling | Predicts 3D protein structures based on known templates | SWISS-MODEL server 1 |
| Molecular Docking Software | Simulates how viral spike proteins interact with ACE2 receptors | FRODOCK 2.0 1 |
| Phylogenetic Analysis Tools | Reconstruct evolutionary relationships between species | MEGA X, MAFFT 1 2 |
| Protein Data Bank Resources | Provide 3D structural models of known protein complexes | PDB entry 6M0J (SARS-CoV-2 RBD + human ACE2) 1 |
Comparing ACE2 protein sequences across species to identify conserved regions
Simulating interactions between viral spike proteins and host receptors
Mapping susceptibility patterns onto evolutionary relationships
In a comprehensive 2024 study, researchers set out to systematically identify potential susceptible species by analyzing ACE2 receptors across a broad spectrum of mammals. Their approach combined multiple bioinformatics techniques to create a robust prediction model 2 5 .
The findings revealed several unexpected potential hosts, including the helmeted guineafowl (Numida meleagris), marking the first time an avian species had been predicted to be susceptible. The study also confirmed high susceptibility across numerous carnivores, primates, and ungulates, providing a molecular explanation for why outbreaks had occurred in mink farms, zoos, and wild deer populations 1 2 .
Perhaps most importantly, the research demonstrated that the LCAS method could successfully retrospectively predict known susceptible species while identifying new potential hosts of concern. This validated the approach as a valuable screening tool for assessing infection risks across domestic and wild animals 2 .
| Prediction Category | Number of Species | Representative Examples |
|---|---|---|
| Known susceptible species correctly identified | 29 | Cats, dogs, minks, deer, tigers 2 |
| Newly predicted susceptible mammals | 20 | Additional bat species, marine mammals 2 |
| Non-susceptible species correctly excluded | 60 | Many rodent and bird species 2 |
The LCAS approach demonstrated 92% accuracy in retrospectively identifying known susceptible species and successfully predicted several new potential hosts that were later confirmed through experimental studies.
The study of ACE2 receptors across species represents a crucial application of the One Health framework—the understanding that human, animal, and environmental health are inextricably linked. Identifying potential animal reservoirs of SARS-CoV-2 is essential for designing effective surveillance systems and preventing future spillback events that could prolong the pandemic or introduce new variants .
This research also carries significant implications for wildlife conservation and animal welfare. Knowing which species are vulnerable can help guide protective measures for endangered populations, inform zoo management protocols, and shape regulations for wildlife trade and farming practices. The devastating outbreaks on mink farms demonstrated the very real consequences of ignoring these interspecies transmission risks .
The molecular analysis of ACE2 receptors across species represents more than just academic curiosity—it's a vital tool in our pandemic preparedness arsenal. By understanding which animals are vulnerable to SARS-CoV-2 and related viruses, we can better monitor potential spillover events and detect emerging threats earlier 2 .
Future research directions include expanding these analyses to include coronavirus spike protein diversity, studying how viral evolution might alter host range, and developing more sophisticated computational models that incorporate additional factors beyond ACE2 binding. Each advance improves our ability to anticipate and prevent future outbreaks 7 9 .
As we continue to navigate the COVID-19 pandemic and prepare for future emerging diseases, this interdisciplinary approach—bridging computational biology, virology, and conservation science—will be essential for protecting both human and animal populations in our interconnected world .
The message is clear: in pandemic prevention, we must think beyond human health alone and consider the complex web of species that share our ecosystems and our vulnerabilities. Through continued scientific innovation and collaboration, we can work toward a future with fewer pandemics and healthier outcomes for all species on our planet.