A newly developed tool that can predict animal susceptibility to Covid-19 provides evidence that horses and camels may be at increased risk from the virus.
Horses and camels should be tested or closely monitored for Covid‐19 infection, the researchers who carried out the work wrote in their just-published paper.
The tool was developed by a team of experts in virology, genetics, structural biology, chemistry, physiology, medicine, immunology and pharmacology from Vanderbilt University in Tennessee.
They collaborated to developed the technology to understand and predict animal susceptibility to the virus that has killed more than a million people and, on the latest estimates by the World Health Organisation, has already infected 1 in 10 people worldwide.
The investigators applied a combination of sophisticated genetic sequence alignment and structural analysis of ACE2, the receptor protein for SARS-CoV-2 (the scientific name for the virus), to a variety of known susceptible and non-susceptible species.
Through the analysis they identified five particular amino acid sites within the protein that distinguish virus susceptibility or resistance, and using these sites developed an algorithm to predict susceptibility of unknown species.
The algorithm, available online, allows other researchers to upload the aligned ACE2 sequence of animals with unknown susceptibility to generate a Covid-19 susceptibility score.
Jacquelyn Brown, a staff scientist at the Vanderbilt Institute for Integrative Biosystems Research and Education, initiated the project.
“When I first learned that Covid-19 had crossed the species barrier into cats and dogs, I became worried about other animals that might act as reservoirs for the disease or be at risk,” explained Brown, an avid equestrian who practices medieval mounted archery.
“Since MERS (Middle East Respiratory Syndrome) infects camels, I was concerned about what would happen if my horse could get it. Horses have massive lungs and a sensitive respiratory system, and we humans often touch their noses and mouths.”
Brown proposed a collaborative research project on the topic to Professor John Wikswo, who holds appointments in physics, biomedical engineering, and molecular physiology and biophysics.
Wikswo immediately assembled a research team spanning Vanderbilt schools and colleges and the Vanderbilt University Medical Center.
“I speak each discipline’s language well enough to make the necessary connections,” Wikswo said. “This proved to be an outstanding group brought together by their interests and skills that produced an important result in very short order.”
The work could not have been achieved without the collaboration of many researchers.
“The multidisciplinary approach revealed how much information can be wrung from the same basic information,” noted Wenbiao Chen, a co-author and associate professor of molecular physiology and biophysics.
“We found potential targets by sequence comparison but wouldn’t have been able to interpret our findings without structural information. The project gave meaning to each researcher, at a time when we all were searching for ways to contribute to fighting Covid-19.”
Matthew Alexander, an assistant professor of medicine who was also involved in the research, said: “Understanding the animals we should more closely scrutinize based on their susceptibility to Covid-19 can help us protect people, pets, wildlife, livestock and our food sources.”
The algorithm the team developed is particular to SARS-CoV-2 because it focuses on its particular receptor binding protein ACE2, but the approach is broadly applicable to predicting susceptibility to other viruses or during future outbreaks.
Meena Madhur, associate professor of medicine and associate director of the Vanderbilt Institute for Infection, Immunology and Inflammation, said: “There is also the opportunity to investigate if the identified five sites on ACE2 that most distinguish susceptible from non-susceptible species can be used as targets to develop drugs that inhibit these sites specifically.
“I hope that our results will inspire future research on both rational drug design and closer examination of at-risk species.”
The work and collaboration were conducted remotely, with an analysis of publicly available data.
Alexander noted: “This experimental approach of using extensive and rapidly accumulating publicly available data in new ways allowed us to efficiently answer a timely question without having to generate new datasets.
“The collaboration was fun and rewarding, and we were able to answer an important question that none of us could have solved alone.”
Wikswo pointed out that while the source data was public, the project required massive calculations of how different versions of the virus would bind to each animal’s ACE2.
The team, in reporting on their work in the Federation of American Societies for Experimental Biology Journal, noted that while SARS‐CoV‐2 is a zoonotic disease, little is known about variations in species susceptibility.
Identifying susceptible species is crucial in identifying potential animal reservoirs and in assessing the risk to pets, wildlife, and livestock.
“Certain species, such as domestic cats and tigers, are susceptible to SARS‐CoV‐2 infection, while other species such as mice and chickens are not,” they noted.
However, most animal species, including those in close contact with humans, have unknown susceptibility.
The study team found that SARS‐CoV‐2 is nearly optimal for binding to the ACE2 of humans compared to other animals, which may underlie the highly contagious transmissibility of this virus among humans.
Their work revealed high scores in the susceptible range for Chinese horseshoe bats, horses and camels; and intermediate susceptibility scores for the Malayan pangolin, cow, goat and sheep.
The animal with the highest susceptibility score tested so far is the rhesus macaque.
Discussing their findings, the study team said: “Our results suggest that horses and camels should be tested and/or closely monitored for evidence of Covid‐19 infection.
“The close interaction of these animals with humans and the importance of these animals as domestic companions and laborers worldwide make the determination of their susceptibility to an urgent need.
“The use of the susceptibility score developed here can also be applied to additional species of interest to help direct resources for focused research and protection efforts in the future.”
The researchers said their work also identified key structural regions of the ACE2 and SARS‐CoV‐2 interaction for therapeutic targeting.
It also identified animal species on which to focus additional research and protection efforts for environmental and public health.
Members of the collaborative project also include Distinguished Research Professor of Chemistry Jens Meiler, Clara Schoeder, co-first author and postdoctoral scholar, Charles Duncan Smart, graduate student in molecular physiology and biophysics, Chris Moth, a computational chemist in the biological sciences department, and Tony Capra, research associate professor of biological sciences.
The work was supported by National Institutes of Health grants and American Heart Association funding.
Predicting susceptibility to SARS‐CoV‐2 infection based on structural differences in ACE2 across species
Matthew R. Alexander, Clara T. Schoeder, Jacquelyn A. Brown, Charles D. Smart, Chris Moth, John P. Wikswo, John A. Capra, Jens Meiler, Wenbiao Chen, Meena S. Madhur.
The FASEB Journal, 04 October 2020 https://doi.org/10.1096/fj.202001808R