Where Did Omicron Come From? Maybe Its First Host Was Mice

It’s one of the perplexing mysteries of the Covid pandemic: Where did Omicron emerge from, almost one year ago? The fast-moving, extremely contagious variant arrived just after Thanksgiving 2021, bristling with weird mutations. When scientists untangled the array, they found that Omicron wasn’t related to Delta or Alpha, the two waves that preceded it. Instead, its divergence from its closest common ancestor dated back more than a year, to the first few months of the pandemic—practically a geologic era in viral-replication time.

That was a conundrum. How could something be so communicable that it ripped through more than 120 countries in two months, yet have evaded detection for so long? Within the riddle lurked a puzzle: If Omicron developed not from earlier variants but in parallel to them, where was it hiding out all that time?

Competing hypotheses jostled for consideration: It had taken shelter in a group of people who had little contact with the outside world and no involvement in sequencing programs. It had found a home in someone so immunocompromised that they could not overcome the infection, ceding the virus territory in which to replicate and change. Or, a third thought: It fell back into the animal world—not into the bats in which it first found a host, but into some new species that would provoke mutation in novel ways.

That possibility, known formally as reverse zoonosis and informally as spillback, was already a known risk. In April 2020, just a few months after the virus began spreading internationally, it migrated into mink farms in the Netherlands, triggering the deaths or preventive slaughter of millions of the animals—and a few months later it traveled back into humans.

No one has been able to say with precision which of those three hypotheses accurately explains Omicron’s arrival—and with Omicron itself spinning off variants so rapidly, the discussion dropped out of researchers’ priorities. Now a new study from a research team at the University of Minnesota is giving that debate fresh energy. Their analysis suggests that Omicron adapted to mice, where it developed its mutational array before it passed into humans.

“These Omicron mutations are evolutionary traces left by the virus during its transmission from one animal species to another,” senior author Fang Li, a professor of pharmacology and director of the university’s Center for Coronavirus Research, said in a statement. (Li declined an interview.)

In the study, published last week in the Proceedings of the National Academy of Sciences, researchers took a structural biology approach—studying the shapes of molecules within the virus—to examine mutations in Omicron’s spike protein, which allows it to invade cells. They found certain mutations that made the virus more efficient in binding to a particular receptor, ACE2, as it exists in the cells of mice, compared to the version of that receptor present in humans. They confirmed that work by assembling non-infectious pseudoviruses expressing the Omicron spike protein and observed their binding with cells engineered to include the mouse or human receptors. They found that Omicron had more affinity for the mouse version.

This is not the first paper to suggest that mice played a role in fostering the emergence of Omicron. Last December, researchers at the Chinese Academy of Sciences proposed that the results of a laser spectroscopy analysis of its mutations are inconsistent with the pace of Omicron's evolution in humans but consistent with a more rapid pace of mutation in rodents. They also identified some Omicron mutations that had previously been spotted in earlier SARS-CoV-2 strains when mice were experimentally infected for Covid lab research.

Neither that study nor the new one comes close to closing the book on Omicron’s roots, of course. “This breathes some more life back into the idea that Omicron could have come from an animal reservoir,” says Angela Rasmussen, a virologist at the Vaccine and Infectious Disease Organization at the University of Saskatchewan. “I don’t think we have enough information to say it did emerge from there, but we can say that hypothesis is still on the table.”

And it underscores the fact that SARS-CoV-2 is able to bounce back and forth between wildlife and domesticated animals and the human world. Since those infections in mink more than two years ago, many more species have been found to be vulnerable. An open-access dashboard created by researchers at the University of Veterinary Medicine Vienna and the Wildlife Conservation Society in the US has recorded 735 identifications or infections in 31 species—almost certainly an undercount, since the underlying software scrapes data only from official sources. Among those identifications: a cat in Thailand, as well as hamsters in Hong Kong, which not only picked up some variety of SARS-CoV-2, but passed it back to their owners.

“We’ve got to be paying more attention to candidate reservoirs in the wild that might be vessels for mixing up this virus and then pose a risk for spillback transmission to humans,” says Sarah Hamer, a veterinary ecologist and professor of epidemiology at Texas A&M University. At the start of the pandemic, her research group pivoted away from work on other infections in which animals provide a bridge to humans—for instance, tickborne diseases and Chagas disease—and started looking for evidence of Covid. So far, they have documented the virus’s presence in domestic dogs and cats and captive white-tailed deer.

Pinning down whether wild animals that acquire the virus can also transmit it is a research challenge; they might be unfortunate victims but dead-end hosts. Last year, researchers from several Canadian universities and federal agencies demonstrated that North American deer mice, which live in woodlands and suburbs, can be experimentally infected with SARS-CoV-2, shed the virus, and expose other deer mice. But whether that would translate into an ongoing infectious risk—among mice or to humans—can’t be assumed from that data, says Darwyn Kobasa, the senior author, who is a research scientist heading high-containment respiratory virus studies at the Public Health Agency of Canada. In the real world, encounters between animals and humans are more difficult to trace.

“Mice are potentially prey for cats, so there could be an indirect connection, from mice through cats to people,” he says. “Or there may be something in the environment, where mice and humans come into contact with each other.”

Not everyone agrees on the role different species play in harboring the virus, let alone whether they can do so long enough for it to mutate and pose a novel threat to humans. And some scientists are changing their points of view as they accrue more data. In 2021, Missouri and New York researchers extracting viral genetic material from wastewater thought they might have identified a rodent signature in what they called “cryptic mutations” that have rarely been identified in humans. A year later, they have reinterpreted that work—and now lean more toward the possibility that immune-impaired people, who have suffered lengthy infections, might accidentally play a role in driving viral evolution.

“Many of the mutations that appear in those persistently infected patients also are the same ones that appeared in Omicron, and are similar to the ones that have appeared in the cryptic samples,” says John Dennehy, a virologist and professor of biology at Queens College of the City University of New York. “And a lot of people have looked for SARS coronavirus in mice and rats, and we’ve never really seen anything that would resemble those cryptic variants, or Omicron for that matter.”

Scientists who want to study the animals most likely to harbor the virus have few options for constructing research programs. At the moment, the most robust animal-disease surveillance programs keep track of species that anchor industries or ecosystems, like poultry, which are vulnerable to avian influenza, or elk, moose, and deer, which are subject to chronic wasting disease. Very broad surveillance for potential threats across multiple species is the dream of pandemic prevention. But it hasn’t yet received the funding—or scored the predictive hits—that researchers would like.

Hamer thinks existing programs, through which researchers are already hunting other diseases, could contribute to defining the spillback threat. They just need a little help. “There’s no shortage of wildlife biologists and field veterinarians that have the skills to safely trap, sample, and release critters. And there’s no shortage of the laboratory expertise to quickly figure out what’s got neutralizing antibodies, what’s got active viral shedding,” she says. In her own work tracking tickborne diseases, she has started taking nasal swabs of wildlife, in addition to the blood samples she already needed. “And then we bank those in the minus-80 freezer,” she says. “We’re waiting until we’ve got the resources to work them up for SARS-CoV-2.”

Where Did Omicron Come From? Maybe Its First Host Was Mice

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