Last Thanksgiving, Rilu, an eleven-year-old snow leopard and father of seven, started sneezing and wheezing. Snow leopards are native to the Himalayas, but Rilu was born in an Oklahoma City zoo and then moved to Miller Park Zoo in Illinois in 2011 to be part of the Species Survival Plan – the effort twinning zoos to maintain a genetically diverse “insurance” population of endangered animals. A PCR test in early December confirmed that Rilu had covid-19. He developed pneumonia and became weak, despite various attempts at treatment. On January 6, he became the fifth snow leopard in captivity in the United States to die from covid-19 complications within three months. There are about five thousand snow leopards in the wild, according to conservationists’ best estimates. Five leopards represent, at the species level, the equivalent of 7.9 million humans, or almost every person in New York City. (More than 5.7 million humans have died from covid-19 worldwide, over two years.) Leopard deaths are perhaps the most tragic example of the reverse zoonotic pandemic – when humans transmit a pathogen to animals.
Because ancestral SARS-CoV-2 first evolved in bats and then somehow ended up in humans, this is called a “zoonosis” – a disease that is transmitted from animals to us. About 75% of all emerging infectious diseases are zoonoses. But, as scientists learned in the early months of the pandemic, SARS-CoV-2 is easily transmitted to other species. Nor is it a picky virus. “I can’t think of a single zoonotic virus with such a wide host range,” Barbara Han, a disease ecologist, told me.
First there were pet dogs and cats, then tigers and lions at the Bronx Zoo. The list of infected zoo animals now includes gorillas, cougars, otters, spotted hyenas and hippos. Dozens of other species have been shown to be susceptible to SARS-CoV-2 in experimental laboratory infections including cows, African green monkeys, macaques, baboons, golden hamsters, dwarf hamsters, ferrets, raccoon dogs, European rabbits, deer mice , bank voles, skunks, marmosets and shrews. Outside of zoos, investigators found wild populations of free-ranging white-tailed deer in North America had been infected with SARS-CoV-2.
More recently, on February 7, scientists at Penn State published a paper (not yet peer-reviewed), revealing that the Omicron variant was prevalent among white-tailed deer on Staten Island. (The blood and nose samples were from an ongoing neutering program to control the borough’s deer population.) It’s not known if infected deer are showing symptoms, but they appear to be shedding and spreading the virus from the same way as humans. Evidence from antibody analysis suggests they may even be susceptible to reinfection, indicating the species’ potential as a SARS-Reservoir of CoV-2 – a distressing thought, given that their population numbers around thirty million and they thrive among humans. But whether the first deer to become infected caught it from a person or another animal “remains an open question,” Suresh Kuchipudi, a Penn State professor of virology and lead scientist on the study, told me. “The type of hidden exposure of the virus in animals is the most alarming part of this whole process.”
When SARS-CoV-2 spreads into new animal hosts, it adapts, accumulating mutations that could give rise to a new variant, which could then spill over to humans. “We were hoping to end this pandemic by, you know, vaccinating everyone,” Kuchipudi told me. “But, when the virus finds refuge in one or more other animals and continues to circulate, it creates a much more complex ecological transmission network, which is much more difficult to understand and manage.”
Reverse zoonosis could explain where Omicron came from. After it appeared in South Africa in November, scientists who sequenced its genome quickly saw something strange. Omicron has nearly fifty mutations compared to the original 2019 virus, and thirty-seven of them are clustered on its spike protein; that’s way more than there was on any of the other four variants of concern (Alpha, Beta, Gamma, and Delta). On the SARS-CoV-2 family tree – a map formed by approximately eight million people shared publicly SARS-CoV-2 genomes—Omicron sits on a branch, at the end of an exceptionally long branch. The scientists concluded that it did not derive from any of the other variants, but rather appeared to have evolved along its own trajectory. But where was he hiding?
In December, Beijing-based scientist Wenfeng Qian and a group of his colleagues came up with a possible answer: mice. In an article published in the Journal of Genetics and Genomicsthey argued that the Omicron mutations had been under greater pressure to evolve than the others SARS-Variants of CoV-2, which had evolved in human hosts, possibly indicating that it had evolved in a different species. They also discovered that some of the mutations in Omicron’s tip are the same mutations that had previously been found to help SARS-CoV-2 infects mice. (Scientists identified these mutations when they created mouse-adapted strains of SARS-CoV-2 in order to search for vaccines and therapeutics.) “Collectively, our results suggest that the progenitor of Omicron jumped from humans to mice, rapidly accumulated mutations conducive to infecting that host, and then returned to humans,” Qian and his co-authors wrote. Nobody can guess how infected mice could have infected people.
Trevor Bedford, a professor at the Fred Hutchinson Cancer Research Center in Seattle, and a leading expert on viral evolution and surveillance, said Qian’s paper “is the most compelling case of rodent origin that I ‘have seen”. But Bedford favors a more popular hypothesis, namely that Omicron evolved in a chronically infected immunocompromised patient, such as an HIV-positive person. “I would place more probability on the chronic infection pathway,” he wrote in an email, “but certainly not certain of that origin.” Richard Lessells, an infectious disease doctor in South Africa who was part of the team that initially identified Omicron, agreed. “My own view is still that chronic infection and evolution in a human host may be the most likely mechanism.”
Omicron has a mysterious insertion in its genome, which Bedford says could have been acquired while replicating for months in the cells of an immunocompromised person. But Qian said this “fragment in Omicron consists of only nine nucleotides, making it too short to reveal its source.” He and his co-authors argue that the more parsimonious explanation is that he came from another place in the SARS-CoV-2 genome itself. “All SARS-CoV-2 genome has this fragment,” he wrote in an email. (A new group formed by the World Health Organization to research the origins of the pandemic – the Scientific Advisory Group on the Origins of Novel Pathogens, or SAGO— is currently finishing a report that will deal with the emergence of Omicron. However, his conclusions, which are largely based on the available data, should not settle the debate.)
Omicron most likely evolved into its current form in South Africa, where it was first detected, or somewhere in the wider region, where vaccination rates and disease surveillance are low, until that it begins to rapidly infect people in South Africa. And yet, its geographical origin remains unclear, Marietjie Venter, South African researcher and president of SAGO, said. Maybe “it was just detected here first because we had almost no SARS-CoV-2 by the end of October, and it could outcompete the Delta variant by partial immune evasion. She added that they later discovered the variant was already circulating in Europe by the time her group detected it. In any case, “at the moment,” Venter said, “the hypothesis of reverse transmission to a mouse is interesting, but at this theoretical stage.” It is based only on the analysis of mouse strains in the laboratory, and not on the detection of Omicron in wild mice.
This could be because disease surveillance in wild animals is difficult, if any. House and deer mice have been shown in the laboratory not only to be susceptible to SARS-CoV-2, but able to transmit the virus through aerosolized particles (from cage to cage). Scientists have postulated that animals could contract the virus from human sewage, which research has found is full of SARS-CoV-2 variants. According to a computer model that Barbara Han and her colleagues have built, the broad-spectrum white-footed mouse, well known to New Yorkers and very close to the deer mouse, is susceptible. “It coexists quite easily with us,” she says, and poses a risk of “carrying SARS-CoV-2, becoming infected and transmitted. But if a mouse could transmit a SARS-The variant of CoV-2 in humans is unknown. “Hermetic evidence of this nature is usually very hard to find,” Han said.
Until recently, there was only one known secondary overflow event – when SARS-CoV-2 infected mink and spread like wildfire in fur farms across Europe; later, in the Netherlands, the virus was transmitted from mink to farmers. Thousands of mink were slaughtered, farms were closed and the fur industry was destroyed. Last week, however, researchers discovered that pet hamsters had likely transported the Delta variant to Hong Kong, sparking an outbreak at a pet store that ultimately led to infections in dozens of people.
Since Hong Kong has a robust contact tracing program, part of a broader effort to keep the number of cases to zero, officials could easily determine that the outbreak started in the pet store. ; that would be nearly impossible in the US and most other places. With wildlife – unsupervised, mostly invisible – anything is possible. “Given the number of infected people around the world,” Han said, “the chances of SARS-CoV-2 establishing itself in a new animal reservoir and just becoming this endemic source of new SARS-CoV-2 virus seems to be quite high.