Eleven days after being bitten by one of her prairie dogs, a 3-year-old girl from Wisconsin on May 24, 2003 became the first person outside of Africa to be diagnosed with monkeypox. Two months later, his parents and 69 other people in the United States had suspected or confirmed cases of the disease, which is caused by a relative of the much deadlier smallpox virus. The monkeypox virus is endemic in parts of Africa, and rodents imported from Ghana had apparently infected captive prairie dogs, North American animals, when an animal dealer in Texas took them in together.
The ongoing outbreak has affected more people outside Africa than ever before – nearly 1,300 cases as of June 7, across multiple continents, many of them men who have sex with men. But like the 2003 episode, today’s outbreak has raised a possibility that has researchers swallowing it: the Monkeypox virus could take up permanent residence in wildlife outside of Africa, forming a reservoir that could lead to repeated human epidemics.
No animal reservoir currently exists outside of Africa, but the 2003 outbreak in the United States was a close call, some scientists suspect, not least because nearly 300 animals of Ghana and the exposed prairie dogs were never found. “We narrowly escaped monkeypox taking hold in a wild animal population” in North America, suggests Anne Rimoin, an epidemiologist at the University of California, Los Angeles, who has long studied the disease in the Republic. Democratic Republic of the Congo (DRC). Ultimately, however, wildlife surveys in Wisconsin and Illinois never found the monkeypox virus, none of the infected humans transmitted the disease to others, and concerns about this exotic epidemic have evaporated.
Will North and South America, Europe, Asia and Australia – all of which reported cases of monkeypox during this outbreak – have the same luck this time around?
Viruses frequently ping-pong between humans and other species. Although COVID-19 is generally thought to result from the passage of SARS-CoV-2 from a bat or other host to humans, humans have, in ‘reverse zoonoses’, also infected white-tailed deer, mink, cats and dogs with the virus. A study in Ohio found antibodies to SARS-CoV-2 in more than a third of 360 wild deer sampled. And in centuries past, when humans transported plague and yellow fever to new continents, these pathogens created reservoirs in rodents and monkeys, respectively, which then re-infected humans.
As this monkeypox epidemic grows, the virus has an unprecedented opportunity to establish itself in non-African species, which could infect humans and provide greater opportunity for more dangerous variants to evolve. “Reservoirs of monkeypox in wild animals outside of Africa are a frightening scenario,” says Bertram Jacobs, a virologist at Arizona State University (ASU), Tempe, who studies vaccinia, the poxvirus that has served as a vaccine. against smallpox and helped eradicate this devastating virus from humans.
Public health officials in several countries have advised people with monkeypox lesions to avoid contact with their pets until they recover. Some 80% of cases occurred in Europe, and the European Food Safety Authority said no pets or wild animals had been infected as of May 24. But he added that “close collaboration between human and veterinary public health authorities is necessary to manage exposed pets and prevent disease transmission to wildlife.”
The potential for humans infected with the monkeypox virus to transmit it to wildlife outside Africa “warrants serious concern,” says William Karesh, a veterinarian at the EcoHealth Alliance who Last week spoke about this possibility at a consultation on monkeypox research organized by the World Health Organization. For now, he says, the limited number of human cases reduces the odds. But pet rodents are of particular concern, as are the large numbers of wild rodents – they make up 40% of all mammals – that frequently scavenge litter and could become infected from contaminated waste. “That’s a lot of opportunities,” he says.
Studies have yet to identify the African reservoir of the monkeypox virus. Although a laboratory in Copenhagen, Denmark, in 1958 first identified it in research monkeys from Asia, scientists now believe primates caught it from an African source. All human cases since the first was reported in 1970, in the DRC (then Zaire), could be linked to the virus which spread from animals in Africa.
So far, however, only six wild animals trapped in Africa gave the virus: three rope squirrels, a Gambian rat, a shrew and a sooty mangabey monkey. Antibodies to the monkeypox virus are most abundant in African squirrels. “We still have a poor understanding of the current reservoir other than its rodents,” says Grant McFadden, a poxvirus researcher who is also based at ASU.
But it is clear that monkeypox can infect many other types of animals in the wild and in captivity. A 1964 outbreak at a zoo in Rotterdam, the Netherlands, sickened giant anteaters, orangutans, gorillas, chimpanzees, a gibbon and a marmoset. Researchers intentionally infected many laboratory animals, including rabbits, hamsters, guinea pigs and chickens, although the virus did not reliably cause disease in several of them.
For many viruses, a lock and key relationship between viral surface proteins and host cell receptors determines which animals it can infect; the SARS-CoV-2 spike protein, for example, locks onto angiotensin-converting enzyme 2, a protein that spikes a variety of cells in humans, minks, cats and many others species. But poxviruses do not appear to require specific host receptors, allowing them to infect a wide range of mammalian cells. Vaccinia, the smallpox vaccine virus, can even infect fruit flies in addition to cows and humans, notes David Evans, a poxvirus researcher at the University of Alberta, Edmonton. Bernard Moss, a virologist at the US National Institute of Allergy and Infectious Diseases (NIAID), postulated that some poxviruses have proteins on their surface that form a “hydrophobic face” a water-repellent zone that can bind non-specifically to hydrophilic cell membranes and initiate the infection process.
But whether a poxvirus can copy itself and ultimately persist in a species to create a reservoir depends on its ability to fend off host immune attacks. Poxviruses have a relatively large number of genes, about 200, and about half undermine a host’s immune response. “Some viruses run and hide or are stealthy, avoiding direct contact with elements of the immune system,” says McFadden. “Poxviruses rise and fight across the board.”
Their defense against host immunity appears to rely heavily on a family of genes scattered around their genomes that code for poorly understood proteins containing domains known as ankyrin repeats. Poxvirus proteins containing these repeats act like “molecular fly paper,” says Evans, attaching themselves to host proteins involved in coordinating the immune response. “Orthopoxviruses have these arrays of ankyrin repeats, and most of them, we don’t really know what they’re targeting,” Evans says. “But the bottom line is that these probably hold the key to trying to figure out why some of these viruses have the host range that they do.”
Smallpox, the pox virus, seems to have lost many of these immune evasion genes. It persists only in humans and has no animal reservoir, which is why the global vaccination campaign could eradicate it. Monkeypox is clearly more promiscuous. But the many questions that remain about it mean it’s impossible to say whether it will create reservoirs in non-African wildlife. “One of the challenges has been a lack of interest,” says Lisa Hensley, a microbiologist with the U.S. Department of Agriculture who began researching monkeypox in 2001 as part of a lab at the University. US Army.
Hensley, who worked on monkeypox at NIAID for nearly a decade and collaborated with Rimoin, urges people to keep an open mind about how the virus behaves and what it might do next. “We recognize that this is a disease we need to be concerned about and that we really don’t know as much as we think we know.”