Virus World

Early in 2017, a team of medical personnel, including doctors, nurses and volunteers, returned home to Florida after volunteering at a clinic in Haiti. Soon after their return, 20 members of the team began to feel a bit under the weather. "They had a slight fever and didn't feel 100% right," says virologist John Lednicky at the University of Florida. "But they weren't very sick." At the time, Zika virus was circulating in Haiti, and health officials were worried the travelers might have been infected, potentially importing the mosquito-borne illness to Florida. So officials took urine samples from each traveler and asked Lednicky to test for Zika. Lednicky ran the standard PCR tests for the virus, and they all came back negative. But he wasn't satisfied. He had a hunch that the urine samples did contain a virus — not Zika but something else. So he took a little bit of the urine from six of the travelers and added it to a special solution of monkey cells. The goal was deceptively simple: to see if any viruses in the urine would infect the monkey cells, start replicating and grow to detectable levels. Then Lednicky could collect the virus's genes and identify it. "This is what we do in our lab," Lednicky says. "We cast a wide net. We try to isolate viruses. And oftentimes, when we do that, the unexpected happens." Indeed, the unexpected occurred. "We found a coronavirus," he says. And not just any coronavirus, but one that many scientists believe may be a new human pathogen — likely the 8th coronavirus known to cause disease in people. Turns out, this coronavirus in the Haiti travelers has cropped up previously, on the other side of the globe.

Research increases worry about the pandemic potential of other members of the virus family. Eight children hospitalized with pneumonia in Malaysia several years ago had evidence of infections with a novel coronavirus similar to one found in dogs, a research team reports today. Only seven coronaviruses were previously known to infect people, the latest being SARS-CoV-2, the spark of the COVID-19 pandemic. The discovery of this likely new human pathogen, along with the report of an instance of a coronavirus that appears to have jumped from pigs to people many years ago, could significantly expand which members of the viral family pose another global threat. “I think the more we look, the more we will find that these coronaviruses are crossing species everywhere,” says Stanley Perlman, a virologist at the University of Iowa who was not involved in the new work.  The researchers have not definitely linked either new virus to human disease. And there’s no evidence that the two new coronaviruses can transmit between people—each infection may have been a dead-end jump into a person from a nonhuman host. But many researchers worry the viruses may evolve that ability within a person or the animals they normally infect. A complete genome sequence of the virus found in one Malaysian patient, reported today in Clinical Infectious Diseases, reveals a chimera of genes from four coronaviruses: two previously identified canine coronaviruses, one known to infect cats, and what looks like a pig virus.  This is the first report suggesting a caninelike coronavirus can replicate in people, and further studies will need to confirm the ability. The researchers have grown the virus in dog tumor cells but not yet in human cells. Unlike with SARS-CoV-2 and other known human coronaviruses, “We don’t have any clear evidence that this particular [coronavirus] strain is better adapted to humans because of its spike structure,” says veterinary virologist Anastasia Vlasova of Ohio State University (OSU), Wooster, lead author of the study. Human infections from dog coronaviruses may occur “at a much higher frequency than we previously thought,” she adds.

This particular virus might not transmit between people, but we don’t know that for sure, Vlasova cautions. The eight children whose tissue samples Vlasova and her colleagues studied were mainly living in traditional longhouses or villages in rural or suburban Sarawak on Borneo, where they likely had frequent exposure to domestic animals and jungle wildlife. They were among 301 hospitalized pneumonia patients during 2017–18 and the researchers screened their nasopharyngeal samples—tissue from the upper part of the throat—for a large variety of human and nonhuman coronaviruses.  Standard hospital diagnostics for pneumonia or other respiratory illness would not have detected dog and cat coronaviruses. No one has been looking for these viruses in patients with such illnesses until recently. “These canine and feline coronaviruses are everywhere in the world,” Perlman says. The entire novel virus sequence from the children’s samples most resembles a canine coronavirus. However, the sequence for its spike protein, which attaches to host cell receptors to initiate an infection, is closely related to the spike sequence of canine coronavirus type I and the one for a porcine coronavirus known as transmissible gastroenteritis virus (TGEV). And one part of the spike protein bears a 97% similarity to the spike of a feline coronavirus.   This chimera is unlikely to have arisen at once, but instead involved repeat genetic reshuffles between different coronaviruses over time. “This is a mosaic of several different recombinations, happening over and over, when nobody’s watching. And then boom, you get this monstrosity,” says virologist Benjamin Neuman at Texas A&M University, College Station.  The animal that actually transmitted the novel virus to the people could have been a cat, pig, dog, “or some wild carnivores,” says Vito Martella, a veterinary virologist at the University of Bari in Italy. He plans to screen stored fecal samples from Italian children with acute gastroenteritis to see whether he can find something similar.  Researchers already knew three canine coronavirus subtypes mix readily with feline and porcine coronaviruses. “What is more surprising is that these [animal] viruses can actually cause disease in a person,” Perlman says, because one would expect them to lack some of the genes important for adapting well to people. Seven of the eight children whose tissues harbored sequences of the virus were younger than 5 years old, and four of them were infants, mostly from Indigenous ethnic groups. Each was hospitalized for 4 to 7 days and recovered. 

Scientists divide coronaviruses into four genera—alpha, beta, gamma, and delta—and the new one is an alpha. It is the third such alpha coronavirus to infect people; the other two cause common colds, and most people are exposed to them early in life. That pattern may explain why only children were perhaps sickened by this new one. Ralph Baric, a virologist at the University of North Carolina, Chapel Hill, suggests adults may have some immunity to the newly discovered alpha coronavirus because of repeated exposure to the other two. So far, the most dangerous human coronaviruses—SARS-CoV-1, SARS-CoV-2, and MERS-CoV—are the betas. Researchers haven’t seen alphas trigger an outbreak of serious disease in humans, Neuman says, “but that doesn’t feel like much comfort in the wild world of viruses.” In March, researchers at the University of Florida reported in a medRxiv preprint the first evidence of a porcine delta coronavirus that infects people, in serum from three Haitian children who had fevers in 2014—15. The researchers transferred serum samples into monkey cells and were able to grow viruses that they matched, genetically, to known porcine coronaviruses (The work has been submitted to a peer-reviewed journal.)

Delta coronaviruses were once thought to infect only birds. Then, in 2012, a delta coronavirus infected swine in Hong Kong. It “appears to have jumped over from songbirds,” says OSU coronavirologist Linda Saif, who went on to isolate the virus in swine cell cultures.    The same virus caused a major fatal diarrheal disease outbreak in baby pigs in the United States in 2014. It has since been shown to infect cell lines from humans, pigs, and chickens; lab studies have shown the virus causes persistent infection and diarrheal disease when put into poultry. “It’s out on its own, a left field–type virus that infects both avian and mammalian species,” Baric says. “There aren’t any other coronaviruses that I know can do this.”   Some virologists have labeled the Hong Kong delta coronvirus a pandemic threat. The Haitian virus differs considerably and virologists want to test local children and adults for antibodies to it. If its ability to infect people is confirmed, it may also be viewed as a pandemic threat, Saif says. Together, the two reports point to the importance of animal diseases in public health, and the need for coronavirus vaccines for domesticated animals. “This research clearly shows that more studies are desperately needed to evaluate critical questions regarding the frequency of cross-species [coronavirus] transmission and potential for human-to-human spread,” Baric says. Gregory Gray at Duke University, senior author on the Malaysian chimeric coronavirus study, also advocates for surveillance among pneumonia patients in areas known to be hot spots for novel viruses or places where large populations of animals and humans mix, such as live animal markets and large farms. “These spillovers take years,” Gray says. “It’s not like in the movies. They go through different steps to infect humans.” So far indications are that the chimeric virus has not evolved to transmit efficiently between people.