Keith Poulsen, the director of the Wisconsin Veterinary Diagnostic Laboratory, encourages anyone who owns domestic poultry to register their flock with the state, keep a close eye on their birds for signs of sickness and to keep their birds away from wild birds. Envato/Maria_Sbytova

While migration can be a time for avid birders and everyday Wisconsinites alike to catch a glimpse of fun-feathered visitors, poultry farmers’ eyes are watching their own flocks like a hawk for signs of avian influenza.

Sometimes called bird flu, avian influenza can spread to flocks from wild birds like a cold through a booger-infested pre-K class. Farmers do their best to prepare.

“It’s like daycare, but on an international scale,” says Keith Poulsen, director of the Wisconsin Veterinary Diagnostic Laboratory.

In a normal year, only a few isolated cases of bird flu will pop up. So far, though, this years’ strain is classified as having high pathogenicity, meaning it spreads quickly through a flock and can kill nearly 100% of birds within 48 hours of infection.

“One in six people in the northwest part of Wisconsin is involved in the poultry industry,” says Poulsen. “So, if you have a problem that has a significant impact on the industry, animal health measures are hugely important.”

To make matters worse, rather than leaving the state with migratory birds as they headed north this spring, Poulsen warns that this year is the first time the virus instead stuck around. Usually, the virus doesn’t survive the summer. This strain, however, remained circulating in bird and mammal populations at low levels, giving it more time to spread.

So far this year, there have been twice as many infected flocks as there were during the last serious outbreak in 2015. With migratory birds starting to fly south again and bringing more virus back to Wisconsin, that number is expected to rise.

Controlling the recent outbreak of avian flu across the state has been complicated not by big commercial poultry farms, but by the increase in the number of backyard hobby flocks. Envato/juliacherk

For testing centers like the WVDL, monitoring the spread is also made more difficult because of an increase in the number of small, backyard hobby flocks.

With outbreaks on large poultry farms, “typically, when you find a positive flock, you don’t want to take anything off the farm. You want to get rid of all the virus on the farm, clean it and disinfect it, then move on,” says Poulsen. “That’s really difficult when you have small premises scattered all over the state.”

Large poultry operations, he explains, have their own systems in place to handle and neutralize an infection quickly and thoroughly so they can get back to making a product fit for market and robust food supply chain.

Many small hobby flocks, however, aren’t registered with the state, he says, even though it’s technically required. Hobby flock owners also don’t often have the resources like a “chicken vet” to call and ask random questions about poultry care or what signs of sickness to look out for.

The virus has also had time to spread to other species, infecting apex avian predators and potentially upsetting the balance in the ecosystem around the state. The virus has killed raptors like bald eagles and snowy owls and in rare cases has caused neurological damage in mammals like foxes and bobcats.

This spill-over into other populations can happen for a number of reasons, and the WVDL sends every virus-positive sample to a national laboratory for genetic sequencing. Keeping track of the virus in this way allows animal health officials to monitor how it’s changing over time and determine whether it poses a threat to human health.

“Some viruses are very stable; they don’t change very much over time. Influenza is very different,” Poulsen says. “That’s the reason why we watch this very closely.”

For some, migration is an exciting time for bird watching. For poultry farmers and hobby flock owners, it’s a time to be on high alert for avian flu infection in their flocks. Envato/bilanol

Right now, animal health officials are assessing the risk of the outbreak to decide whether they should implement poultry vaccination requirements. But it isn’t a simple decision to make since vaccinations would add to farmers’ production costs and could deter international poultry buyers.

With so many people connected to poultry, Poulsen encourages all flock owners to register their flock with the state. It benefits their own flock, their neighbors’ flocks and the health of the ecosystem.

While it can be difficult to find a veterinarian that works specifically with poultry, there are several associations and resources for smaller flock owners that can help to fill those gaps. Poulsen names a few: the Wisconsin Poultry and Egg Association, the National Poultry Improvement Plan and the Wisconsin 4-H Poultry Project.

Poultry owners should watch their flocks for warning signs like sudden death without clinical signs of illness, sluggishness and lower egg yields. Infected birds may also experience swelling or discoloration of their head, comb, eyelids, wattles or legs. Poulsen says flock owners should also report any dead birds to the Wisconsin Department of Agriculture, Trade, and Consumer Protection animal diseases reporting hotline: 608-224-4872 or DATCPAnimallimports@wisconsin.gov.

“Maintain vigilance for your birds,” Poulsen says. “Keep your birds away from wild populations and watch them very carefully.”

Egg cells harvested from Mauritian cynomolgus macaques (top left) were fertilized (top right) and injected with CRISPR gene editing materials to insert a genetic mutation that cured two men of HIV in the last decade. The growing embryos (developing in the bottom images), if carried to maturity by surrogates, will help researchers study the mutation as a potential treatment for HIV. Courtesy of Golos and Slukvin labs

A gene that cured a man of HIV a decade ago has been successfully added to developing monkey embryos in an effort to study more potential treatments for the disease.

Timothy Brown, known for years as “the Berlin Patient,” received a transplant of bone marrow stem cells in 2007 to treat leukemia. The cells came from a donor with a rare genetic mutation that left the surfaces of their white blood cells without a protein called CCR5. When Brown’s immune system was wiped out and replaced by the donated cells, his new immune system’s cells carried the altered gene.

“This mutation cuts a chunk out of the genome so that it loses a functional gene, CCR5, that is a co-receptor for HIV,” says Ted Golos, a University of Wisconsin–Madison reproductive scientist and professor of comparative biosciences and obstetrics and gynecology. “Without CCR5, the virus can’t attach to and enter cells to make more HIV. So, in Timothy Brown’s case, his infection was eliminated.”

In 2019, a second cancer patient — Adam Castillejo, initially identified as “the London patient” — was cleared of his HIV by a stem cell transplant conferring the same mutation.

“That’s very exciting, and there have been some follow up studies. But it’s been complicated, to say the least,” Golos says.

Between the two transplants came a more infamous application of the mutation, when in 2018 Chinese biophysicist He Jiankui announced he had used the DNA-editing tool CRISPR to write the mutation into the DNA of a pair of human embryos. His work drew criticism from scientists concerned with the ethics of altering genes that can be passed down to human offspring, and he was jailed by the Chinese government for fraud.

The promise of the CCR5 mutation remains, but not without further study. The mutation occurs naturally in fewer than 1 percent of people, suggesting that it may not be associated only with positive health outcomes. An animal model for research can help answer open questions.

“Given interest in moving forward gene-editing technologies for correcting genetic diseases, preclinical studies of embryo editing in nonhuman primates are very critical,” says stem cell researcher Igor Slukvin, a UW–Madison professor of pathology and laboratory medicine.

Golos, Slukvin and colleagues at UW–Madison’s Wisconsin National Primate Research Center and schools of Veterinary Medicine and Medicine and Public Health employed CRISPR to edit the DNA in newly fertilized embryos of cynomolgus macaque monkeys. They published their work recently in the journal Scientific Reports.

Slukvin’s lab had already established a method for slicing the CCR5-producing gene out of the DNA in human pluripotent stem cells, which can be used to generate immune cells resistant to HIV.

“We used that same targeting construct that we already knew worked in cells, and delivered it to one-cell fertilized embryos,” says Jenna Kropp Schmidt, a Wisconsin National Primate Research Center scientist. “The thought is that if you make the genetic edit in the early embryo that it should propagate through all the cells as the embryo grows.”

Primate Center scientist Nick Strelchenko found that as much as one-third of the time the gene edits successfully deleted the sections of DNA in CRISPR’s crosshairs — base pairs in both of the two copies of the CCR5 gene on a chromosome — and were carried on into new cells as the embryos grew.

“The goal now is to transfer these embryos into surrogates to produce live offspring who carry the mutation,” Schmidt says.

Cynomolgus macaques are native to Southeast Asia, but a group of the monkeys has lived in isolation on the Indian Ocean island of Mauritius for about 500 years. Because the entire Mauritian monkey line descends from a small handful of founders, they have just seven variations of the major histocompatibility complex, the group of genes that must be matched between donor and recipient for a successful bone marrow transplant. There are hundreds of MHC variations in humans.

With MHC-matched monkeys carrying the CCR5 mutation, the researchers would have a reliable way to study how successful the transplants are against the simian immunodeficiency virus, which works in monkeys just like HIV does in humans.

“Anti-retroviral drugs have really positively changed the expectation for HIV infection, but in some patients, they may not be as effective. And they’re certainly not without long-term consequences,” says Golos, whose work is funded by the National Institutes of Health. “So, this is potentially an alternative approach, which also allows us to expand our understanding of the immune system and how it might protect people from HIV infection.”

The animal model could lead to the development of gene-edited human hematopoietic stem cells — the type that work in bone marrow to produce many kinds of blood cells — that Slukvin and Golos say could be used as an off-the-shelf treatment for HIV infection.

This research was supported by grants from the National Institutes of Health (R24OD021322, P51OD011106, K99 HD099154-01, RR15459-01 and RR020141-01).

Andrew Bennett, a former graduate student in the UW–Madison School of Veterinary Medicine, holds a cyclops leaf-nosed bat during field work in Uganda’s Kibale National Park, in search of viruses carried by the animals. Bennett was part of an international team that just described the first two relatives of rubella virus ever found. Photo: Emily Julka

At night in a Ugandan forest, a team of American and African scientists take oral swabs from insect-eating cyclops leaf-nosed bats.

In a necropsy room near the Baltic Sea, researchers try to determine what killed a donkey, a Bennett’s tree-kangaroo and a capybara at a German zoo — all of them suffering from severe brain swelling.

Neither team was aware of the other, yet they were both about to converge on a discovery that would forever link them — and help solve a long-enduring mystery. They were each about to find two new relatives of the rubella virus, which had been, since it was first identified in 1962, the only known member of its virus family, Matonaviridae.

In Africa, this relative is ruhugu virus, named for the place where it was found, Ruteete Subcounty, and the word in the local Tooro language that describes the flapping of bat wings in the hollow of a tree: obuhuguhugu. The virus found in Germany, slightly different from rubella and ruhugu, is rustrela, named for the nearby Strela Sound.

The two teams have now collaborated to publish their findings in Nature. They describe the new viruses, their similarities to rubella virus, and their differences. Neither of the new viruses is known to infect people.

Tony Goldberg

“Why has it been so challenging to track down the origins or relatives of rubella virus?” asks Tony Goldberg, a University of Wisconsin–Madison professor of epidemiology at the School of Veterinary Medicine, who led the American efforts. “Why did it take 206 years from the time George Maton first described rubella, and why did two teams working independently figure it out within three months of each other, get lucky enough to learn of one another’s results, and then lucky enough to work together to publish?”

It isn’t because people haven’t tried, Goldberg says. It may be that advancing technology has made it easier — rubella virus genomes are notoriously difficult to work with, and the new viruses share these characteristics.

It may just be serendipity.

Goldberg’s team — whose efforts in the new study were led by his former graduate student Andrew Bennett — wasn’t even looking for rubella-like viruses. They were, pre-COVID-19 pandemic, working with their Ugandan colleagues to look for coronaviruses carried by bats. Ruhugu virus popped up as a strange string of letters in the giant analyses of genetic code the team was performing on samples collected from the bats.

When they looked closer, they saw that it was quite similar to rubella virus, just one short word, or amino acid, different in a key region of the genome that lets viruses bind to host cells. (Rustrela virus has a few more amino acid differences.) The researchers are currently working to further study both viruses in the lab.

Rubella is an airborne virus that has largely been eradicated thanks to an effective vaccine, though pockets of disease still exist throughout the world. It can cause rash and flu-like symptoms. During pregnancy, the virus can cause miscarriage, stillbirth or fetal development defects — as many as 100,000 children each year are born with congenital rubella syndrome and may be deaf, blind or experience heart problems.

Rubella has not been found in animals, which has made it easier for the World Health Organization to target elimination of the virus. However, both of the new viruses have been found in common mammal species in Uganda and in Germany (researchers have found rustrela virus in yellow-necked field mice). Up to half of the bats and half of the mice tested were carriers of their respective viruses. This suggests both species may act as viral reservoirs, carrying and transmitting pathogens without getting sick.

“Why did it take 206 years from the time George Maton first described rubella, and why did two teams working independently figure it out within three months of each other, get lucky enough to learn of one another’s results, and then lucky enough to work together to publish?”

Tony Goldberg

The study also indicates that rubella, like many other human viruses, probably originated in animals. Researchers do not know whether rubella virus can jump back into animals.

“There is no evidence that ruhugu virus or rustrela virus can infect people, yet if they could, it might be so consequential that we should consider the possibility,” Goldberg says. “We know that in Germany, rustrela virus jumped among species that are not at all closely related. If either of these viruses turns out to be zoonotic, or if rubella virus can go back into animals, that would be a game changer for rubella eradication.”

The team’s analysis suggests the three viruses may be similar enough that the current rubella vaccine could be effective against all of them — a key question for research going forward, says Goldberg, also a member of the UW–Madison Global Health Institute.

The new viruses also provide scientists with new tools to probe the biology of rubella virus and the Matonaviridae family. There are no good animal models for rubella, but rustrela virus provides a new opportunity to explore one. Mice are common model species in the laboratory.

Additionally, the findings reinforce the critical importance of conservation efforts in Uganda to protect forests from encroaching development, and the important work scientists and others there are undertaking to study the effects of a changing environment on human and animal diseases.

Ugandan red colobus monkeys in Kibale National Park. With the discovery of two relatives of rubella virus, including a virus found in bats in the park, scientists and others stress the importance of protecting Uganda’s forests from human encroachment.

For instance, Deputy Director of Field Operations for the Uganda Wildlife Authority Charles Tumwesigye says the study’s findings will be incorporated into UWA’s community conservation awareness programs, especially around Kibale National Park, where the ruhugu virus was found.

The study “will help management to further protect unique aspects of the ecosystem as well as keep the population safe,” he says. “Uganda Wildlife Authority values scientific research because it provides key information for decision-making in protected area management.”

Tumwesigye adds that the ways in which people and wildlife relate are “key to harmonious co-existence … When communities around Kibale National Park appreciate the value of the bats, for example, they become supportive in their conservation initiatives and learn how to protect themselves.”

If not for the country’s “long history of excellent medical and conservation science,” says Goldberg, “there might have been no bats to study.”

Protecting habitat is of utmost importance to animals and to people, he adds.

“Viruses stay in their place when ecosystems are intact.”

Adrian Paskey, from Uniformed Services University of the Health Sciences, and Arnt Ebinger are co-lead authors of the study with Bennett, who is now employed as a scientist for the Naval Medical Research Center. Goldberg is co-corresponding author along with Martin Beer, from the Institute of Diagnostic Virology at the Friedrich-Loeffler-Institut in Germany. The study includes additional coauthors from the Friedrich-Loeffler-Institut; the Naval Medical Research Center; the State Office for Agriculture, Food Safety and Fisheries in Western Pomerania, Germany; and the German Center for Infection Research.

The study was supported by the U.S. National Institute of Allergy and Infectious Diseases (T32 AI078985 and GEIS P0062_20_NM_06), and by the German Federal Ministry of Education and Research (01KI1722A). It was also supported through an NIAID contract with Laulima Government Solutions, LLC (HHSN272201800013C) and a former NIAID contract with Battelle Memorial Institute (HHSN2722007000161). Additional support came from the German Center for Infection Research and the UW–Madison Global Health Institute, the Institute for Regional and International Studies, and the John G. MacArthur Professorship Chair.

In a study published in Cell Reports Medicine today (Sept. 22), scientists describe a T-cell-based vaccine strategy that is effective against multiple strains of influenza virus. The experimental vaccine, administered through the nose, delivered long-lasting, multi-pronged protection in the lungs of mice by rallying T-cells, specialist white blood cells that quickly eliminate viral invaders through an immune response.

This three-dimensional, semi-transparent rendering of a whole influenza virus shows both the clover-like surface proteins on the outside of the virus, as well as the internal ribonucleoproteins on the inside. Existing influenza vaccines introduce proteins found on the surface of flu viruses to help induce immune protection. A new study by researchers at the UW School of Veterinary Medicine uses an internal nucleoprotein to stimulate the immune system in an effort to create a universal flu vaccine. Centers for Disease Control and Prevention

The research suggests a potential strategy for developing a universal flu vaccine, “so you don’t have to make a new vaccine every year,” explains Marulasiddappa Suresh, a professor of immunology in the School of Veterinary Medicine who led the research. The findings also aid understanding of how to induce and maintain T-cell immunity in the respiratory tract, a knowledge gap that has constrained the development of immunization strategies. The researchers believe the same approach can be applied to several other respiratory pathogens, including the novel coronavirus that causes COVID-19.

“We don’t currently have any vaccine for humans on the market that can be given into the mucosa and stimulate T-cell immunity like this,” says Suresh, a veterinarian with specialty training in studying T-cell responses to viral infections.

The strategy addresses the Achilles’ heel of flu vaccines, which is to achieve specific antibody responses to different circulating influenza strains annually, by harnessing T-cell immunity against multiple strains. In particular, the new approach calls into action tissue-resident memory T-cells, or TRM cells, which reside in the airways and lining of lung epithelial cells and combat invading pathogens. Like elite soldiers, TRM cells serve as front line defense against infection.

Marulasiddappa Suresh

“We didn’t previously know how to elicit these tissue-resident memory cells with a safe protein vaccine, but we now have a strategy to stimulate them in the lungs that will protect against influenza,” explains Suresh. “As soon as a cell gets infected, these memory cells will kill the infected cells and the infection will be stopped in its tracks before it goes further.”

Flu vaccines work by arming the immune system with an enhanced ability to recognize and fight off the flu virus. Vaccines introduce proteins found on the surface of flu viruses, prompting the immune system to produce antibodies that are primed to react should the virus attack.

However, because strains must be predicted ahead of flu season in order to produce vaccines, the vaccine in any given year may not completely match the viral strains in circulation that season. Flu viruses frequently mutate and can differ across time and from region to region. In addition, protection is neither long-lasting nor universal.

“Even though current vaccines that people get annually stimulate antibody responses, these antibodies don’t cross-protect,” notes Suresh. “If there is a new flu strain not found in that year’s vaccine, the antibodies that we generated last year won’t be able to protect. That’s when pandemics happen because there is a completely new strain for which we have no antibodies. That is a really big problem in the field.”

The vaccine developed by Suresh and his team is directed against an internal protein of influenza — specifically, nucleoprotein. This protein is conserved between flu strains, meaning its genetic sequences are similar across different strains of flu.

The vaccine also utilizes a special combination of ingredients, or adjuvants, that enhance an immune response, which the researchers developed to stimulate protective T-cells in the lungs. These adjuvants spur T-cells to form into different subtypes — in the case of the experimental flu vaccine, memory helper T-cells and killer T-cells. By doing so, the vaccine leverages multiple modes of immunity.

Killer T-cells hunt down and kill influenza virus-infected cells. Helper T-cells assist killer T-cells and produce molecules to promote influenza control. In laboratory studies, the team found that both T-cell types were needed to protect against flu.

Researchers demonstrated in a mouse model of influenza that the vaccine provides long-lasting immunity — at least 400 days after vaccination — against multiple flu strains. They will next test the vaccine in ferrets and nonhuman primates, two animal models of influenza research more biologically similar to human infection and transmission.

The vaccine’s combination of adjuvants makes it adaptable to other pathogens and “expands the toolbox” for vaccine research, notes Suresh. He and his team have devised ways to program immunity to target multiple respiratory viruses. They are currently testing the same vaccine strategy against tuberculosis, which infects more than 10 million people globally each year, and human respiratory syncytial virus, or RSV, a major cause of lower respiratory tract infections during infancy and childhood.

The researchers believe the same vaccine technology can applied against SARS-CoV-2, the coronavirus that causes COVID-19. “Based on the COVID-19 immunology, we know this vaccine strategy would most likely work,” says Suresh.

The team is now developing an experimental vaccine against COVID-19 and conducting laboratory tests to measure its effectiveness in mice and hamsters, animal models for COVID-19. Initial unpublished studies in mice show that the vaccine stimulates strong T-cell immunity against COVID-19 in the lungs.

Along with its adaptability, this vaccine approach may harbor important safety benefits. Typically, long-lasting T-cell immune responses are stimulated by live vaccines. For instance, the measles, mumps and chickenpox vaccines administered worldwide are live, replicating vaccines — essentially benign versions of the pathogenic organism. These live vaccines stimulate strong, almost lifelong immunity. However, they can’t typically be given to pregnant or immunocompromised individuals due to health risks.

In the case of the UW–Madison team’s vaccine, because it is a protein vaccine and not a live vaccine, it should be safe for delivery to those who are pregnant or immunocompromised — an advantage in delivering protection to a wider patient population. Suresh says that in recent years, vaccine development efforts have shifted away from live vaccines toward protein vaccines because an increasing number of people are living with compromised immune systems due to chemotherapy, radiation treatments or conditions such as HIV/AIDS.

“Previously, we didn’t know how to induce T-cell immunity in the lung without live viruses,” says Suresh. “If we cleverly use a combination adjuvant, which we have developed, you can induce T-cell immunity that should stay in the lungs and protect longer.”

THIS WORK WAS supported by THE NATIONAL INSTITUTES of HEALTH (GRANT UO1124299).

Syrian hamsters, commonly found as pets, have served critical roles in understanding human infectious diseases for decades. The new study, led by Yoshihiro Kawaoka and published today (June 22, 2020) in the Proceedings of the National Academy of Sciences, demonstrates they are also a useful small animal model for researchers trying to understand SARS-CoV-2 and in evaluating vaccines, treatments and drugs against the disease it causes.

“Hamsters are good models for human influenza and SARS-CoV,” says Kawaoka, professor of pathobiological sciences at the UW School of Veterinary Medicine and a virology professor at the University of Tokyo. “This is why we decided to study them with COVID-19. We wanted to see if the disease course is similar to humans in these animals from beginning to end.”

Images of the lungs of hamsters before and after infection with SARS-CoV-2, from CT scans at UW Veterinary Care at the School of Veterinary Medicine. In blue are the trachea and bronchi. In red is a region of gas in the cavity just outside the lungs, indicating severe lung damage in the affected animal. The opaque clouding is similar to the “ground glass” appearance in the lungs of some human patients sick with COVID-19. Signs of severe disease in the lungs of hamsters became apparent within eight days of infection and began to improve by 10 days. The effects lingered for longer, as evident on the scan taken 16 days after initial infection. Courtesy of Yoshihiro Kawaoka

A study led by scientists at the University of Hong Kong, published in late March, also showed Syrian hamsters to be a good model for COVID-19-related research. In that study, the hamsters lost weight, became lethargic, and developed other outward signs of illness.

Kawaoka’s group extended this work further, demonstrating that both low and high doses of the virus, from patient samples collected in the U.S. and Japan, replicate well in the airways of juvenile hamsters (1 month old) and adults (7 to 8 months old). The virus can also infect both the upper and lower respiratory tracts.

The research team also showed that SARS-CoV-2 causes severe disease in the lungs of infected animals. This includes lesions and the kind of “ground glass” appearance often found in lung scans in human patients. Scans also revealed a region of gas in the cavity surrounding the hamster’s lungs, indicating severe lung damage. Researchers observed the most severe effects within eight days after infection, and improvement by 10 days.

“Hamsters infected with SARS-CoV-2 share CT imaging characteristics with human COVID-19 disease,” says Samantha Loeber, a veterinarian and radiologist at UW Veterinary Care.

SARS-COV-2 virus particles. Courtesy of Yoshihiro Kawaoka. Masaki Iman and Michiko Ujie

By day 10 following infection, the researchers no longer detected virus in the organs of most of the hamsters, but lung damage persisted for 14 days in a majority of the animals, and for at least 20 days in most of those infected with a high dose.

Overall, the researchers were able to detect virus in all of the respiratory organs of the infected hamsters within six days of infection, and also from samples collected from their brains, though these also contained portions of the olfactory bulb, which is involved in smell and may have been the source of virus in these samples. The initial dose of the virus did not affect how much of the virus researchers ultimately found in the hamster’s organs.

The researchers also looked for but did not detect virus in the kidneys, the small intestine, the colon or in blood.

To determine whether hamsters developed antibodies against SARS-CoV-2 that protected them from reinfection, the researchers administered another round of the virus to a number of the same animals about three weeks following initial infection and were unable to detect virus in their respiratory tracts. They did find virus in the airways of control animals not previously infected.

“The animals all possessed antibodies and did not get sick again, which suggests they developed protective immunity,” says Pete Halfmann, a research professor in Kawaoka’s U.S. lab. “But we still can’t say how long this protection lasts.”

In early April, researchers across the U.S., including at the UW School of Medicine and Public Health and UW Health, initiated a clinical trial to examine whether the antibody-bearing component of blood — the plasma or sera — from recovered COVID-19 patients could be given to sick patients to assist in their recovery. While convalescent plasma has been used in other disease outbreaks, it remains poorly understood as a treatment.

So, Kawaoka’s team extracted convalescent sera from previously sick hamsters and then pooled it together. They infected new hamsters with SARS-CoV-2 and then gave them this antibody-laden sera either one day or two days following infection.

The hamsters that received treatment within a day of infection had much lower amounts of infectious virus in their nasal passages and lungs than those given a mock treatment. Those that received sera on day two showed a less appreciable benefit, though they still had lower levels of virus in their respiratory organs compared to control animals.

A study published just last week in Science showed that transfer of human antibodies to hamsters may also help protect the animals from severe illness from SARS-CoV-2 infection.

“This shows us that convalescent sera, still experimental in human patients, may be part of an effective treatment for COVID-19,” Kawaoka adds.

Finally, the research team also obtained the first images of the internal features of the SARS-CoV-2 virus that aid its ability to replicate, or make copies of itself, in host cells. This, Kawaoka says, warrants further study.

The study was supported by the Japan Research Program on Emerging and Re-emerging Infectious Diseases, the Japan Project Promoting Support for Drug Discovery, the Japan Initiative for Global Research Network on Infectious Diseases, the Japan Agency for Medical Research and Development Program for Infectious Diseases Research and Infrastructure, and the U.S. National Institutes of Allergy and Infectious Diseases.

Professor of Pathobiological Sciences at the University of Wisconsin School of Veterinary Medicine Yoshihiro Kawaoka led the study, in which researchers administered to three cats SARS-CoV-2 isolated from a human patient. The following day, the researchers swabbed the nasal passages of the cats and were able to detect the virus in two of the animals. Within three days, they detected the virus in all of the cats.

The day after the researchers administered virus to the first three cats, they placed another cat in each of their cages. Researchers did not administer SARS-CoV-2 virus to these cats.

Each day, the researchers took nasal and rectal swabs from all six cats to assess them for the presence of the virus. Within two days, one of the previously uninfected cats was shedding virus, detected in the nasal swab, and within six days, all of the cats were shedding virus. None of the rectal swabs contained virus.

Yoshihiro Kawaoka

Each cat shed SARS-CoV-2 from their nasal passages for up to six days. The virus was not lethal and none of the cats showed signs of illness. All of the cats ultimately cleared the virus.

“That was a major finding for us — the cats did not have symptoms,” says Kawaoka, who also holds a faculty appointment at the University of Tokyo. Kawaoka is also helping lead an effort to create a human COVID-19 vaccine called CoroFlu.

The findings suggest cats may be capable of becoming infected with the virus when exposed to people or other cats positive for SARS-CoV-2. It follows a study published in Science by scientists at the Chinese Academy of Agricultural Sciences that also showed cats (and ferrets) could become infected with and potentially transmit the virus. The virus is known to be transmitted in humans through contact with respiratory droplets and saliva.

“It’s something for people to keep in mind,” says Peter Halfmann, a research professor at UW–Madison who helped lead the study. “If they are quarantined in their house and are worried about passing COVID-19 to children and spouses, they should also worry about giving it to their animals.”

Both researchers advise that people with symptoms of COVID-19 avoid contact with cats. They also advise cat owners to keep their pets indoors, in order to limit the contact their cats have with other people and animals.

Kawaoka is concerned about the welfare of animals. The World Organization for Animal Health and the Centers for Disease Control and Prevention say there is “no justification in taking measures against companion animals that may compromise their welfare.”

Humans remain the biggest risk to other humans in transmission of the virus. There is no evidence cats readily transmit the virus to humans, nor are there documented cases in which humans have become ill with COVID-19 because of contact with cats.

There are, however, confirmed instances of cats becoming infected because of close contact with humans infected with the virus, and several large cats at the Bronx Zoo have also tested positive for the virus.

For instance, according to an April 22 announcement from the U.S. Department of Agriculture, two cats in two private homes in New York state tested positive for COVID-19. One had been in a home with a person with a confirmed case of the viral disease. The cats showed mild signs of respiratory illness and were expected to make a full recovery.

Additional cats have also tested positive for COVID-19 after close contact with their human companions, says Sandra Newbury, director of the UW–Madison Shelter Medicine Program. Newbury is leading a research study in several states in the U.S. to test animal-shelter cats that might have previously been exposed to human COVID-19 cases.

“Animal welfare organizations are working very hard in this crisis to maintain the human-animal bond and keep pets with their people,” says Newbury. “It’s a stressful time for everyone, and now, more than ever, people need the comfort and support that pets provide.”

“It’s something for people to keep in mind,” says Peter Halfmann, who helped lead the study. “If they are quarantined in their house and are worried about passing COVID-19 to children and spouses, they should also worry about giving it to their animals.”

Newbury has worked with the CDC and the American Veterinary Medical Association to develop recommendations for shelters housing potentially exposed pets, which they may do while owners are hospitalized or otherwise unable to provide care because of their illness. The UW–Madison study helps confirm experimentally that cats can become infected, though the risk of natural infection from exposure to SARS-CoV-2 seems to be quite low, Newbury says. Of the 22 animals the program has tested, none have had positive polymerase chain reaction tests for the virus, she adds.

“Cats are still much more likely to get COVID-19 from you, rather than you get it from a cat,” says Keith Poulsen, director of the Wisconsin Veterinary Diagnostic Laboratory, who recommends that pet owners first talk to their veterinarians about whether to have their animals tested. Testing should be targeted to populations of cats and other species shown to be susceptible to the virus and virus transmission.

With respect to pets, “we’re targeting companion animals in communal residences with at-risk populations, such as nursing homes and assisted living facilities,” Poulsen says. “There is a delicate balance of needing more information through testing and the limited resources and clinical implications of positive tests.”

So, what should pet owners do?

Ruthanne Chun, associate dean for clinical affairs at UW Veterinary Care, offers the following advice:

• If your pet lives indoors with you and is not in contact with any COVID-19 positive individual, it is safe to pet, cuddle and interact with your pet.
• If you are COVID-19 positive, you should limit interactions with your pets to protect them from exposure to the virus.
• Additional guidance on managing pets in homes where people are sick with COVID-19 is available from the American Veterinary Medical Association and CDC, including in this FAQ from AVMA.

“As always, animal owners should include pets and other animals in their emergency preparedness planning, including keeping on hand a two-week supply of food and medications,” she says. “Preparations should also be made for the care of animals should you need to be quarantined or hospitalized due to illness.”

The study was supported by the U.S. National Institute of Allergy and Infectious Diseases and by the Japan Agency for Medical Research and Development.

—Meghan Lepisto provided assistance with this story

Yoshihiro Kawaoka will participate in a virtual public event on May 20, 2020, from 5 until 6 p.m., called Crossroads of Ideas. The event, the third in a series focused on COVID-19, is themed “Where Do We Go From Here?” For more information visit: https://discovery.wisc.edu/programs/crossroads-ideas or register for the event at https://warf.wufoo.com/forms/z12tp4tc1y66k1j/.

The 2019 Novel Coronavirus (2019-nCoV), portrayed in an illustration created at the Centers for Disease Control and Prevention. Alissa Eckert, MS; Dan Higgins, MAM

Back in 2016, when Zika virus first began to cause infections in the Americas, University of Wisconsin–Madison researchers pulled together a coalition of scientists to study the virus and openly share their data for others.

Two weeks ago, those researchers — David O’Connor, professor at the UW School of Medicine and Public Health, and Thomas Friedrich, professor in the UW School of Veterinary Medicine  — used the 2016 playbook to start planning efforts to study the novel coronavirus that first emerged in Wuhan, China, in late December 2019.

The virus, which causes flu-like symptoms and respiratory illness, has sickened more than 43,000 people in China and across several nations, according to health officials. At least 1,018 people have died.

David O’Connor

Thomas Friedrich

Within the next few weeks, Friedrich, O’Connor, and their interdisciplinary partners hope to begin studies to better understand the novel coronavirus, 2019-nCoV.

“We are working together to develop a plan to build out nonhuman primate models to test medical countermeasures such as vaccines and therapeutics,” says O’Connor. “We want to make sure we are recapitulating the kind of clinical signs (of virus infection) that happen in people.”

The researchers are interested in understanding how much of the virus makes its way into the body and in bodily fluids; where in the lungs the virus infects; and in creating opportunities to test new vaccines and antivirals. They also hope to look at how the immune system responds and whether there are indicators that can help clinicians distinguish who might be at risk for developing severe disease.

Yoshihiro Kawaoka

At the Influenza Research Institute (IRI) in Madison, Professor of Pathobiological Sciences Yoshihiro Kawaoka is also preparing to study 2019-nCoV.

Among the research questions he hopes to address is the efficiency with which the natural virus transmits among animal models for disease. The novel coronavirus is capable of transmitting from person to person, but it most likely originated in bats. However, as with other coronaviruses known to cause significant illness in humans, such as SARS-CoV and MERS-CoV, the virus likely passed through another animal before becoming infectious in humans. Researchers have not identified the animal or animals involved.

With SARS, the virus passed to humans through contact with civet cats, and with MERS, through dromedary camels.

Kawaoka is also interested in studying how the virus causes illness and what cells the virus is capable of infecting. The results of the work could be used to help develop treatments and vaccines to protect people against infection.

The work at IRI will be conducted in a Biosafety Level 3 Agriculture (BSL-3 Ag) laboratory, which is just below Biosafety Level 4. The Centers for Disease Control and Prevention guidelines call for research using the 2019-nCov virus to be conducted in a BSL-3 laboratory since important aspects of how the virus causes disease and transmits are not well understood.

“We are using SARS as a biosafety and biosecurity model for this coronavirus because we don’t know enough about the virus yet,” says Rebecca Moritz, Responsible Official and the Institutional Contact for Dual Use Research at UW–Madison. The SARS coronavirus caused an outbreak in more than two dozen countries in 2003, infecting more than 8,000 people and killing 774.

“My lab is interested in why things like this happen, why do viruses emerge from somewhere and begin causing diseases in humans? What are the evolutionary pathways they need to take hold, and how do they adapt to our immune responses?

“If we can understand that, hopefully we can erect more barriers to prevent this sort of thing from happening in the future.”

Thomas Friedrich

The university has worked proactively with Public Health Madison and Dane County, the Wisconsin Department of Health Services, the State Lab of Hygiene, infectious disease specialists and University Health Services to prepare to conduct the research.

“We are requiring researchers to monitor their health and to take their temperatures twice per day,” says Moritz. Fever is one symptom of 2019-nCoV illness. “If they are not feeling well, our exposure control plans in place involve infectious disease and public health authorities. We would quarantine and test them for the virus.”

With the studies planned, UW–Madison researchers are at the leading edge of efforts to understand an emerging human illness. Kawaoka stresses that basic research studies are necessary to combat pathogens that make animals and people sick. O’Connor, Friedrich and their collaborators plan to once again share their data publicly so that other researchers may use it to advance the science, and hopefully lead to efforts to improve and protect human health.

Says Friedrich: “My lab is interested in why things like this happen, why do viruses emerge from somewhere and begin causing diseases in humans? What are the evolutionary pathways they need to take hold, and how do they adapt to our immune responses? If we can understand that, hopefully we can erect more barriers to prevent this sort of thing from happening in the future.”

UW–Madison University Health Services answers to frequently asked questions

Wisconsin Department of Health Services information about 2019-nCoV

Near the end of the second quarter of Sunday’s game, Scout appeared in a 30-second spot alongside UW–Madison faculty and staff who have been part of his cancer journey.

The inspirational and heartwarming commercial, titled “Lucky Dog,” was the idea of Scout’s dog dad, WeatherTech founder and CEO David MacNeil. In gratitude for Scout’s treatment, the ad urges viewers to donate to SVM’s cancer research efforts via weathertech.com/donate.

Scout’s story received an overwhelming reaction since it was first released on Tuesday, with the Los Angeles Times calling it one of the best 2020 Super Bowl ads.

Media coverage: Scout’s story has been shared by outlets as far away as Ireland and New Zealand and has also included domestic coverage from NBC Nightly News, ABC’s World News Tonight, NPR’s Morning Edition, NBC’s Today Show, the Chicago Tribune, New York Post, Washington Post and People Magazine, among hundreds of others.

Donations: The School of Veterinary Medicine has received thousands of gifts from 49 states, plus Europe and South America. The gifts have ranged from $5 to a $250,000 gift of generous support from Petco Foundation. (Full gift totals are not immediately available, and gifts will continue to be accepted well after the game.)

Social media: Scout’s spot has been seen a total of nearly 900,000 times on YouTube between UW and WeatherTech channels. It has become UW’s most widely watched YouTube video of all time, with UW channel views up more than 4,000 percent. Across social media, the spot has garnered millions of impressions and thousands of engagements that are still being totaled.

(See below for additional coverage and reaction from across Instagram and Twitter.)

The experience has been hugely positive for Scout, WeatherTech and UW–Madison, says Chancellor Rebecca Blank.

The event elevated UW’s faculty and staff, shares a cancer research message to a global audience and lifts the entire veterinary medicine field.

“This is an incredible story. We’ve never been featured in a Super Bowl ad before — I’m not sure any university has been the beneficiary of such a commercial.

“This chance helps us share Scout’s story with the biggest possible audience, all in an effort to save the lives of other animals and raise funds for research.”

To read more about Scout’s story and make a donation, please visit weathertech.com/donate.

More information about the School of Veterinary Medicine and canine oncology is here: https://www.vetmed.wisc.edu/scout/.

Goldens watching Goldens:

Scout-inspired fashion:

Family group chat bonding over NPR Morning Edition:

Turn empathy into action:

Petco gift ($250K):

Golden retriever solidarity:

UW proud:

Three cross-section images of nerve tissue from cats, each showing an individual oligodendrocyte cell (marked with “O”) among nerve cell axons surrounded by dark-colored sheaths of myelin. Mature myelin sheaths (around axons marked with asterisks) are thick. Thin sheaths (marked with arrows) are remyelinated by the pictured oligodendrocyte. Images from Duncan et al, PNAS, 2018

Nerve cells stripped of their insulation can no longer carry vital information, leading to the numbness, weakness and vision problems often associated with multiple sclerosis. A new study shows an overlooked source may be able to replace that lost insulation and provide a new way to treat diseases like MS.

Cells called neurons make the central nervous system work by passing electrical signals along threadlike connections called axons. Axons do their work best when wrapped in an insulating coating of a fatty substance called myelin.

“When you lose myelin, axons don’t conduct at their normal speed or don’t conduct at all,” says Ian Duncan, a neuroscientist at the University of Wisconsin–Madison’s School of Veterinary Medicine. “And if enough of them are affected — such as in a big area of demyelination in MS — you develop clinical symptoms related to that part of the nervous system.”

Ian Duncan

Myelin is made by oligodendrocytes, cells that can reach out to several nearby axons to wrap parts of them in the protective myelin sheath.

Consensus has held that once an axon is robbed of its myelin, the only way to bring it back is by starting with fresh oligodendrocytes. Only oligodendrocytes arising from precursors called oligodendrocyte progenitor cells can apply a new coat of myelin to axons, goes the dogma. Thus, MS treatments aimed at remyelination have focused on recruiting progenitor cells in demyelinated areas (called plaques), and spurring them to develop.

However, researchers led by Duncan have shown in a study published today in the Proceedings of the National Academy of Sciences that starting from progenitor cells is not the only route to remyelination. In cats and rhesus macaques experiencing a severe loss of myelin, Duncan found fully developed oligodendrocytes already in place were reaching out and beginning to coat affected axons with myelin once again.

The catch, if there is one, is that to be helpful and remyelinate damaged axons, the adult oligodendrocytes may still need to have connections to surviving myelin segments — called “internodes” — on other axons.

“If this cell is still biologically active and maintaining these internodes, it can re-extend processes out to these demyelinated segments,” says Duncan, whose work is supported by the National Multiple Sclerosis Society. “Those processes can make new myelin sheaths, which end up being thinner and shorter than the previous internodes.”

But even thinner myelin will restore nerve function, as Duncan and colleagues reported in 2009.

Cats fed irradiated food for several months develop severe myelin loss throughout the nervous system. When the cats returned to a regular diet, nerve function was restored because of extensive myelin repair.

Nerve cell extensions called axons (green) are sheathed in protective myelin (red) provided by nearby cells called oligodendrocytes (blue). New research shows oligodendrocytes can respond to damage to myelin sections by creating a thin replacement coating of myelin. Graphic modified from Duncan et al, PNAS, 2018

The cats’ demyelination problems are unusual as a lab model of the disease.

“The de facto model to study demyelination and remyelination is in a mouse fed a toxin called cuprizone,” Duncan says. “But the toxin kills oligodendrocytes. So, studying the mouse, you naturally wouldn’t see any of the original oligodendrocytes beginning remyelination.”

In the new study, the researchers looked at the cats’ nervous tissue and found a unique myelin mosaic — axons surrounded by thick layers of myelin (formed during development when the axons themselves grew) were interspersed with other axons surrounded by thin layers of myelin.

“The most likely explanation of that mosaic appearance is surviving oligos,” Duncan says. “Thick myelin sheaths are never seen following remyelination, just thin sheaths. And surviving adult oligodendrocytes are adjacent to these sites of demyelination, making them likely candidates for myelin repair.”

Sure enough, the researchers found oligodendrocytes connected to both thick and thin myelin sheaths in the cat spinal cord.

The discovery of the mature myelin-producing cells’ capacity for repair opens new opportunities to slow or reverse the disease.

They also found this association when they reached back to a decades-old monkey model of demyelination. Neuropathologist Dimitri Agamanolis tried to make a model of another human demyelinating disease — called sub-acute combined degeneration and caused by Vitamin B12 deficiency — at Case Western Reserve University in the 1970s. Agamanolis had saved preserved blocks of sampled nervous tissue from the monkeys, and he shared them with Duncan. The monkeys’ myelin lesions resembled those in the cats.

“You see in the monkeys, too, single oligodendrocytes connected to mature myelin sheaths that also have processes extended out to and surrounding demyelinated axons,” Duncan says.

The UW–Madison researchers enlisted Grahame Kidd and the private research lab Renovo Neural in Cleveland to reconstruct stacks of electron microscope images of cat nerve cells into 3D representations that show oligodendrocytes reaching up and down the spinal cord, sustaining mature myelin and remyelinating damaged sheaths.

The process may not be playing out in human MS patients fast enough to help mitigate the progression of the disease, Duncan says. Or too many oligodendrocytes may lose so many of their internodal connections that they become inactive or die.

But the discovery of the mature myelin-producing cells’ capacity for repair opens new opportunities to slow or reverse the disease.

“Right now, the emphasis is on promoting the numbers of oligo progenitors and their differentiation, particularly into adult oligodendrocytes,” says Duncan. “What this work provides is a different target.”

That target will call for new therapeutic approaches — finding drugs, for example, that rally the oligodendrocytes to reach out with new lifelines to damaged myelin sheaths.

“In fighting complex diseases, such as MS, the more tools you have on hand, the better,” Duncan says. “If these adult cells are recruitable in some fashion, we should be looking at ways to do it.”

Duncan’s co-authors on the study include Kidd and UW–Madison neuroscience researchers Abigail Radcliff and Moones Heidari, veterinary medicine student Lauren Wierenga, and electron microscopy specialist Benjamin August.