In spring 2022, a handful of red foxes in Wisconsin were behaving oddly. Veterinary pathologist Betsy Elsmo learned that a local wildlife rehabilitation center was caring for foxes with neurological symptoms like seizures, tremors, uncoordinated movements and lethargy.

But tests for common pathogens like canine distemper virus and rabies that typically cause the symptoms came back negative. Then a red fox kit tested positive for influenza A. This group of viruses includes seasonal flus that cause respiratory disease in people and many other strains that commonly circulate among animals such as waterfowl and other birds.

“I was surprised,” says Elsmo, of the University of Wisconsin–Madison. “And to be honest, at first I kind of wrote it off.”

That is, until a veterinary technician at the rehab center sent Elsmo a study describing cases of avian influenza in red foxes in the Netherlands. Examinations of the Wisconsin kit’s tissues under the microscope revealed lesions in the brain, lung and heart that matched what had been seen in the Netherlands animals. “And I thought, I think it is [bird flu],” she recalls.

Additional testing confirmed the diagnosis in the kit and the other foxes, Elsmo and colleagues reported in the December 2023 Emerging Infectious Diseases. The animals had contracted a lethal strain of H5N1 avian influenza that emerged in late 2020 in Europe and has since spread around the world. At the time infections were discovered in the Wisconsin red foxes, bird flu was expanding its incursion into North America.

Since H5N1 arrived on North American shores in December 2021, it has infected animals as wide-ranging as polar bears, skunks, sea lions, bottlenosed dolphins and cows (SN: 7/8/24). And one unwelcome revelation of the ongoing outbreak is the virus’s propensity to invade the brains of myriad mammals.

Bird flu on the brain

H5N1 is now known to infect more than 50 mammal species. Scientists had documented bird flu cases in only about a dozen species during previous outbreaks.

There’s nothing particularly special about this strain that allows it to plague so many species, research suggests. Rather, because the strain has spread so far and wide among birds — both wild and domesticated — there are simply more opportunities for mammals to be exposed, says virologist Emmie de Wit of the National Institutes of Health’s Rocky Mountain Laboratories in Hamilton, Mont. (SN: 1/25/24). For some mammals, infected birds may be on the menu. For others, their water or food might be contaminated with virus-laden bird excrement.

Water-loving birds are exposed to influenza A viruses so often that most have some form of immunity that can protect them from a serious case of H5N1. If the birds do exhibit symptoms, they are usually mild and respiratory or gastrointestinal in nature. But other birds that don’t get infected as frequently, such as eagles, vultures and pelicans, can become severely ill and die.

In mammals, bird flu typically causes respiratory symptoms such as congestion or shortness of breath. Neurological symptoms such as seizures or paralysis are among the most striking and common signs that the virus has reached the brain. And once it does, the infection is often fatal. In the ongoing H5N1 outbreak, such cases have been confirmed posthumously in house cats, raccoons, sea lions, dolphins and several other species (SN: 5/31/24).

H5N1 and its close relatives have an easier path to the brain compared with other flu strains, de Wit says. And the virus is exceptionally good at making copies of itself inside a variety of cells, including nerve cells.

To break inside a cell, flu viruses exploit a protein called sialic acid on the cell’s surface. Bird cells and mammalian cells in the upper airway typically have different types of sialic acids, which means that bird flu viruses don’t easily infect mammals and vice versa.

But studies have shown that parts of the human brain, for instance, are covered in birdlike sialic acid proteins. Many cells, including the nerve cells in the olfactory bulb — which is important for sense of smell and links directly to the brain — also have additional proteins that allow H5 viruses to replicate. Both of those traits mean that “there’s a direct entry route [to the brain] from your nose,” de Wit says. So avian flu viruses may pose a bigger threat to the brain than, say, seasonal influenzas that mostly target cells in the nose, throat and lungs.

Since 2003, there have been 891 cases of H5N1 in people, about half of which were fatal according to the World Health Organization. In the current outbreak, 15 people have been infected with the strain hitting mammals hard. Four people had severe disease — two developed pneumonia — and at least one died.

Symptoms in people can vary from mild to severe, and some individuals infected with avian influenza viruses during previous outbreaks have developed neurological symptoms. Such cases are rare, the agency says, although how often the virus makes it to the brain is unclear.

How often the virus invades the brains of other mammals is also unknown. Most countries don’t regularly test healthy-looking wildlife for viral infections, so such cases likely represent only the sickest individuals, Elsmo says. It’s possible that some infected animals never develop severe disease and therefore escape the notice of people.

Avian influenza viruses can affect other parts of the body as well. “When you break it out by species, it seems like the pattern of tissues that are most affected are little bit different,” Elsmo says.

For instance, foxes and raccoons seem to have severe brain lesions as well as lesions in the heart and lungs. Striped skunks, meanwhile, tend to have few brain lesions, some of which are mild compared with red foxes. Instead, at least in Elsmo’s experience, H5N1 seems to target the skunk livers and organs in the lymphoid system, which protects against infection and removes waste from the body.

Stranger things

Some animals that have been killed by H5N1 weirdly had signs of infection only in the brain. “Flu’s a respiratory virus,” says Richard Webby, a virologist at St. Jude Children’s Research Hospital in Memphis, Tenn. “So [the respiratory system is] where it should be before anywhere else.”

The brain of a red fox in the Netherlands, for instance, was infected with H5N1 but not the animal’s lungs. Red foxes and mink in Canada similarly had mostly neurological disease. And bird flu didn’t seem to touch the lungs of a bottlenosed dolphin found off the coast of Florida in 2022, despite the animal having virus-infected brain tissue, Webby and colleagues reported April 18 in Communications Biology.

It’s possible that the dolphin had cleared the respiratory infection before it died, but the team found no evidence of pulmonary disease. Nor do dolphins have a sense of smell, which eliminates the possibility that the virus could reach the brain through the nose.

Exactly how the virus might sometimes sidestep respiratory tissues and hitch a ride directly to the brain is unclear. One possibility is that H5N1 already has that ability. “Maybe it was more common, but we just never had the numbers [of mammalian infections necessary] to see it,” Webby says.

Or perhaps when a mammal like a red fox or a dolphin takes a bite out of an infected bird, viral particles in the meat gain a direct path to the brain via nerves lining the mouth and digestive tract.

Virologist and veterinarian Víctor Neira thinks that’s what may be happening in some sea lions in Chile. He and colleagues investigated an outbreak in the animals in 2023 along the coast of Chile, including two animals that the team necropsied. Although one animal didn’t have neurological symptoms, the other had paralysis, disorientation, lack of coordination and tremors, the researchers reported in October 2023 in Veterinary Quarterly. The virus had infected multiple organs including the lungs, liver and kidneys, but the highest viral counts came from the brain.

Because H5N1 hasn’t been infecting sea lions for very long, since just 2023, there is still a lot to learn about how the virus affects the animals, says Neira, of the University of Chile in Santiago.

Just how many mammal species are susceptible to infection is an open question. “Usually, scientists study influenza virus in swine, mice, humans and birds,” Neira says. “Different wild animals, even several domestic animals, have not been studied with this virus.”

There’s an urgency to finding out. That’s because every infection gives the virus an opportunity to adapt in ways that could allow it to spread more readily among mammals, de Wit says. Some research suggests that the virus may be spreading from marine mammal to marine mammal in parts of South America. But so far, infections in other animals are largely dead ends, with no spread to other individuals. The risk to people remains low, although workers on poultry and cattle farms who work closely with animals are at a higher risk than the general public.

Still, “we cannot stop paying attention,” de Wit says. The ongoing outbreak serves as a reminder that viruses are versatile foes.