Bird flu has invaded the mammalian brain. That is why

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

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

Additional testing confirmed the diagnosis in the kit and other foxes, Elsmo and colleagues reported in December 2023 Emerging infectious diseases. The animals had contracted a deadly strain of H5N1 bird flu that emerged in late 2020 in Europe and has since spread around the world. By the time the infections were discovered in 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 diverse as polar bears, skunks, sea lions, bottlenose dolphins, and cows (SN: 7/8/24). And an unwelcome discovery of the ongoing outbreak is the virus’ propensity to invade the brains of a host of mammals.

Bird flu in the brain

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

There is nothing particularly special about this strain that allows it to harm so many species, the research suggests. Rather, because the strain has spread so far and widely among birds—both wild and domesticated—there’s simply more opportunity 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 may be contaminated with virus-laden bird droppings.

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

In mammals, bird flu usually 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 outbreak of H5N1, such cases have been confirmed postmortem in domestic 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 than other flu strains, de Wit says. And the virus is extremely good at making copies of itself inside a variety of cells, including nerve cells.

To break into a cell, flu viruses use a protein called sialic acid on the cell’s surface. Avian cells and mammalian cells in the upper respiratory tract usually have different types of sialic acids, meaning that avian influenza viruses do not easily infect mammals and vice versa.

But studies have shown that parts of the human brain, for example, are covered in bird-like sialic acid proteins. Many cells, including nerve cells in the olfactory bulb—which is important for the sense of smell and connections directly to the brain—also have additional proteins that allow H5 viruses to replicate. Both of these features mean that “there is a direct path of entry [to the brain] from your nose,” says de Wit. So bird flu viruses may pose a greater threat to the brain than, say, seasonal flu, which mainly targets cells in the nose, throat and lungs.

Since 2003, there have been 891 cases of H5N1 in humans, about half of which were fatal, according to the World Health Organization. In the current outbreak, 15 people have been infected with the strain that hits mammals hard. Four people were seriously ill – two developed pneumonia – and at least one died.

Symptoms in humans 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 passes into the brain is unclear.

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

Bird flu viruses can also affect other parts of the body. “When you break it down by species, it looks like the pattern of tissues that are most affected is a little bit different,” says Elsmo.

For example, foxes and raccoons appear to have severe brain lesions, as well as heart and lung lesions. Meanwhile, striped foxes tend to have few brain lesions, some of which are mild compared to red foxes. Instead, at least in Elsmo’s experience, H5N1 appears to target the liver and other organs in the lymphoid system, which protects against infection and removes waste from the body.

Strange things

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

The brain of a red fox in the Netherlands, for example, was infected with H5N1, but not the animal’s lungs. Red foxes and mink in Canada similarly had mostly neurological diseases. And bird flu did not appear to affect the lungs of a bottlenose dolphin found off the coast of Florida in 2022, despite the animal having virus-infected brain tissue, Webby and colleagues reported April 18 in Biology of communications.

It’s possible the dolphin had cleared a respiratory infection before it died, but the team found no evidence of pulmonary disease. Dolphins also have no sense of smell, which eliminates the possibility of the virus reaching the brain through the nose.

It is unclear exactly how the virus can sometimes bypass respiratory tissues and go directly to the brain. One possibility is that H5N1 already has that ability. “Maybe it was more common, but we never had the numbers [of mammalian infections necessary] to see it,” says Webby.

Or perhaps when a mammal like a red fox or a dolphin bites an infected bird, viral particles in the flesh gain a direct route to the brain via the nerves that line the mouth and digestive tract.

Virologist and veterinarian Victor Neira thinks this may be happening to some sea lions in Chile. He and colleagues investigated an animal outbreak in 2023 along the coast of Chile, including two animals that the team necropsied. Although one animal had no 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 number of viruses came from the brain.

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

How many species of mammals are susceptible to infection is an open question. “Usually, scientists study the flu virus in pigs, mice, humans and birds,” says Neira. “Various wild animals, even some domestic animals, have not been studied with this virus.”

There is an urgency to find out. That’s because each infection gives the virus an opportunity to adapt in ways that may allow it to spread more easily among mammals, de Wit says. Some research suggests that the virus may spread from marine mammal to marine mammal in parts of South America. But so far, infections in other animals are mostly dead ends, without spreading to other individuals. The risk to humans remains low, although workers on poultry and livestock farms who work closely with animals are at a higher risk than the general public.

Still, “we can’t stop paying attention,” says de Wit. The continued spread serves as a reminder that viruses are versatile enemies.