"Bird Flu is Infecting Mammalian Brains: Understanding the Reasons Behind It"

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. And one unwelcome revelation of the ongoing outbreak is the virus’s propensity to invade the brains of myriad mammals.

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. 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.

From a bottlenosed dolphin in Florida to a polar bear in Alaska, many mammals across the United States have tested positive for avian influenza since 2022. Click on a colored dot to find out what species the virus was detected in and the county in which the animals were found. Zoom in for a closer look.

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.