A little more than 10 years ago, when neurobiologist Richard Smeynewas working at St. Jude Children’s Research Hospital in Memphis, he saw a video of a duck acting strangely. The white-feathered, orange-billed bird was standing slightly apart from its flock on a farm in Laos. It walked in circles and flipped up a wing, then lost its balance and fell over. It got up, tried to flap both wings, and fell over again.
Smeyne saw the video while attending a seminar being given by then-postdoc David Boltz and Boltz’s advisor, a “flu hunter” named Robert Webster, who headed the influenza research program at the hospital. The duck, Boltz and Webster explained, was infected with the H5N1 bird flu virus that had sickened thousands of birds and killed hundreds of people in 2006 and 2007. Smeyne, who had been studying the neurobiology of Parkinson’s disease in mice, recognized the animal’s motor issues. That duck has Parkinson’s, he thought.
He told Webster this after the seminar, and Webster laughed, Smeyne recalls. “He said, ‘Well, it’s a sick bird.’” But Smeyne was curious about the neural mechanisms underlying the duck’s abnormal behavior. He wondered if healthy ducks infected with H5N1 in the lab would show Parkinson’s-like neurodegeneration. In St. Jude’s biosafety level 3 lab, he and his colleagues infected ducks with the virus, then sacrificed the birds and removed their brains, storing them in formaldehyde for three weeks to kill the active virus.
When Smeyne began to dissect the once-infected duck brains, he focused on a region called the substantia nigra, which is often damaged in Parkinson’s patients. “When I opened it up, when I cut the brain, the substantia nigra was devastated. All the neurons were completely gone,” Smeyne says. He went back to Webster, he recalls, and said, “I wasn’t wrong. Your duck does have Parkinson’s disease.”
Because the bird had had the flu, Smeyne wondered whether there was a connection between the viral infection and the extensive neurodegeneration he observed. He asked Webster about the symptoms experienced by people infected with H5N1. Webster’s answer—inflammation of the brain that leads to tremors and other motor malfunctions—didn’t sound like “full-blown Parkinson’s disease,” Smeyne says, “but it was parkinsonism,” a subset of symptoms of the disease.
Looking into the literature, Smeyne found more hints of influenza’s ability to damage the brain. One of the earliest links between influenza and neural dysfunction was a correlation between the 1918 Spanish flu, caused by a subtype called H1N1, and an epidemic of Parkinson’s a few decades later. In the 1940s and early 1950s, diagnoses of the neurodegenerative disease appeared to increase abruptly, from 1–2 percent of the US population to 2.5–3 percent, then fell back down to 1–2 percent, Smeyne says. “Basically, 50 percent more people in those years got Parkinson’s.”
The evidence to suggest that influenza infection caused the neurodegenerative disorder was tenuous, to say the least, but the correlation was enough for Smeyne to investigate further. With his colleagues, he shot nonlethal doses of H5N1 or H1N1 up the noses of six- to eight-week-old mice, then tracked how the viruses spread through the animals’ nervous systems. The results were startling, he says: some viruses weren’t blocked from entering the brain by the blood-brain barrier—a semipermeable layer of cells that separates the central nervous system from the body’s circulation. H5N1, for example, could easily infiltrate nerve cells in the brain and kill them, and it appeared to especially target the dopamine-producing neurons in the substantia nigra.1 And while the H1N1 flu strain couldn’t cross the blood-brain barrier, it still caused central nervous system immune cells called microglia to flow into the substantia nigra and the hippocampus, causing inflammation and cell death in the area.2
“So these were two different flus, two different mechanisms, but the same effect in a sense,” says Smeyne, who moved to Thomas Jefferson University in Philadelphia in 2016. “They were inducing inflammation and death in the parts of the brain that we see degenerate in Parkinson’s disease.”
Smeyne’s experiments aren’t the only ones to suggest that viral infections can contribute to neurodegenerative disorders, and the connection is not limited to influenza. Several different viruses, including measles and herpes, can give rise to symptoms of multiple sclerosis (MS) in rodents, for example.3 And levels of herpesvirus are higher in the brains of people who died from Alzheimer’s than in those without the disease,4 while some HIV patients develop dementia that appears to be associated with the infection.
“Viruses are often ignored in relation to neurodegenerative diseases,” Yale University neurobiologist Anthony van den Pol tells The Scientist. “That’s in part because there’s no clear sign that a virus causes a neurodegenerative disease. But it might.”
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