It all started with the duck who had influenza and Parkinson’s disease.
Part I: The Duck
In a 2007 seminar, David Boltz and his supervisor Robert Webster , professor emeritus of biochemistry and pioneer of influenza research , showed a video of a duck infected with H5N1 bird flu that took hundreds of human lives in 2006-2007. The duck flapped its wings but lost balance and fell, repeatedly.
That duck has Parkinson’s, noted Richard Smeyne , professor of neuroscience and director of the Jefferson Comprehensive Movement Disorder and Parkinson’s Center in Pennsylvania, who recognized its uncanny motor deficits.
He informed Webster soon after the seminar. But Webster found it amusing. “Well, it’s a sick bird,” he laughed.
When Smeyne got back to his lab, he led a team to examine the brains of ducks infected with the flu. When dissecting the brains of sacrificed ducks, they discovered that the substantia nigra — a brain region responsible for motor functions — was ruined.
“All the neurons were completely gone,” Smeyne observed. “I wasn’t wrong. Your duck does have Parkinson’s disease,” he told Webster later. It may not be “full-blown Parkinson’s disease, but it was parkinsonism."
Smeyne then asked the influenza expert about the symptoms of H5N1-infected patients. The now serious Webster described them detailedly including the little intricacies in their movement patterns and motor disturbances.
Part II: Historical Records
After the conversation with Webster, Smeyne looked at the past for hints. He noted that the Spanish flu in 1918 — caused by the H1N1 subtype of Influenza A virus — preceded the Parkinson’s epidemic in 1940–1950s. Parkinson’s diagnosis soared to 2.5-3% in the US population and returned to baseline at 1–2% in the following decades.
“Basically, 50% more people in those years got Parkinson’s,” Smeyne said.
“These data would indicate that most cases of Parkinson’s syndrome have a single etiology possibly related to subclinical infection in 1918 to 1920 resulting in the onset of Parkinson’s syndrome up to 40 or more years later,” the authors of the 1963 statistic paper wrote. One of the possible ‘subclinical infection’ was the influenza virus, they suspected.
Part III: Search for Causation
Epidemiological studies, like the above, only provide association. To study causation, Smeyne made mice inhaled H5N1 or H1N1 (at nonlethal dose) and observed the viruses’ activity in the nervous system.
The H5N1 subtype easily infiltrated the blood-brain-barrier and showed a preference for the substantia nigra — destroying dopaminergic neurons responsible for movement therein. Whereas the H1N1 subtype did not enter the brain per se but caused neuroinflammation that eats up cells in the substantia nigra and hippocampus responsible for memory.
“So these were two different flus, two different mechanisms, but the same effect in a sense,” explains Smeyne. “They were inducing inflammation and death in the parts of the brain that we see degenerate in Parkinson’s disease.”
Part IV: A Risk Factor for Parkinson’s
Later in 2017, Smeyne and colleagues gave mice the heroin toxin, MPTP, which is known to induce Parkinson’s in humans. Half of those mice had recovered from the flu and in this bunch of mice, MPTP destroyed 25% more neurons in the substantia nigra than the MPTP-treated mice never exposed to the flu. Importantly, the nasty effects of MPTP can be prevented if the mice were given influenza vaccines or antivirals.
“While the H1N1 infection alone did not cause Parkinson’s, it primed the nervous system to be sensitive to other things that would,” Smeyne said. “Seasonal flu vaccination could have on long-term brain health."
Smeyne, therefore, proposed that the influenza virus is a ‘hit’ in the multiple-hit hypothesis, which states that “multiple exposures — over periods of time — can synergize to induce Parkinson’s.” This means that the influenza virus contributes to the development of Parkinson's disease, on top of other factors such as genetics, lifestyle choices, and possibly other viruses.
Smeyne further said that this influenza hit can be removed from the equation via vaccination or antivirals at the time of infection — providing another reason why the flu shot is essential.
Our identification of influenza as one of these factors and the finding that this “hit” can be eliminated by vaccination, or prompt treatment with anti-viral medications after infection, provides another reason to get a flu vaccine.
Part V: Current Understanding
Scientists are beginning to decipher the intricacies underlying how microbes enter the brain, with the hope to design therapeutics that can interfere with the cell-to-cell spread of microbes.
Microbes, especially viruses, with neurodegenerative potential have been dismissed for a long time. Professor Emeritus Ruth Ithzaki’s grant applications for clinical trials investigating the efficacy of antivirals for Alzheimer’s were denied many times previously. Why? The neurobiologist Anthony Van del Pol from Yale University explains:
“Viruses are often ignored in relation to neurodegenerative diseases. That’s in part because there’s no clear sign that a virus causes neurodegenerative disease. But it might.”
The keyword is that ‘it might’. This complicates things as a definitive cause (e.g., smoking and lung cancer) cannot be established.
Whether influenza or herpes simplex virus-1 will lead to neurodegenerative diseases would depend on and compound with other factors — such as genetic predisposition, upbringing, nutrition, physical activity, emotional stress, environmental pollutants, gut health, and other medical conditions— in a multiple-hit manner. Perhaps the best we can do is to mitigate each component cause to the best of our ability.
This article was previously published in Microbial Instincts with minor modifications.
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