Flu and Parkinson's - how H5N1 bird flu causes neural degeneration in mice

Not Exactly Rocket Science
By Ed Yong
Aug 11, 2009 2:00 AMNov 5, 2019 12:13 AM


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People infected with the bird flu virus - influenza A subtype H5N1 - go through the usual symptoms of fever, aching muscles and cough. The virus is so virulent that 60% of infected humans have died. But according to a study in mice, the infection could also take a more inconspicuous toll on the brain, causing the sorts of damage that could increase the risk of diseases like Parkinson's and Alzheimer's many years after the virus has been cleared.

The link between influenza and Parkinson's disease is hardly old but certainly controversial. Previous studies have found no traces of flu genetic material in Parkinson's patients, but one of the strongest pieces of evidence for a link comes from analysing an outbreak of von Economo disease  following the 1918 flu pandemic.

To date, 433 people have been infected with H5N1, and a few cases have shown problems with their nervous system, running the gamut from inflammation of the brain to coma. For the survivors, it's too early to say if their brief time with the virus could lead to neurological problems later on in life. Instead, Haeman Jang from St Jude's Children's Research Hospital turned to mice for answers.

He clearly showed that the H5N1 virus can infect mouse neurons within a few days, where it causes certain proteins to gather in the sorts of clumps that are so strongly associated with neurodegenerative disease. It kills off important cells, triggers symptoms reminiscent of Parkinson's like tremors, and even stimulates an over-the-top immune response that lasted for months after the original infection was cleared.

Jang thinks that this long-lasting immune response may be how the virus leads to a higher risk of chronic diseases long after it has left its host. It's a hit-and-run strategy, where the initial infection paves the way for something else to come along later on in life and make a "second hit". According to this model, the flu virus doesn't directly cause Parkinson's or related diseases, but it primes the neurons for other things that do. This could also explain why scientists have been unable to detect influenza RNA in Parkinson's patients.

Jang managed to track the virus's progress in the nervous system by using an antibody designed to latch onto a protein on the virus's shell Around 2-3 days after infection, the virus first appeared in the animals' peripheral nervous systems, the neurons that connect their organs and limbs to the brain and spine. By day 3, it had infiltrated the brainstem and by day 7, it was found in the brain itself. Jang even caught firsthand glimpses of the virus in the brain's neurons using powerful microscopes.

 As the infection permeates the nervous system, it clearly causes problems, for the majority of the mice experienced neurological symptoms like ataxia (malcoordination), bradykinesia (slowed movements) or tremors. But by day 21, the survivors had fought off the virus. Their neurological symptoms were gone, as was the virus from their nervous systems.

In the brains of the infected mice, Jang saw that various neurons were dying away. The infected mice had high levels of microglia, cells that act as the brain's immune defenders. These high levels indicate that the brain was inflamed and that carried on for the entire 90-day span of the study, long after the actual infection had cleared.

Worst of all, the infected mice also showed changes to the proteins in their neurons that have been implicated in neurodegenerative diseases. One of the most telling is an alteration to the alpha-synuclein protein (SYN), which gets a phosphate group attached to its 129^th amino acid. This simple chemical add-on allows the SYN protein to clump together, to form large insoluble plaques that are hallmarks of Parkinson's and Alzheimer's diseases. The brains of H5N1-infected mice contained neurons that were rife with this altered protein, which had indeed started to clump together.

Whether these changes appear in humans, and what their long-term effects might be, are still open questions. Nonetheless, Jang's work is compelling, especially given that the world is currently facing a flu pandemic (albeit thankfully not of the H5N1 type). It is a matter of more than just academic interest to work out whether other flu types have the same effects, and how strongly these infections increase the risk of neurological diseases, if at all.

Reference: PNAS 10.1073/pnas.0900096106

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