Chances are, when asked to list possible causes for Parkinson and Alzheimer diseases, many scientists would not think to include flu virus. Yet a study in this week’s PNAS Early Edition lifts the so-called “pathogen hypothesis” off the backburner. Led by Richard Smeyne, researchers at St. Jude Children’s Research Hospital in Memphis, Tennessee, report that a deadly bird flu virus can reach the central nervous system of infected mice, triggering neuroinflammation and PD-like pathology.

“I think it was a well-done study, and I think the data do suggest that this type of influenza virus can cause the damage we would see with Parkinson's,” said Brian Balin, who studies diseases of aging at the Philadelphia College of Osteopathic Medicine, Pennsylvania. “It fits with what a lot of people have been doing, or have intimated over the years—that infection can cause a neurodegenerative process.” (For reviews, see Mattson, 2004; Itzhaki et al., 2004; Balin et al., 2008).

Motivated in part by controversial epidemiological data linking neurological problems with past flu outbreaks such as the devastating 1918 “Spanish” flu (Maurizi, 1985; Ravenholt and Foege, 1982), the project got off the ground after a lunchtime chat between two postdocs. Three years ago, when people feared the H5N1 bird flu virus would become pandemic, Kennie Shepherd of Smeyne’s group and a postdoc working with influenza scientist Robert Webster suggested that their labs pool resources to ask what H5N1 could do in the nervous system. Smeyne’s lab had the neurodegenerative expertise, Webster’s the flu virus. Around the same time, Smeyne had had an “aha” moment while viewing video footage of H5N1-infected geese from Webster’s research expedition in Laos. “Those birds had trouble initiating movement. They'd fall side to side, and the like,” Smeyne recalled. “I said to myself, ‘they look like they have Parkinson disease.’”

For the current study, first author Haeman Jang and colleagues infected mice intranasally with a 50 percent mouse-lethal dose of H5N1. “We wanted the mode of inoculation to be the same, and we wanted the mice to get the equivalent dose of influenza that a human would be exposed to,” Smeyne said. Mimicking human disease patterns, half of the mice died quickly, while the other half got sick and recovered by three weeks post-infection.

In immunohistochemistry studies, the researchers used antibody to the influenza virus nucleoprotein (NP) to trace H5N1’s journey through the nervous system. “Our prediction was that it was going to get into the nervous system through areas where the blood-brain barrier breaks down, but it didn't,” Smeyne said. Instead, H5N1 appeared to reach the nervous system via neurons connecting from the lungs and gut. The virus began at the cranial nerves—first detectable in the vagus nerve, then the nose and olfactory bulb, and onward through the respiratory system.

The progression of H5N1 in mice bears uncanny resemblance to the timing of symptoms in PD patients, many of whom first experience gut motility problems. “They get really badly constipated,” Smeyne said. “Then it progresses to changes in sleep-wake cycles. And then you finally start getting motor symptoms.” Altered sense of smell resulting from damaged olfactory neurons also seems to develop before cardinal symptoms in PD and AD (see ARF related news story). On the pathological side, aggregation of phosphorylated α-synuclein, is believed to precede clinical symptoms in both diseases.

In H5N1-infected mice, the researchers found that the presence of virus seemed to correlate with levels of phosphorylated α-synuclein. “It basically doubled wherever the virus was, and where the virus was not, there was no change at all,” Smeyne said. Infected mice had a 17 percent loss of dopaminergic neurons in the substantia nigra pars compacta (the brain region most affected by neurodegeneration in PD). They also had upregulation of activated microglia, which persisted well beyond day 21, when scientists could no longer detect virus in the brain. “We've looked up to 120 days later, and it looked like it did the day we first saw the active infection,” Smeyne said of the microglial response.

To Smeyne, this implicates a hit-and-run mechanism. “The virus is gone, but you’ve primed the nervous system for other things to affect the brain that ordinarily wouldn’t,” he said. “The infection is sort of like a stealth hit, and we think you need something else to then cause disease.” However, Paul Ewald, an evolutionary biologist at the University of Louisville, Kentucky, offered a more cautious interpretation in an e-mail to ARF. “It has become clear over the past three decades that infectious agents may persist cryptically within their hosts far longer than is suggested by techniques that measure the conspicuous first flush of infection,” he wrote, noting that the scientists’ inability to detect virus at 21 days post-infection does not exclude the possibility that neuronal damage was induced by cryptic persistent infection. (See full comment below.)

Whatever the mechanism, “if uncommon flu strains such as H5N1 can damage dopaminergic neurons, it is worth considering the question of whether common flu strains that spread through the population each year also damage dopaminergic neurons,” wrote clinician-investigator Russell Swerdlow, University of Kansas School of Medicine, Kansas City, in an e-mail to ARF. “If so, flu viruses may contribute more to the development of parkinsonism or perhaps even Parkinson disease than we currently appreciate.”

Other studies suggest that pathogens could be involved in AD, too. CD33, one of four genes found to significantly associate with AD in a recent genomewide association screen (Bertram et al., 2008), is involved in activating the innate immune system. Herpes simplex virus has been found associated with amyloid precursor protein (Satpute-Krishnan et al., 2003 and ARF related news story). But perhaps the most prominent example of a dementia linked to viral infection is human immunodeficiency type 1 (HIV-1)-associated dementia (for a recent review, see Jayadev and Garden, 2009).

Based on his recent findings, Smeyne suspects that West Nile virus, Coxsackie virus, and others that have caused neurological symptoms traverse the nervous system in distinct ways. “Without any experimental proof, I will bet that each virus has a very specific effect on the nervous system,” he said. “It wouldn’t surprise me at all that some viruses affect cholinergic neurons. Then AD becomes important. In our case [H5N1] reached dopaminergic neurons, which are important for PD.”

At this point, it remains unknown whether the new findings are relevant to other flu strains—for example, H1N1, the virus behind the current flu scare. Preliminary evidence had suggested that H1N1 does not reach the nervous system. However, according to a July 24 report from the Centers for Disease Control, there are now four cases in Dallas where H1N1-infected children developed neurological complications. “It could be that the H1N1 virus is mutating and now making itself accessible to the nervous system,” Smeyne said. “Clearly, it would be worthwhile for someone to examine these emerging viruses and ask the simple question, do they get into the nervous system or not?”—Esther Landhuis

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Comments on News and Primary Papers

  1. The evidence implicating viral infection with neuronal damage is interesting and significant, but the authors need to be more careful in their application of the data to human neurological diseases. They mention that their results might help explain parkinsonisms, such as von Economo’s encephalitis, which is the illness described in Oliver Sacks’s book Awakenings, and the movie of the same name starring Robin Williams and Robert De Niro. The authors mention that the high prevalence of von Economo’s encephalitis after World War I has led some to link it to the 1918 influenza epidemic and refer readers to quarter-century-old papers. They then suggest that their study offers an explanation for this link. But the epidemic of von Economo’s encephalitis began in 1915. Von Economo described it in 1917. Recently it has been linked to streptococcal infection. So the link emphasized in this paper is a big stretch.

    The authors also need to be a bit more careful in linking their data to a hit-and-run autoimmune mechanism. They state, “we show the virus is gone from the brain in 21 days” and then suggest that this absence implicates a hit-and-run mechanism of neuronal damage. It would have been better for them to say “we were unable to detect the virus 21 days after infection.” It has become clear over the past three decades that infectious agents may persist cryptically within their hosts far longer than is suggested by techniques that measure the conspicuous first flush of infection. This tendency to invoke a hit-and-run mechanism without adequately excluding low-level persistence is a general problem in the study of immunologically mediated diseases because it has led to a tendency to accept too quickly mechanisms of infectious triggers of immunological damage when evidence does not exclude damage induced by cryptic persistent infection. The authors didn’t need to make the claim that the virus was gone. Rather, they need only to make the point that their assays did not detect the virus.

    View all comments by Paul W. Ewald
  2. This work makes several interesting points and raises important questions. It puts us on notice that, like the flu epidemic of 1918, an H5N1 epidemic could potentially cause immediate or delayed parkinsonism in a significant part of the population. It demonstrates yet another example of how neuron damage can drive downstream protein aggregation. Also, if uncommon flu strains such as H5N1 can damage dopaminergic neurons, it is worth considering whether common flu strains that spread through the population each year also damage dopaminergic neurons. If so, flu viruses may contribute more to the development of parkinsonism, or perhaps even Parkinson disease, than we currently appreciate.

    View all comments by Russell Swerdlow

References

News Citations

  1. Oxidative Damage to the Olfactory Epithelium—Smells Like AD
  2. Herpes and AD—Virus Hitches Ride with APP

Paper Citations

  1. . Infectious agents and age-related neurodegenerative disorders. Ageing Res Rev. 2004 Jan;3(1):105-20. PubMed.
  2. . Infiltration of the brain by pathogens causes Alzheimer's disease. Neurobiol Aging. 2004 May-Jun;25(5):619-27. PubMed.
  3. . Chlamydophila pneumoniae and the etiology of late-onset Alzheimer's disease. J Alzheimers Dis. 2008 May;13(4):371-80. PubMed.
  4. . Why was the 1918 influenza pandemic so lethal? The possible role of a neurovirulent neuraminidase. Med Hypotheses. 1985 Jan;16(1):1-5. PubMed.
  5. . 1918 influenza, encephalitis lethargica, parkinsonism. Lancet. 1982 Oct 16;2(8303):860-4. PubMed.
  6. . Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE. Am J Hum Genet. 2008 Nov;83(5):623-32. PubMed.
  7. . Fast anterograde transport of herpes simplex virus: role for the amyloid precursor protein of alzheimer's disease. Aging Cell. 2003 Dec;2(6):305-18. PubMed.
  8. . Host and viral factors influencing the pathogenesis of HIV-associated neurocognitive disorders. J Neuroimmune Pharmacol. 2009 Jun;4(2):175-89. PubMed.

External Citations

  1. July 24 report

Further Reading

Papers

  1. . Infectious agents and age-related neurodegenerative disorders. Ageing Res Rev. 2004 Jan;3(1):105-20. PubMed.
  2. . Chlamydophila pneumoniae and the etiology of late-onset Alzheimer's disease. J Alzheimers Dis. 2008 May;13(4):371-80. PubMed.
  3. . Infiltration of the brain by pathogens causes Alzheimer's disease. Neurobiol Aging. 2004 May-Jun;25(5):619-27. PubMed.

Primary Papers

  1. . Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration. Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14063-8. PubMed.