20 June 2002 16:00 GMT

by Bea Perks, BioMedNet News

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Is migraine infectious? Can you catch arthritis or Alzheimer's disease? A growing body of research suggests that these and other chronic diseases do have an infectious component, but it's a notoriously tricky area to study.

Thus - despite landmark discoveries such as the association between Helicobacter pylori infection and stomach ulcers - those trying to link microbes with chronic disease continue to wage an uphill battle.

It's much easier to study cause and effect with acute infection, which is the traditional focus of microbiology, says Ruth Itzhaki, professor of molecular neurobiology at the University of Manchester Institute of Science and Technology, who is in the process of writing up her latest findings on the association between herpes simplex 1 (HSV1) infection and Alzheimer's disease (AD).

"People are getting more and more interested" in links between bacteria or viruses and chronic conditions, said Itzhaki. "The only thing is, there are still some die-hards who don't believe a word of it."

Itzhaki has detected, for the first time, antibodies against the virus in samples of cerebrospinal fluid from patients with AD. Importantly, she has ruled out the possibility that they have simply leaked across the blood-brain barrier.

"We're very excited about that, because it really very strongly supports our findings by the polymerase chain reaction of the viral [HSV1] DNA in the brain," she said.

Itzhaki surprised AD researchers when she provided the first evidence, in 1991, for a link between herpes simplex virus 1 (HSV1) infection in the brain and Alzheimer's disease (AD).

Most people are infected with HSV1 at some point, but the virus lurks in the peripheral nervous system, not in the brain. Itzhaki used PCR to show that the virus can find its way into the brains of older people, including people with AD. Crucially, she found that people who have the infection and carry the Apoe4 allele, which was identified by a separate research group as a risk factor in AD, are at high risk of developing the disease - higher than if they had either Apoe4 or HSV1 alone.

The situation bears similarities with cold-sore pathology, says Itzhaki. Cold sores are the result of HSV1 infection in the peripheral nervous system, but not all infected individuals have cold sores. She looked for the Apoe4 allele in people with cold sores, and discovered that, as with AD, people who carry the Apoe4 allele are much more likely to develop cold sores. The discovery has important implications for her work with AD, suggesting an interaction between the Apoe4 protein product and HSV1.

Itzhaki wants to find out whether people who have cold sores are more likely to develop AD. In the absence of relevant medical records, this would be a Herculean task. Even her approaches to the British Medical Association and the UK General Medical Council have failed to provide a workable solution. "It seemed to be almost impossible to set it up and I haven't got the time," she sighed.

The next question on Itzhaki's agenda is HSV1's whereabouts in the brain. Is the virus associated with abnormal features of the Alzheimer's brain, or more evenly distributed? She is also looking to see whether other viruses play roles in different types of dementia.

"There's so much to look at and so little money to do it," she said. "The trouble is the more original and unexpected the work, the harder it is to get funding."

Itzhaki applauds researchers who investigate the contribution of microbial infection to chronic disease in the face of opposition. She cites the example of research into the link between H. pylori infection and stomach ulcers, which took ten years to gain acceptance. "People just didn't want to know," she recalled.

Even Itzhaki is surprised, though intrigued, to hear of a recently proposed link between H. pylori infection and migraine.

Maria Rita Gismondo at the Ospedale Luigi Sacco in Milan has found that H. pylori infection is common among people with migraine without aura. The number of CagA-positive bacterial strains significantly outweighs the number of VacA-positive strains in these patients, she reports - an observation previously associated with stomach ulcers and active gastritis.

In a follow-up clinical study, Gismondo showed that treatment with the harmless bacteria Lactobacillus, which reportedly wards off stomach ulcers by outcompeting H. pylori in the gut, significantly reduced migraine symptoms. The results are unpublished.

Bacterial infection is implicated in numerous chronic-disease processes, from heart disease to cancer. But with a few notable exceptions, such as tuberculosis and leprosy, the infectious component of those processes is poorly understood, says Alan Hudson, professor of microbiology at Wayne State University in Detroit.

"We've been absolutely fabulously successful over the last 300 years at fishing out microbial causes of diseases," said Hudson. "But essentially 99.9% of everything that's been sorted out is acute diseases, and those are easy."

Microbiologists need to focus on all the diseases with no known cause, he says. Hudson and his team are investigating the role of Chlamydia infection in reactive arthritis. Half of all patients with reactive arthritis subsequently develop chronic arthritis, which particularly interests him.

Reactive arthritis had been correlated with Chlamydia infection for ages, says Hudson, but how this led to chronic disease, which can last for 30 years, was a mystery. It was assumed that bacteria that migrated to patients' joints and triggered the acute disease were dead once chronic symptoms set in.

Looking for Chlamydia in synovial fluid from patients' joints supported this: The samples were culture-negative. But examining joint tissue by electron microscopy revealed round objects that resembled bacteria.

Hudson's research over the past ten years has shown that Chlamydia is living there, although in tissue rather than fluid.

"It's perfectly alive," he said. "It's viable, it's metabolically active, but there's something funny about its biochemistry in this long-term infection state."

Hudson's research is now focused on the molecular genetics and biochemistry of Chlamydia that distinguishes long-term from acute infection. The cytokine profiles in patients with either acute or chronic arthritis are completely different, he adds.

Based on his unpublished findings and earlier data, Hudson anticipates that an altered host-pathogen relationship distinguishes the transition from acute to chronic infection. "We think that this organism overtly manipulates its long-term host cell to maintain itself," he said.

Hudson has also reported a controversial association between C. pneumoniae infection and AD (though even he is not convinced that this relationship is causal). Others have reported associations between the bacterium and multiple sclerosis, atherosclerosis, and meningoencephalitis. The findings join data on a range of other viral and bacterial pathogens and chronic disease.

How many of these connections will turn out to have been ephemeral? "We're at the beginning," he said. "I think some of this stuff is going to turn out to be, if not wrong, not exactly right."

Picture caption and credit:
Helicobacter pylori, NIH.

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