Science: THE GERM BUG

Far from being defeated, germs are responsible for many of the ills being blamed on genes and vices. Hilary Bower reports
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There is a quiet revolution going on in medicine. Diseases that were once thought to be caused by our way of life, or by something wrong with the body, are turning out to be due to germs.

The germs that used to get us, got us quickly. Cholera, measles, typhoid, smallpox and tuberculosis swept through communities, killing millions. But beaten back by a combination of hygiene and vaccination, death by infectious disease now seems as anachronistic in the developed world as smoking to prevent asthma. What Western masses now die of are cardiovascular disease and cancer prompted, it has been popularly thought, by life-style vices with a little help from our genes.

Far from giving up the ghost, though, the pathogens that once wreaked such obvious havoc on human life are increasingly being revealed to work in more subtle ways, that are just as deadly, but less rushed. Infection hypothesizers have long been the conspiracy theorists of medicine and their arguments dismissed by doctors and patients alike. Most of us will attribute a few days off work to "just a bug", while GPs suggest the same to those who troop into their surgeries demanding antibiotics. But this lack of trepidation could be quite misjudged. As increasing organ transplantation and diseases like HIV produce rising numbers of immunosuppressed people, there is a growing realisation of just how many viruses and bacteria we carry around with us. Plus new, highly sensitive investigation techniques are finding them in places no one ever considered they might be.

One example of this is the discovery of the respiratory infection Chlamydia pneumoniae - a bug so common that 70 per cent of us will have been infected with it at some time in our lives - in an inflammatory reaction in the artery walls of patients with heart disease. According to researchers from St George's Hospital, Tooting, immune system attempts to destroy this chronic infection appear not only to scar the artery wall but cause a cascade of the chemicals and proteins involved in narrowing of the arteries, setting the scene for a heart attack.

Curing C pneumoniae with antibiotics could change the progress of the disease, says British Heart Foundation research fellow Dr Sandeep Gupta. The first evidence of this came last month when Dr Gupta reported results from a pilot trial of antibiotic therapy in heart disease. It showed that patients who had already had a heart attack and were given a single dose of antibiotics had two thirds fewer admissions to hospital for angina, coronary surgery or further heart attacks in the following 18 months than patients given placebo.

Dr Gupta cautions that the trial was small, but adds: "50 per cent of heart disease cannot be explained by traditional risk factors like smoking and cholesterol - we simply don't know why one person develops severe heart disease and another doesn't. This could be an answer."

Another example are recent observations from Germany and Japan that patients with neuro-psychiatric diseases like schizophrenia are six times as likely as people at large to be infected with Borna virus, a pathogen known to affect nerve and brain cells in horses and cats. So too were 30 per cent of subjects with acute depression. Interestingly, viral activity appeared to wax during periods of dire depression and wane during reprieves.

While it's unlikely that eradicating Borna virus will remove mental disease, if you are struck with a sudden and inexplicable burst of severe depression, it may be comforting to be able to think it might be something you've caught, as opposed to an inherent flaw in your character.

We are a long way from proving viral causes of mental illness, says Simon Wessely, professor of epidemiological psychiatry at Kings College Hos- pital, London, but there are "entirely plausible" mechanisms by which infection could act. "When you get a viral infection, the body produces cyto-kines [chemical messengers of the immune system] like interleukin in its response and we know there are receptors in the brain that respond to cytokines and that the same receptors are implicated in psychiatric disease. But A+B+C doesn't always add up and the thought that any of this might lead to an intervention is very very theoretical."

As an illustration of the difficulties in investigating viral causes, Professor Wessely also notes that mood can alter immunity, so infection could in fact be a consequence of a disorder rather than a cause.

That these ideas are being given credence is largely due to Australian gastroenterologist Barry Marshall. Dr Marshall spent years trying to persuade his peers that a bacterium called Helicobacter pylori causes stomach ulcers. Finally in 1984 he provided proof by drinking a soup of the bug, giving himself a stomach ulcer, then swept away centuries of treatment by curing it with antibiotics. In one fell swoop, those insipid diets and milky ant-acids suffered by our parents were gone for many.

Much research is now underway into H pylori. Not only is there the link to stomach ulcers, but three out of four gastric cancers are thought to be attributable to it. Last month Marshall, now a respected professor in the US, reported that his research team had found an unexpectedly high rate of H pylori infection in a small group of babies who had died of sudden infant death syndrome (cot death). Since parents who lose one child in this way have a higher risk of losing another, the suggestion is that eradicating H pylori from the whole family might reduce that risk.

According to Professor Peter Beverley, scientific head of the Edward Jenner Institute for Vaccine Research, the medical profession's reluctance to accept Marshall's bug theory was not surprising.

"Everybody thought ulcers were a disease in which there was an over-secretion of acid due to stress, or certain foods. Particular personality types were implicated, there were long-established treatments and so a great myth built up. All that superstructure is hard to demolish."

But if the extent of viral research is anything to go by, it looks like doctors may have to get very good at demolition. The causation of skin cancer, premature birth, Parkinson's disease, rheumatoid arthritis, multiple sclerosis, Crohn's disease and childhood leukaemia are all coming under the scrutiny of viral proponents. But pinning the blame on a pathogen is tricky because of the complex ways in which they work.

Some viruses are straightforward: they take over the machinery of a cell and churn out viral proteins to such an extent that the cell can no longer make its own "housekeeping" proteins and dies. Smallpox was a lethal master at this, says Professor Beverley, not only because it could completely overpower the cell for its own benefit, but because it could also get into many different types of cells and cause widespread tissue damage.

Most viruses do not have such a "master key" and can only enter certain types of cells - Hepatitis infections target the liver, human papilloma virus type 16 (there are 77 of them) the cervix. This lessens the extent of tissue damage but does not necessarily lessen the impact. HIV can only get into one type of white blood cell - CD4. But this cell is found in two thirds of T lymphocytes - the cells which switch on an immune reaction to infection - and the damage cripples the immune system.

Other viruses are stealthy. Instead of riding the host cell to death, they become parasitic, replicating slowly and keeping the cell alive. They may just mark time until something triggers them into higher activity. Stress or low health can trigger the varicella zoster virus - which lurks in the nerves after chicken pox - into an outbreak of shingles.

Scarier are the viruses which seem to disappear from the immune system's view, but are, in fact, ensconced in cells, gradually causing damage that only becomes evident later. Hepatitis B, for example, can destroy the liver only causing symptoms when the damage is done. "Many pathogens have mechanisms specifically designed to bamboozle the immune system," says Professor Beverley. "It is a continuing race evolved over thousands of years. At every stage of a virus' lifecycle it could be killed by some immune mechanism and at every stage some virus will develop a mechanism that will interfere with that immune system attack," he says.

Dr Alan Storey, research scientist at the ICRF Skin Tumour Laboratory, is interested in viral strategy and subterfuge. Working with immunosuppressed kidney transplant patients, his team has discovered that not only do 40 to 50 per cent of these patients appear to be developing skin cancers about 10 years after their transplant, but all the cancers contain a previously undescribed, human papilloma virus (HPV). It is not known how widespread this virus is, but Dr Storey says it is possible this HPV could explain why some people get skin cancer and some do not.

"Viruses are very small and have limited genetic information. What each virus wants is to make more virus but it has to have the mechanism to do that, so it infects a cell that wouldn't normally divide and overrides its normal growth controls. Cells normally sense this and are programmed to die, but the virus, which has evolved over millions of years, has figured this out and produces a code for a factor that blocks this programmed death. So the cell stays alive when it shouldn't. If you then shine something like UV light, which we know causes changes to genetic material, on the cell that shouldn't be alive, it may be that the cells pick up changes that lead to cancer.

A similar strategy seems to occur in cervical cancer, says Dr Storey. A protein (E6) produced by HPV 16 interacts with a key down-regulator of cell growth. But life and viruses are not so simple; not everyone who is infected with a virus has the same outcome. Eight per cent of women are infected with human papilloma virus 16, but only 1 per cent of these will develop cancerous cells.

"What's not clear is what makes the difference, whether it is a defective immune system, or something else wrong with the cells, or outside influences like smoking or ultraviolet light," says Dr Storey.

Finally, says Professor Beverley, it may not be the invader that causes the damage, but the policeman - the immune system. Programmed to kill anything that is "non-self", the immune system may kill cells that happily co-exist with their virus, causing tissue damage. This may produce such a toxic response to a pathogen that it damages healthy cells. Or it may be tricked into self-injury by pathogens which have evolved to look like one of its own cells. And it may go on killing its own cells long after the virus has gone.

This last scenario offers a footing for suggestions of a viral cause for multiple sclerosis. Most British experts believe MS is an auto-immune disease and viral theories have been dismissed. The MS Society no longer funds virology research, instead it pours funds into genetic work. Critics maintain MS cannot have a viral cause because although viruses have been associated with it no one pathogen has been found in all MS patients.

But Dr John Fazakerley, senior lecturer in virology at the University of Edinburgh says the fact that the virus is not immediately obvious may be a classic example of viral deviousness. "If you have a virus in the central nervous system that causes the damaging release of a lot of protein and lipid constituents (or demyelinisation), this may break the tolerance of the immune system. So you get an auto-immune reaction. If the virus then goes away, all you are left with is an auto-immune reaction. People say MS is an auto-immune disease but they have no evidence to prove that it wasn't triggered by a virus."

Epidemiological data backs exposure to a virus in pre-puberty as a cause and there are models which show viruses can cause the demyelinisation in MS, says Dr Fazakerley. He adds that the success of the drug beta-interferon in reducing the relapse rate of MS is consistent with a viral cause: beta interferon was developed as an anti-viral therapy.

Viral theories are likely to continue causing controversy, not least because finding a viral involvement does not set the outcome. Whether you get skin cancer, or die of liver failure, or suffer depression may depend on a number of things, including genetic susceptibility, environmental pollutants or lifestyle - all of which can affect the way the immune system functions.

But if viruses are involved in triggering the diseases that cost us so much, thwarting them with vaccines, antibiotics and anti-viral treatments could un-cock the gun of factors less easily remedied.

INFECTIOUS IDEAS

SKIN CANCER

Scientists from the ICRF have found that up to 50 per cent of immunosuppressed kidney trans-plant patients develop skin tum-ours and all of them are infected with a new human papilloma virus (HPV). They believe the virus may predispose cells to being dam-aged by UV sun rays.

CERVICAL CANCER

Women with cervical cancer have been found to lack antibodies to a protein (E2) produced by HPV type 16 which is found in 95 per cent of cervical tumours. Their immune system thus does not recognise HPV-infected cells as foreign. Smoking, which increases the risk of cervical cancer is also thought to reduce immune system ability to eliminate HPV. US researchers have launched human trials of an HPV vaccine.

LEUKAEMIA

The Institute of Public Health in Cambridge reported last month that lymphocytic leukaemia - the commonest type of cancer in children - could be caused by a seasonal virus. After studying 4,000 cases, they found people were 40 per cent more likely to be diagnosed with the condition between May and October.

RHEUMATOID ARTHRITIS

Chlamydia pneumoniae has been isolated in the inflamed joints of people with rheumatoid arthritis. Antibiotic trials have improved pain and mobility.

CROHN'S DISEASE

Researchers at the Royal Free Hospital, London believe chronic infection with measles virus causes Crohn's Disease. They have found live virus in ulcerated parts of the colon and suggest it is period-ically triggered into action, causing an immune response that causes long-term damage to blood vessels in the bowel lining.

MENTAL ILLNESS

Research suggests that chemical agents produced when the im-mune system attacks a virus can affect the brain. These chemicals have been implicated in various psychiatric disorders. People with glandular fever, which is linked to pathogens such as Epstein Barr virus, have four times the risk of developing clinical depression.

PARKINSON'S DISEASE

Researchers in Leeds suggest Parkinson's could be due to a virus which enters the central ner-vous system through the nose (up to 90 per cent of Parkinson's patients lose their sense of smell). Studies in mice show viruses introduced through the nose spread rapidly in the brain.

PREMATURE BIRTH

Many pre-term births may be due to infection in the mother's genito-urinary tract. Abnormal levels of bacteria may increase produc-tion of prostaglandins which are the trigger for labour contrac-tions. A 10,000-patient study is underway to test whether giving antibiotics to women in premature labour can delay birth (this may only work if the infection is iden-tified before labour starts, as prostaglandin production is self- perpetuating once triggered).

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