Patients and pathogens - the complexities of genetic susceptibility to disease revealed
28 March 2008
Researchers at the Wellcome Trust Major Overseas Programme based at the Hospital for Tropical Diseases and the Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam, have identified a particular host genetic variant that predisposes people to developing a lethal form of tuberculosis (TB) - tuberculous meningitis - if infected with a particular strain of TB known as the Beijing strain. The work underlines the importance of studying both sides of the complex host-pathogen interaction. The results are published today in the open access journal 'PLoS Pathogens'.
TB, which is caused by the bacterium Mycobacterium tuberculosis, kills over 2 million people each year. It is estimated that approximately one-third of the world population is infected with M. tuberculosis, though the majority will never show symptoms. Some will develop a latent infection, with symptoms only showing if they become sick or immunocompromised, for example through HIV infection. A small number will develop an active TB infection, usually in their lungs, occasionally progressing to 'disseminated TB' - a condition in which failure of the immune system to control the infection allows its spread to other parts of the body.
Some of the risk factors that determine whether individuals develop active TB following exposure are well known; these include HIV infection, malnutrition and smoking. The researchers from Vietnam have previously shown the role played in susceptibility to TB of a gene involved in the immune system, known as TLR2, which is important for recognising and initiating the defensive response when the bacterium enters the body.
People with a particular variant of TLR2, commonly found in the Vietnamese population, are particularly susceptible to developing the most severe form of TB, in which the infection spreads to the meninges, the membranes that envelope the brain and the spinal cord. One in three people who develops TB meningitis dies, even among those who receive hospital treatment.
Now, Dr Caws and colleagues have shown that the predisposition to developing TB meningitis appears to be strongest in people who carry the variant of TLR2 and who are infected with the specific Beijing strain of TB.
"We are seeing an increasing number of cases of the Beijing strain worldwide, a strain that is becoming more and more resistant to drugs," says Dr Caws.
The World Health Organization estimates that around 5 per cent of the TB cases in the world are now multidrug resistant. People who have multidrug resistant TB meningitis have almost 100 per cent mortality at the moment because there are no effective treatment regimens.
"Our findings are important because they show that we need to look at both the patient's susceptibility to the disease and the genetics of the pathogen that is infecting them at the same time," says Dr Caws. "Many studies have shown a genetic association with disease in one population but the finding has not been repeated in different populations. This might be not only because of ethnic differences in the population, but also because the pathogen populations are different.
"Understanding the mechanisms that influence our susceptibility to infectious diseases may allow us to develop more sophisticated and targeted treatments and vaccines. This is particularly important in this era of emerging 'untreatable' bacterial infections due to antibiotic resistance."
Image: TB meningitis; Wellcome Images
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Wellcome Trust
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Notes for editors
1. Caws, M. et al. The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis. PLoS Pathogens, 28 March 2008.
Download a copy of the paper [PDF 206KB]
2. The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending around £650 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing.
3. Oxford University's Medical Sciences Division is one of the largest biomedical research centres in Europe. It represents almost one-third of Oxford University's income and expenditure, and two-thirds of its external research income. Oxford's world-renowned global health programme is a leader in the fight against infectious diseases (such as malaria, HIV/AIDS, tuberculosis and avian flu) and other prevalent diseases (such as cancer, stroke, heart disease and diabetes). Key to its success is a long-standing network of dedicated Wellcome Trust-funded research units in Asia (Thailand, Laos and Vietnam) and Kenya, and work at the MRC Unit in The Gambia. Long-term studies of patients around the world are supported by basic science at Oxford and have led to many exciting developments, including potential vaccines for TB, malaria and HIV, which are in clinical trials.