A tale of two Mals: researchers identify key protein in immune response to malaria and TB
26 March 2007
An international team of researchers has identified a key protein involved in the immune system's response to malaria, tuberculosis (TB) and a number of other infectious diseases. The insights suggest possible new therapies to tackle these major global diseases.
Professor Luke O'Neill from Trinity College Dublin, Ireland, identified the protein in 2001. The protein, known as Mal, alerts the immune system to respond against invading bacteria. Now, Professor Adrian Hill from the Wellcome Trust Centre for Human Genetics, University of Oxford, UK, has shown that there are two variants of Mal in humans and that the combination of these variants determines how the immune system responds.
The results of the study, funded by the Wellcome Trust, Science Foundation Ireland, Irish Health Research Board and the Agency for Science, Technology and Research (Singapore) are published in the April edition of Nature Genetics.
"Mal is in effect an alarm system for the immune system," explains Professor O'Neill. "When the body is infected with the malaria parasite or other germs, a set of sensors called 'toll-like receptors' (TLRs) lock onto the intruder. TLRs relay the detection via Mal, which wakes up the immune system to mobilise and defend us."
However, working with patients in Kenya, the Gambia, Vietnam and the UK, Professor Hill and his team showed that there are two common variants of the protein, one which allows the immune system to work normally, the other resulting in too strong a stimulation. A person will carry a combination of two copies of the protein, one from the mother and one from the father.
"If you have the overactive type, you are twice as likely to succumb to infection because your immune system goes into overdrive, often leading to severe forms of the disease, in a manner akin to 'friendly fire'," explains Professor Hill, a Wellcome Trust Principal Research Fellow. "Similarly, if you have two copies of the less active form, the body does not fight the infection and you get the disease. The optimum situation is to have one copy of each variant, giving a balanced system, sufficient to mount a response, but not overly activating."
The researchers found that having the overactive Mal doubled the risk of disease, with a four times greater risk of severe malaria in some populations. Malaria and TB account for over five million deaths per year in the developing world, particularly among children.
"We hope that a drug that modulates the balance of Mal variants might prevent disease in those who are at greater risk," says Professor O'Neill. "Our next step is to work towards developing such drugs."
The research has been welcomed by Dr Mark Walport, Director of the Wellcome Trust, which funds research into diseases of the developing world such as malaria and TB, mainly through its Major Overseas Programmes.
"Malaria and TB present a major challenge to the health of people in the developing world," says Dr Walport. "Particularly given the recent rise in the number of cases of drug-resistant strains, it is essential that we understand how the immune system responds to infection if we are to develop novel treatments."
The researchers also believe that the findings may provide a valuable insight into how dysfunctional immune systems can lead to non-infectious diseases, specifically autoimmune diseases such as type 1 diabetes and rheumatoid arthritis.
Contact
Craig Brierley
Media Officer
Wellcome Trust
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c.brierley@wellcome.ac.uk
Notes for editors
1. Khor C et al. A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nature Genetics 2007; [Epub ahead of print].
2. The Wellcome Trust is the largest independent charity in the UK and the second largest medical research charity in the world. It funds innovative biomedical research, in the UK and internationally, spending around £500 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.
4. The Health Research Board (HRB) is the lead agency in Ireland supporting and funding health research. The HRB currently has commitments of €100 million throughout hospitals, universities and institutions on the island of Ireland. Its aim is to improve people's health, build health research capacity and make a significant contribution to Ireland's knowledge economy.
5. The Agency for Science, Technology and Research aims to foster world-class scientific research and talent for a vibrant knowledge-based Singapore. The Agency comprises the Biomedical Research Council, the Science and Engineering Research Council, the A*STAR Graduate Academy, the Corporate Planning and Administration Division and a commercialisation arm, Exploit Technologies Pte Ltd.
6. Trinity College Dublin is recognised internationally as Ireland's premier university and is the only Irish university to rank in the top 100 world universities (78th) and among the top 50 European universities (25th) by the Times Higher Education Supplement (THES) university league tables.
Founded in 1592, Trinity College is the oldest university in Ireland and one of the older universities of western Europe. Based on the general pattern of the ancient colleges at Oxford and Cambridge, Trinity has a main campus extending over 40 acres. Currently the College has a student population of over 15 000, over 65 000 alumni and 2500 members of staff. The student population represents every county in Ireland and over 90 countries; not only is it diverse in nationality, it also represents a wide range of social classes and age-groups.
Trinity has been a central force in the social, cultural and economic development of Irish society, partly because it was for many years the only institution of advanced learning and education, but also because of the participation of its staff in the arts, public debate, external committees and consultancy, among other things. The College is committed to excellence in both research and teaching across a wide range of disciplines to the enhancement of the learning experience of each of its students and to an inclusive College community with equality of access for all.
7. 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 tuberculosis, malaria and HIV, which are in clinical trials.