A tale of two Mals: researchers identify key protein in immune response to malaria and TB

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 this week.

“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 amongst 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.