Irish researchers have made a key discovery regarding the risk of contracting infectious diseases, writes Dick Ahlstrom
Irish researchers working in Dublin and Oxford may have discovered why some people succumb to disease and others don't. The findings may also explain why one patient might contract the hospital superbug MRSA while another escapes.
World attention has focused on the research led by Trinity College Dublin's professor of molecular immunology, Prof Luke O'Neill, and by the University of Oxford's professor of human genetics, Prof Adrian Hill. The two Dubliners published their results last Monday in the leading journal Nature Genetics.
Their deep analysis of aspects of our complex immune system has resulted in an important new understanding of disease susceptibility and why one person might be four times more likely than another to contract malaria.
"There is a frenzy around this now," says O'Neill. "Lots of labs are going to jump on this."
Their new study focuses on four important infections, malaria, tuberculosis, pneumonia and sepsis or blood poisoning. They found that the level of activity of a single immune system gene had a bearing on a person's susceptibility to these conditions.
The story actually begins six years ago with the discovery at Trinity College Dublin of an immune system gene that expresses a protein called Mal. "Mal is in effect an alarm system for the immune system," explains O'Neill.
When a person becomes infected, a set of sensors on white blood cells called toll-like receptors (TLRs) lock onto the intruder, O'Neill explains. Activation of the TLRs alerts Mal which acts as a switch to turn on the immune system and initiate a cascade of biochemical events that protect us. "It is a bit like a domino effect with TLRs first and then Mal," he says.
Hill built on that work, looking for variations in the Mal gene across a range of patients. In particular he wanted to know if variations in the Mal gene were a predictor of how well a person did after contracting malaria.
This study allowed him to discover that Mal actually comes in two types. More work in Dublin showed that one type allows the immune system to work properly, but the second form causes the immune system to become overactive.
If you have the overactive type, you are twice as likely to succumb to infection because your immune system goes into overdrive and disease results, O'Neill explains. In the case of malaria there is a four-fold additional risk for some patients.
The work has huge implications given a large fraction of the world's population lives in areas where malaria is endemic. "One third of the world population is at risk of malaria, but it is now moving north because of climate change," says O'Neill. Malaria also causes a staggering death toll, killing up to five million a year, mainly children.
Alarmingly the study showed that about 75 per cent of subjects had the overactive form of Mal, leaving them more at risk of the four diseases studied. And O'Neill suggests that Mal's actions may in time be associated with other diseases.
An early target for Trinity is the affect of Mal on susceptibility to MRSA infection. "Even more relevant are the auto-immune diseases, for example arthritis, MS and psoriasis," he adds.
This class of disease arises when the immune system loses the ability to recognise self and begins to attack healthy tissues. The overactivity of Mal may be proven in time to be associated with auto-immune damage.
Yet this also provides researchers with a target that can be exploited using drug therapy, O'Neill suggests. A drug that could moderate Mal activity up or down could block auto-immune activity.
It also offers new diagnostic targets, allowing a rapid assessment of risk for patients presenting with various infections.
"We are very excited by the prospect that our work might be useful in the effort to come up with new strategies to prevent death during these infections," says O'Neill.
"This work provides key evidence that modulating this pathway in humans could lead to better resistance against many important infectious diseases," Prof Hill adds.