Irish scientists have identified a possible new target in the battle against death caused by meningitis. Trinity College researchers have identified a key protein in the immune system that sets off the alarm when bacteria invade.
An 11-person team in the Department of Biochemistry and Biotechnology Institute led by Prof Luke O'Neill and including Dr Kate Fitzgerald and Dr Eva Palsson-McDermott located the protein, which they named "Mal".
"We have discovered a human protein never before described which is a key part of the controlling mechanism inside immune cells that becomes activated when the cells sense bacterial invaders," Prof O'Neill explained.
Our immune systems are enormously complicated and involve a wide range of cell types. Messaging proteins signal back and forth, launching a powerful response to infection in a cascade of events.
The Trinity team found a key switch protein that forms part of the response to gram-negative bacteria, a group which includes the agent that causes meningitis.
The immune system recognises invading bacteria as foreign or "non- self" because they have a different chemistry. Often molecules in the bacteria's surface, known as "coat proteins", are first to be recognised as non-self.
One such bacterial protein is LPS, lipopolysaccharide, and it was discovered in 1998 that this stranger is first identified by a human protein called TLR-4. Researchers were unable to understand what happened after this until the Trinity team discovered the next step.
When TLR-4 encounters bacterial proteins it activates Mal, which in turn acts like an on switch that alerts killer white blood cells called macrophages. The macrophages carry the emergency call on further, bringing in other cells and waking up the full immune response. "Mal acts like a volume control knob, which is turned up by TLR-4, acting as a wake-up call for the immune system," Prof O'Neill said.
There is evidence that the TLR-4 and Mal are actually connected together, but the Mal does nothing until the TLR-4 switches it on. "It is like the system is charged and ready to go," Prof O'Neill said. When it locates LPS, the Mal comes into play, turning on the macrophage attack.
This could have implications for the treatment of meningitis infections, he said. Many people get infected but only some die from infection, and researchers don't know why. It could be that some people are "hypersensitive" to LPS, putting these patients at particular risk, he said.
The immune system can also be overwhelmed by an infection in which too much LPS to handle occurs in the blood. In this case, the immune response is over-stimulated in a condition called "sepsis syndrome" that kills 150,000 each year in the US alone, Prof O'Neill said.
This causes immune cells to target and destroy healthy tissue, in effect bringing down "friendly fire" that causes unnecessary damage.
It may be possible to dampen down Mal using drugs, either to reduce hypersensitivity or to block sepsis syndrome. Equally it may be possible to stimulate the immune response in the very young or elderly by boosting the action of Mal.