Septic shock or sepsis syndrome occurs when the body's immune system over-reacts to bacterial infection, says Trinity College Dublin's Prof Luke O'Neill, professor of molecular immunology.
Septic shock is a major killer, accounting for 300,000 deaths in the US and 200,000 in Europe annually. The hope is that the discovery of a key protein switch might provide a target for new drug therapies to help reduce deaths, says O'Neill.
Details of the research collaboration by Trinity and the University of Massachusetts were published in separate papers in the prestigious Proceedings of the National Academy of Sciences in the US. The most recent of the two papers appeared late last month.
"We have identified the precise switch in the immune system which gets flipped on in sepsis," says O'Neill. "There is a huge effort to save people with sepsis and this gives the drug development companies a target to try to block."
The work arose out of an effort to learn exactly how white blood cells, key cells in the immune system that patrol the body in search of infections, actually sense the presence of bacteria.
They found that it all comes down to a single molecular switch, a protein called Tram. "What we found is how that protein actually changes during a bacterial attack. Now we know it goes through a process known as phosphorylation."
The Trinity team found that Tram must be modified by two processes before it issues its alert to the immune system and calls in a full immune defence against infection.
First a fatty substance called myristic acid must attach to the Tram protein. Then it is changed by an enzyme called protein kinase C epsilon. This causes the chemical change involved in phosphorylation and is the activating mechanism stimulated directly by the presence of bacteria.
"Kinase C epsilon is directly responsible for the phosphorylation, making it a very interesting drug target. It is an enzyme so it would be possible to design a drug to block it - this would then block this process and prevent Tram from working," he says. "Given that over-activation of Tram is a key part of the process that leads to sepsis, such a drug would be predicted to be useful as a treatment for sepsis."
O'Neill likens the action of Tram in the body to a bugle call to arms. The warning signal issued by Tram is essential if the body is to protect itself from infection.
Sometimes, however, the bugle is too loud and raises too powerful a reaction from the immune system and over stimulation of the white blood cells, which leads to septic shock.
This over stimulation unleashes the inflammatory response in the body leading to disease, in a manner akin to friendly fire, he says. "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 infection."
The goal is to reduce but not fully block the bugle call issued by Tram. "What we would try to do is limit it," O'Neill explains. "Now it gives us a chance to try to get in and interfere with that signal."
The work is a collaboration between the Trinity team led by Dr Anne McGettrick working in O'Neill's laboratory in Trinity, and a team led by Dr Kate Fitzgerald who is working in the University of Massachusetts. Fitzgerald is originally from Waterford and is a former member of the O'Neill laboratory in Dublin. The work was funded by the Health Research Board and Science Foundation Ireland.
