What happens when bacteria infect the human body? In an attempt to shed light on this process, Dr. Maya Saleh, researcher at the critical care division and the centre for the study of host resistance of the McGill University Health Centre (MUHC) Research Institute, describes previously unsuspected metabolic pathways involved in the inflammatory response. This discovery could lead to many potential benefits, particularly for the treatment of sepsis: infections that spread to the blood and deteriorates into a whole-body inflammatory state.
Her study is published in the Journal of Biological Chemistry. Because of the high quality of the research, this article was selected as a "Paper of the Week" for the December 14, 2007 issue of the journal, a distinction awarded to only one percent of its publications.
One of the body's first defenses against a bacterial infection is the activation of pathogen-eating cells called macrophages, which ingest the bacteria. This ingestion activates a protein inside the macrophage called Caspase-1. Dr. Saleh's study shows that Caspase-1 is the starting point for many metabolic reactions that, together, lead to the death of the macrophage and activate the rest of the immune system.
One of the roles of Caspase-1 in inflammation has been known for many years, namely that it activates immune system messengers called cytokines, which in turn activate the body's entire defense mechanism. But we now know this is not its sole function: "Our study demonstrates that Caspase-1 also causes the death of the macrophage by destroying some of the cell's basic structures and by blocking many metabolic pathways. The main pathway it blocks is glycolysis, or the production of energy through the breakdown of glucose," said Dr. Saleh, who is also an assistant professor in the faculty of medicine at the McGill University.
This finding opens new doors for fundamental research. Previous results suggested that Caspase-1 is also involved in fatal respiratory arrest that can occur during septic shock. Further research will be required to determine if that blockade of glycolysis by caspase-1 is a contributing factor.
This study could also have an important impact on the applied research of pharmaceutical companies. Currently, most anti-inflammatory drugs prescribed to fight sepsis target cytokines. "We know empirically that the effect of medications that target cytokines during sepsis is limited; our study demonstrates that Caspase-1 would be a more effective target", added Dr. Saleh. Since sepsis is no longer considered simply as a "cytokine storm", but as a more complex network of metabolic reactions, our vision of how to fight it needs to evolve accordingly.
The Research Institute of the McGill University Health Centre (RI MUHC) is a world-renowned biomedical and health-care hospital research centre. Located in Montreal, Quebec, the institute is the research arm of the MUHC, a university health center affiliated with the Faculty of Medicine at McGill University. The institute supports over 500 researchers, nearly 1000 graduate and post-doctoral students and operates more than 300 laboratories devoted to a broad spectrum of fundamental and clinical research. The Research Institute operates at the forefront of knowledge, innovation and technology and is inextricably linked to the clinical programs of the MUHC, ensuring that patients benefit directly from the latest research-based knowledge. For further details visit: www.muhc.ca/research.