The roles of soluble and membrane TNF and TNFa-converting enzyme (TACE) in meningococcal septicaemia.

Research archive

Meningococcal septicaemia is an extremely dangerous type of infectious disease, being an important cause of death and disability in children and young adults in the UK despite recent advances in intensive care. Breakthroughs in the understanding of its mechanisms are urgently required for improved treatment of the disease. A protein inflammatory messenger called "tumour necrosis factor (TNF)" is a strong candidate to play a crucial role in the progression of meningococcal septic shock. TNF has two active forms, one that floats in the blood (soluble TNF), and the other that sits on cell surfaces (membrane TNF). An enzyme called "TNF-alpha converting enzyme (TACE)" cuts off soluble TNF from membrane TNF on the cell surfaces. Recent studies in basic science suggest that membrane TNF is indeed much more active and important in inflammatory diseases than previously considered. Understanding how these two forms of TNF act, and how TACE controls the balance of these two forms over time, may be the key to understanding how to treat septic shock and multi-organ failure. This project will bring together scientists and clinicians with complementary areas of expertise to address this problem, by analysing clinical blood samples from the actual patients as well as using cell/blood culture experiments in the laboratory. The results will provide a re-evaluation of the role of TNF in the progression of meningococcal septicaemia, and may give us insights into new therapies for sepsis and multi-organ failure.

Results from this study have been published in a scientific journal as follows:

Alvarez-Iglesias M, Wayne G, O'Dea KP, Amour A, Takata M. 
Continuous real-time measurement of tumor necrosis factor-alpha converting enzyme activity on live cells.
Lab Invest 2005 Nov;85(11):1440-8.
http://www.nature.com/labinvest/journal/v85/n11/pdf/3700340a.pdf