Clinical treatment of meningococcal disease involves antibiotic therapy, the administration of anti-inflammatory steroids (e.g. dexamethasone), and intensive care management. In contrast to therapies directed towards managing inflammation in the patient, the recent clinical trials of the anti-LPS therapies, HA-1A and rBPI, represents the only investigations of anti-inflammatories directed against a specific meningococcal component. However, recent in vitro studies have questioned whether LPS within the meningococcus is the only stimulus of inflammation, and therefore raised doubts concerning the sole use of anti-LPS therapies in attempting to reduce the inflammatory response. In this project, we propose to identify modulins - inflammatory molecules -of Neisseria meningitides, other than LPS, as potential targets for therapeutic intervention during septicaemia and meningitis. We will use panels of defined mutants and variants of N. meningitides, outer membrane preparations, and individual meningococcal components purified in the absence of LPS and other contaminating proteins. These will be used to challenge, in vitro, cells corresponding to several human cell types involved in septicaemia and meningitis. Initially, experiments will involve the whole human blood model and then focus on purified inflammatory cells, as well as blood vessel endothelial cells and meningeal cells. The host cell inflammatory (and innate/adaptive immune) response(s) to meningococcal modulins will be examined using a variety of molecular, biological and biochemical assays. It is expected that any potential trial therapies will be tested in vitro against candidate modulins identified during the course of the project.
Results from this study have been published in scientific journals as follows:
Al-Bader T, Christodoulides M, Heckels JE, Holloway J, Semper AE, Friedmann PS.
Activation of human dendritic cells is modulated by components of the outer membranes of Neisseria meningitidis.
Infect Immun 2003 Oct;71(10):5590-7.
Al-Bader T, Jolley KA, Humphries HE, Holloway J, Heckels JE, Semper AE, Friedmann PS, Christodoulides M.
Activation of human dendritic cells by the PorA protein of Neisseria meningitidis.
Cell Microbiol 2004 Jul;6(7):651-62.
Humphries HE, Triantafilou M, Makepeace BL, Heckels JE, Triantafilou K, Christodoulides M.
Activation of human meningeal cells is modulated by lipopolysaccharide (LPS) and non-LPS components of Neisseria meningitidis and is independent of Toll-like receptor (TLR)4 and TLR2 signalling.
Cell Microbiol 2005 Mar;7(3):415-30.
Williams JN, Skipp PJ, Humphries HE, Christodoulides M, O'Connor CD, Heckels JE.
Proteomic Analysis of Outer Membranes and Vesicles from Wild-Type Serogroup B Neisseria meningitidis and a Lipopolysaccharide-Deficient Mutant
Infect Immun 2007 Mar;75(3):1364-72. Epub 2006 Dec 11.
Fowler MI, Yin KY, Humphries HE, Heckels JE, Christodoulides M.
Comparison of the inflammatory responses of human meningeal cells following challenge with Neisseria lactamica and with Neisseria meningitidis.
Infect Immun 2006 Nov;74(11):6467-78. Epub 2006 Sep 5.