A cyanobacterial LPS-antagonist inhibits cytokine production induced by Neisseria meningitidis in a human whole blood model of septicaemia

Neisseria Research Group, Molecular Microbiology, Division of Infection, Inflammation and Repair, University of Southampton Medical School, Southampton General Hospital, Southampton, SO16 6YD, UK; Institute for Research in Biomedicine, Via Vincenzo Vela 6, CH-6500 Bellinzona, Switzerland; Department of Biotechnology and Molecular Sciences, University of Insubria, Via Dunant 3, 21100 Varese, Italy

^* To whom correspondence should be addressed. Email: mc4{at}soton.ac.uk.

	Abstract

Septicaemia caused by Neisseria meningitidis is characterised by increasing levels of lipopolysaccharide (Nm-LPS) and cytokine production in the blood. We have used an in vitro human whole blood model of meningococcal septicaemia to investigate the potential of CyP, a selective Toll-like receptor (TLR)4-MD-2 receptor antagonist derived from the cyanobacterium Oscillatoria planktothrix FP1, for reducing LPS-mediated cytokine production. CyP (1µg/ml) inhibited the secretion of pro-inflammatory cytokines TNF-, IL-1 and IL-6 (by >90%) and chemokines IL-8 and MCP-1 (by 50%), induced by treatment of blood with pure Nm-LPS, isolated outer membranes and after infection with live meningococci of different serogroups. In vitro studies with human dendritic cells and TLR4-transfected Jurkat cells demonstrated that CyP competitively inhibited Nm-LPS interactions with TLR4 and subsequent NF-kB activation. These data demonstrate that CyP is a potent antagonist of meningococcal LPS and could be considered as a new adjunctive therapy for treating septicaemia.