Pathways that determine the endotoxic and adjuvant properties of meningococcal lipopolysaccharide
Dr Jeanette Leusen, Dr Liana Steeghs
- Start Date:
01 January 2002
University Medical Centre, Utrecht, The Netherlands
Outer membrane vesicle (OMV) vaccines are currently being developed against Neisseria meningitidis serogroup B strains. Lipopolysaccharide (LPS), naturally present in OMVs, could have a potential role as adjuvant and immunogen in such a vaccine. However, the high endotoxin activity of LPS, primarily resulting from the activation of monocytes and macrophages to produce inflammatory mediators such as TNF-a, has severely limited its use in vaccines so far.
The endotoxic activity of LPS is primarily determined by the lipid A moiety, which anchors the LPS molecule in the outer membrane. We have shown in our previous work that modification of the acylation pattern of N. meningitidis lipid A by genetic modification of the lipid A biosynthesis pathway can result in reduced endotoxic activity without loss of adjuvanticity. Apparently, the ability of N. meningitidis LPS to induce proinflammatory activity is not necessarily linked to its adjuvant activity, suggesting that multiple signalling pathways determine its biological activity.
The key objective of the present research proposal is to identify the presumed "adjuvant pathway" for meningococcal LPS. By using our unique set of lipid A mutants we plan to unravel the receptor recognition and signalling events of meningococcal LPS. The resulting detailed molecular understanding of LPS adjuvant activity will undoubtedly lead to novel applications in vaccination and immune modulation. In particular, meningococcal LPS with altered lipid A can be included in novel OMV vaccines in order to make them less toxic while retaining its immune-stimulating properties.
Results from this study have been published in a scientific journal as follows:
Steeghs L, van Vliet SJ, Uronen-Hansson H, van Mourik A, Engering A, Sanchez-Hernandez M, Klein NJ, Callard R, van Putten JP, van der Ley P, van Kooyk Y, van de Winkel JG.
Neisseria meningitidis expressing lgtB lipopolysaccharide targets DC-SIGN and modulates dendritic cell function.
Cell Microbiol 2006 Feb;8(2):316-25.