RESEARCH

Immunity & Infection

Mechanisms of acute and chronic CNS infection
Josephin Held, Michael Meisen, Lydia Richter, Frank Heppner, Werner Stenzel

This project aims to examine acute and chronic cellular and molecular processes for pathogen invasion of the CNS. The role of i) brain derived cells ii) the cells of the (peripheral) immune system and iii) pro and anti-inflammatory mediators in the various phases of infection and healing, as well as their influence on the termination of the inflammatory infection will be looked at. The focus of the experimental research will be studies of brain abscess, acute bacterial infection of the brain tissue to cerebral cryptococcosis, which as an opportunistic fungal infection typically leads to a chronic meningoencephalitis.

Collaborative partner is Prof. Gottfried Alber, Institute of Immunology, Leipzig. The projects are funded by the Else Kröner Stiftung (WS-P11/06//A82/05; P06/09//A114/08).

The role of glyco-lipids in Lyme's disease
Nicolas Schröder, Frank Heppner

Unlike lipoproteins, the biological significance of membrane glycolipides for the immune reaction of the host during an infection of Borrelia burgdorferi (BB) is on the whole unclear. We were able to isolate, chemically characterise and synthetically reproduce a previously unknown immunogenic glycolipid, the acyl-cholesteryl Galaktosid (ACGal). The focus of the current studies is the development of an ACGal based vaccination including testing on a mouse model. The longer term aim is to examine the role of ACGal in the pathogenesis of Lyme disease using ACGal-deficient mutants in mouse models.

Collaborative partners include Prof. R. R. Schumann, Institute for Microbiology at the Charité (joint project leader with DR. N. W. J. Schröder) and Prof. U. Zähringer, Research Center Borstel.

Selected publications:

Stenzel W, Soltek S, Sanchez-Ruiz M, Akira S, Miletic H, Schlüter D, and Deckert M. Both TLR2 and TLR4 are required for the effective immune response in Staphylococcus aureus-induced experimental murine brain abscess. American Journal of Pathology; 127(1):132-145 (2008).

Müller U, Stenzel W, Köhler G, Hansen H, Schütze N, Straubinger R, Blessing M, McKenzie A, Brombacher F, and Alber G. IL-13 induces disease-promoting development of alternatively activated macrophages and increased type 2 cytokine production during pulmonary infection of mice with Cryptococcus neoformans. J Immunol 179: 5367-5377 (2007).

Kleinschek MA, Mueller U, Brodie SJ, Stenzel W, Köhler G, Blumenschein W, Straubinger RK, McClanahan T, Kastelein RA, and Alber G. IL-23 enhances the inflammatory cell response in Cryptococcus neoformans infection and induces a cytokine pattern distinct from IL-12. J Immunol 176: 1098-1106 (2006).

Stenzel W, Dahm J, Sanchez-Ruiz M, Miletic H, Utermöhlen O, Courts C, Schwindt H, Hermann M, Schlüter D, and Deckert M. The inflammatory response to murine Staphylococcus aureus-induced brain abscess in Interleukin-10 deficient mice. J Neuropathol Exp Neurol 64: 1064-1057 (2005).

Stenzel W, Soltek S, Miletic H, Hermann MM, Körner H, Sedgwick JD, Schlüter D, and Deckert M. An essential role for tumor necrosis factor in the formation of experimental murine Staphylococcus aureus-induced brain abscess and clearance. J Neuropathol Exp Neurol 64(1): 27-36 (2005).

Schröder NWJ, Diterich I, Zinke A, Eckert J, Draing C, v. Baehr V, Hassler D, Priem S, Hahn K, Michelsen KS, Hartung T, Burmester GR, Göbel UB, Hermann C, and Schumann RR. Heterozygous Arg753Gln Polymorphism of Human TLR-2 Impairs Immune Activation by Borrelia burgdorferi and Protects from Late Stage Lyme Disease. J Immunol 175: 2534-2540 (2005).

Schröder NWJ and Schumann RR. Single Nucleotide Polymorphisms of Toll-like Receptors and Susceptibilty to Infectious Disease. Lancet Infect Dis 5: 156-164 (2005).

Stenzel W, Soltek S, Schlüter D, Deckert M. The intermediate filament GFAP is important for the control of experimental murine Staphylococcus aureus-induced brain abscess and Toxoplasma encephalitis. J Neuropathol Exp Neurol 63: 631-640 (2004).

Roers A, Siewe L, Strittmatter E, Deckert M, Schlüter D, Stenzel W, Gruber AD, Krieg T, Rajewsky K, and Müller W. T cell-specific inactivation of the interleukin-10 gene in mice results in enhanced T cell responses but normal innate responses to lipopolysaccharide or skin irritation. J Exp Med 200: 1289-97 (2004).

Schröder NWJ, Schombel U, Heine H, Göbel UB, Zähringer U, und Schumann RR. Acylated cholesteryl galactoside as a novel immunogenic motif in Borrelia burgdorferi sensu stricto. J Biol Chem 278:33645-53 (2003).

Schröder NWJ, Opitz B, Lamping N, Michelsen KS, Zähringer U, Göbel UB, und Schumann RR. Involvement of Lipopolysaccharide Binding Protein, CD14, and Toll-like Receptors in the Initiation of Innate Immune Responses by Treponema Glycolipids. J Immunol 165: 2683-2693 (2000).