Complement evasion of Pathogens
Immune and Complement evasion of Pathogens
Directly upon infection any microbe comes in contact with host complement system and in order to survive a pathogens must inactivate host complement response. Apparently most or even all pathogenic microbes utilize a common strategy for immune disguise, they interfere and inactivate the human complement system. These pathogens express specific surface proteins, that when in contact with human blood, bind specifically the host complement regulators Factor H. Also additional members of the Factor H protein family, i.e. the Factor H like protein 1 (FHL-1), the Factor H related protein 1 (CFHR1) and plasminogen are bound to the surface of the pathogen.
We are characterizing complement evasion strategies of several pathogens including Gram negative bacteria such as Pseudomonas aeruginosa, Borrelia burgdorferii, Hemophilus influenza and Staphylococcus aureus and Gram positive bacteria in form of Strepococcus pneumonia and S. pyogenes. Apparently this immune and complement disguise is a rather common escape mechanisms as most or even all pathogens bind host complement regulators to their surface.
A wide range of complement regulator binding proteins have been identified, cloned and characterized (Table 1).
Despite their common functions and binding characteristic these divers pathogenic proteins lack common sequence motive. In addition to the identification and characterization of these single microbial virulence factors a major goal of our work is to identify the common binding characteristics of these bacterial proteins. This will help to identify or even design inhibitors which interfere with this interaction. The identification of such inhibitors will allow to directly interfere with complement escape, allow an inactivation of the pathogen and might also allow a reprogramming of the host immune and complement attack.
Table I Pathogen Surface Proteins that bind host complement regulators
CRASP Complement regulator acquiring surface protein. Bilder Structure CRASP-1. Übersicht Pathogenen und bindeproteine#
Collaborations
Prof. Sven Hammerschmidt , Ernst-Moritz-Ardnt University Greifswald
Prof. Peter Kraizy, Prof. Volker Brade, Johann Wolfgang Goethe University Frankfurt
Prof. Reiner Wallich, University of Heidelberg
Prof. Michael Kirschfink University of Heidelberg
Prof. Susan Lea, Oxford University, United Kingdom
Prof. Brian Stevenson, University of Kentucky, Lexington, USA
Prof. Rolf Hilgenfeld University of Lübeck
Prof. Kristian Riesbeck, University of Malmö, Sweden
Dr. Jean van den Elsen, University of Bath, United Kingdom
Prof. Anna Erdei, Eötvös University, Hungary
Selected Literature
Haupt K, van den Elsen J, Burman J, Hälbich S, Reuter M, Richter H, Skerka C, Zipfel PF (2008) The Staphylococcus aureus protein Sbi acts as a complement inhibitor and forms a ternary complex with host complement Factor H and C3b. PLOS pathogens 4(12), e1000250
Poltermann S, Kunert A, von der Heide M, Eck R, Hartmann A, Zipfel PF (2008)
Gpm1p is a Factor H, FHL-1 and Plasminogen-Binding Surface Protein of Candida albicans. J Biol Chem 282, 37537 - 37544.
Cordes FS, Roversi P, Kraiczy P, Simon MM, Brade V, Jahraus O, Wallis R, Skerka C, Zipfel PF, Wallich R, Lea SM (2005). A novel fold for BbCRASP-1, a key complement factor H-binding outer surface protein of Borrelia burgdorferi. Nat Struct Mol Biol 12, 276-277.
Hammerschmidt S, Kunert A, Agarwal V, Skerka C, Zipfel PF (2007) The host immune regulator Factor H interacts via two contact sites with the PspC Protein of Streptococcus pneumoniae and adhesion to host epithelial cells1. J Immunol, in press
Review
Zipfel PF, Hallström T, Hammerschmidt S, Skerka C (2008) The Complement Fitness Factor H: Role in Human Diseases and for Immune Escape of Pathogens, like S. pneumoniae Vaccines 26S, 167 -174.
Zipfel PF, Skerka C, Hellwage J, Jokiranta TS, Meri S, Brade V, Kraiczy P, Noris M, Remuzzi G (2002). Factor H family proteins: On Complement, Microbes and Human Diseases. Biochem Soc Trans 30, 971-978.
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