Introduction
The key objective within the group is understanding bacterial pathogenesis in order to optimize treatment strategies for infectious diseases. Within the complex array of events that underlie the pathophysiology of infections our focus is on the main element that determines clearance of invading bacteria, the innate immune system. Innate immunity, with neutrophils and the complement system as main players, is a highly effective and redundant system to remove and kill invading bacteria. Molecules involved in microbe-immune system interactions are the ideal focal spot for novel and highly specific intervention strategies. In order to survive in the human host, bacteria have developed strategies to escape from innate immunity. In fact, those bacteria that can withstand this attack can be pathogens. Evasion is achieved by either a capsule or an intracellular lifestyle. Both strategies, however, have important limitations. In order to adhere to surfaces, bacteria have to release the capsule at a certain time point during infection. Bacteria that hide within cells are still confronted with intracellular elements of innate immunity as the NOD proteins and several Toll like receptors.
We have demonstrated that there is a third evasion strategy; bacteria secrete small proteins that specifically and with high affinity block crucial effectors and recognition molecules in innate immunity. In the past years, we identified a large array of innate immune evasion molecules in staphylococci. Over 20 truly novel functions to unknown ORF’s, all related to innate immune evasion. In the process we have gained insight in both bacterial pathogenesis and our immune system. Next to our approaches in genomics, proteomics and phage display, our functional
assays are the key element in this process, together with a strong protein expression platform. Recently, we were able to determine the importance of these molecules in bacterial pathogenesis in vivo (Efb/Ecb). For the near future we will aim at understanding the importance of all these genes, both on a molecular mechanistic level as well as in vivo and especially in the context of their redundancy. Also the search for similar molecules and strategies in other pathogenic bacteria as in Pseudomonas, Group A and B Streptococci and Pneumococci, Mycobacteria and
Meningococci, continues. Also we will start to explore similar strategies in commensal bacteria as lactocobaccilli and bifidobacteria and even in Fungi (especially aspergillus). Further we aim to proof that in smart vaccine development the elimination of these evasion molecules could hold the key to natural enhancement of our own immune system during infections.
In 2010 Dr. S.H.M. (Suzan) Rooijakkers was awarded a NWO VIDI grant ("Bacteriële munitie tegen het menselijke afweersysteem").
Techniques
Moleculair biology (protein expression, receptor expression, gene regulation, knockouts, mutagenesis, in both bacteria and cell lines), cell biology (isolation, culture, functional assays), protein biology (purification, SDS-PAGE, Western, ELISA, Biacore, Seldi-Tof), general microbiology, flow cytometry.
Contact
Dr. Kok van Kessel
University Medical Center Utrecht
HP G04.614
Heidelberglaan 100, 3584 CX Utrecht, The Netherlands,
Tel.: 088 - 75 599 62
k.kessel@umcutrecht.nl
Review publications
Serruto D, Rappuoli R, Scarselli M, Gros P, van Strijp JA. (20110). Molecular mechanisms of complement evasion: learning from staphylococci and meningococci. Nat Rev Microbiol. 2010 Jun;8(6):393-9.
Laarman A, Milder F, van Strijp J, Rooijakkers S. (2010). Complement inhibition by gram-positive pathogens: molecular mechanisms and therapeutic implications. J Mol Med (Berl). 2010 Feb;88(2):115-20.
Jongerius I, Ram S, Rooijakkers S. Bacterial complement escape. (2009). Adv Exp Med Biol. 2009;666:32-48.
Bestebroer J, de Haas CJ, van Strijp JA. (2009). How microorganisms avoid phagocyte attraction. FEMS Microbiol Rev. 2009 Dec 11.
Veldkamp KE, van Strijp JA. (2009). Innate immune evasion by staphylococci. Adv Exp Med Biol. 2009;666:19-31.
Rooijakkers SH, van Strijp JA. (2007). Bacterial complement evasion. Mol Immunol. 2007 Jan;44(1-3):23-32.