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Kirsten Koymans

Tuesday 22 November 2016

SSLs in Staphylococcal Immune Evasion

Promotor: Prof.dr. J.A.G. van Strijp
Date: 22 November 2016
Time: 14.30 h

Immune evasion is defined as a strategy employed by pathogenic microorganisms to evade or antagonize a hostís immune response, thereby maximizing survival and transmission to a new host. To fully understand immune evasion, both the pathogen and the host, and especially the interaction between the two, must be examined. Staphylococcus aureus is a successful bacterial pathogen and a known manipulator of host immune responses, of which its immune modulating properties have been widely explored. Research towards these immune evasion molecules is of high importance as their secretion is closely related to bacterial virulence and pathogenesis. S. aureus is becoming increasingly resistant to antibiotics, first with the appearance of hospital-associated (HA)-MRSA strains, but now also with the rise of highly virulent and rapidly spreading antibiotic resistance strains in the community, the so called community-acquired (CA)-MRSA strains. With S. aureus becoming more difficult to treat with antibiotics, along with the lack of a functional vaccine, and combined with its ability to inhibit the host immune system, S. aureus has become a growing health risk of global importance.

Understanding the host-pathogen interaction and the role of immune evasion proteins therein can define new targets for the possible treatment of disease. Research on these evasion proteins is multi-factorial and can focus on the identification of novel immune evasion factors, unraveling their mechanism of action, revealing the molecular basis for the interaction, examining their role in pathogenesis in in vivo models, and finally exploring possible therapeutic applications. In this thesis we have examined these different aspects by investigating a family of 14 small secreted proteins, the staphylococcal superantigen-like proteins, also called the SSLs. This family is highly structurally related however has very diverse functions in immune evasion. We have identified the matrix metalloproteinases (MMPs) as novel host targets for SSL1 and SSL5. Consequently, we show that SSL1 and SSL5 limit neutrophil migration and chemotaxis. Furthermore, we have unraveled the molecular mechanism behind the inhibition of toll-like receptor 2 (TLR2) by SSL3, which revealed the amino acids involved in the protein-protein interaction and showed that SSL3 inhibits TLR2 in a dual mechanism; SSL3 interferes with both ligand binding to and subsequent TLR2 dimerization with TLR1 or TLR6. We continued research into the molecular basis of the SSL3-TLR2 interaction, with a focus on the TLR2 side, which uncovered the species specificity of SSL3 and revealed that SSL3 does not inhibit bovine TLR2. Additionally, we have taken initial steps to investigate the importance of SSL3 in vivo in a mouse model, which confirmed its potential as a virulence factor. Finally, we have constructed SSL3-based bicyclic peptides and characterized these for their ability to mimic the SSL3 interaction with TLR2. SSL3-based derivatives could have therapeutic potential in the treatment of inflammatory disorders in which there is aberrant TLR2 activation.

The SSLs are promising candidates for anti-staphylococcal approaches and understanding their exact roles and function can aid in the development of therapeutics. New intervention strategies for bacterial diseases will be of great value in this era of rising antibiotic resistance.