Abstract
The innate immune system plays a critical role in our first line of defense against bacterial infections. Phagocytes are immune cells that migrate from the blood to the site of infection to engulf bacteria and kill them intracellularly. Phagocyte responses largely depend on the activation of the complement system, a family of thirty plasma proteins that labels bacteria with opsonins (C3b) to support phagocyte recognition and generate chemo-attractants (C5a) to attract cells to the site of infection. The last decade it has become clear that bacterial pathogens have evolved specific mechanisms to withstand the constant attack of the immune system. My group discovered that the prominent pathogen Staphylococcus aureus produces a number of secreted proteins that block critical steps in the complement cascade. We discovered a highly unique bacterial complement inhibitor (SCIN) that blocks a key enzyme of the complement cascade: the C3 convertase. In close collaboration with crystallographers, we managed to resolve the structure of SCIN in complex with the C3 convertase. This was key to the complement field, since the C3 convertase is highly instable (half-life of 90 seconds) and its structure could only be revealed thanks to the stabilizing properties of SCIN. Since complement is also involved in triggering autoimmune diseases, these insights have paved the way to development of new anti-inflammatory drugs.
Further, my group has discovered other immune inhibitors in bacteria and we have shown that these inhibitors are essential to bacterial virulence in vivo. The immune evasion strategies deployed by pathogenic bacteria hold information crucial for future drug development. Bacterial immune escape will be turned into our own advantage, creating new opportunities for treatment of inflammatory and infectious diseases.
Biography
In 2001, I received my Master’s degree in Biomedical Sciences at the Radboud University of Nijmegen, The Netherlands. From 2001-2005, I was a PhD student at the Department of Medical Microbiology, University Medical Center (UMC) Utrecht, The Netherlands. This work resulted in my thesis entitled: “Innate Immune evasion by Staphylococci”. From 2005-2008 I worked as a post-doc in this laboratory on a personal VENI-grant entitled “Evading complement” for Innovational Research Incentives from NWO. From 2008-2009, I worked as a post-doctoral fellow in the laboratory of Professor Victor Nizet at the Department of Pharmacology & Drug Discovery, University of San Diego, California, supported by an European Molecular Biology Organization (EMBO) long term fellowship. In November 2009 I returned to the UMC Utrecht to start my own research group working on immune escape mechanisms of bacterial pathogens.