The Staphylococcus aureus secretome - TI Pharma

Introduction and scope of this thesis
adherence to host tissues and evasion of the host defense systems. In addition, the virulence
factors that are released into the host milieu may damage host cells, degrade
biomacromolecules of the host, or cause strong inflammatory responses, thereby contributing
to the symptoms of disease caused by a particular bacterium (For reviews see Tjalsma et al.,
2000; Tjalsma et al., 2004; Sibbald et al., 2006; van Dijl et al., 2007; Sibbald and van Dijl,
2009).
Staphylococcus aureus is a Gram-positive bacterium that is part of the human microbiota,
residing mostly in the mucosal environment in the nose. In fact, ~20% of the human
population is a persistant carrier of S. aureus, while 60% is an intermittent carrier.
Unfortunately, S. aureus can transform from an apparently harmles commensal into a
dangerous pathogen. Once the organism crosses the defense systems of the human host, it can
spread to almost every organ and tissue, causing a wide range of diseases. These can vary
from superficial lesions, styes and furunculosis, to more serious infections such as
pneumonia, urinary tract infections, endocarditis, and in rare cases even meningitis (Cheng et
al., 2009; Dubrac et al., 2008; Fedtke et al., 2004; García-Lara et al., 2005; Novick, 2003;
van Belkum A., 2006; Wardenburg et al., 2007). Moreover, S. aureus has an amazing ability
to develop resistance against several antibiotics, which became evident already shortly after
the introduction of penicillin for clinical applications. In the mean time, S. aureus strains
exhibiting resistance to most antibiotics are known, the methicillin resistant S. aureus
(MRSA) being most notorious (annual Report EARSS 2007; http://www.rivm.nl/earss/
results/Monitoring_reports). Up till now, most MRSA infections were nosocomial (i.e.
hospital-acquired). However, recent reports indicate an increase in dangerous communityacquired
MRSA infections (Centers for Disease Control and Prevention, 2003; Grundmann et
al., 2002; Vandenesch et al., 2003). Vancomycin has been for long time a last resort antibiotic
against MRSA, but in 1996 the first vancomycin intermediate resistant strain (VISA) was
reported (Hiramatsu et al., 1997). Since then, several other cases of other VISA strains and
even strains with complete resistance (VRSA) against vancomycin have been isolated (Cui et
al., 2003; Weigel et al., 2003). Because of the anticipated rise of multiple antibiotic resistant
S. aureus strains, innovative strategies for prevention and intervention of S. aureus infections
are urgently needed. Recent studies are therefore focusing on the development of novel
antibiotics, anti-staphylococcal vaccines and therapeutic protective antibodies (Arrecubieta et
al., 2008; Glowalla et al., 2009; Middleton, 2008; Nanra et al., 2009; Otto, 2008; Schaffer
and Lee, 2009; Zweers et al., 2009).
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