genomewide characterization of host-pathogen interactions by ...
genomewide characterization of host-pathogen interactions by ...
genomewide characterization of host-pathogen interactions by ...
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Maren Depke<br />
Introduction<br />
(Foster 2009). Others have already published polymorphisms associated with each phenotype,<br />
linking variants enhancing the immune response with reduced colonization risk (van den Akker et<br />
al. 2006, Emonts et al. 2007; Foster 2009). In the main site <strong>of</strong> colonization, the anterior nares,<br />
S. aureus uses its adhesins like ClfB, IsdA, SdrC, SdrD, and SasG to attach to the <strong>host</strong> tissue (Foster<br />
2009).<br />
Normally, such carriage does not cause any symptoms <strong>of</strong> illness. On the other hand, S. aureus<br />
can be responsible for a broad variety <strong>of</strong> diseases: S. aureus can cause mild to severe local<br />
infections <strong>of</strong> skin or pharyngeal mucosa, but also <strong>of</strong> inner organs (e. g. endocarditis,<br />
osteomyelitis) and systemic disease like sepsis. The <strong>pathogen</strong>icity <strong>of</strong> S. aureus is a world-wide<br />
problem. By the “SENTRY Surveillance Program”, S. aureus was described to be leading cause <strong>of</strong><br />
bloodstream, lower respiratory tract and skin/s<strong>of</strong>t tissues infections (Diekema et al. 2001).<br />
S. aureus produces several toxins that are responsible for toxin related diseases like toxic shock<br />
syndrome or scalded skin syndrome. Staphylococcal endotoxin can cause food poisoning in case<br />
<strong>of</strong> consumption <strong>of</strong> contaminated meals. S. aureus carriage is a risk factor for bacteremia. In the<br />
majority <strong>of</strong> bacteremia cases, the strain isolated from blood is identical with the nasal colonizing<br />
strain. But paradoxically, carriers have a lower mortality than non-carriers in case <strong>of</strong> bacteremia<br />
(van Eiff et al. 2001, Wertheim et al. 2004).<br />
S. aureus has been known to be an extracellular <strong>pathogen</strong> for long time (Finlay/Cossart 1997).<br />
But it has been also proven that S. aureus is not only an extracellular <strong>pathogen</strong> but that it can be<br />
internalized <strong>by</strong> non-pr<strong>of</strong>essional phagocytes like epithelial cells (Almeida et al. 1996, Hudson et<br />
al. 1995). Staphylococcal fibronectin-binding proteins (FnBP) are important mediators for the<br />
uptake <strong>of</strong> bacteria <strong>by</strong> the <strong>host</strong> cell, but it is not clear whether the uptake is an attribute <strong>of</strong><br />
bacterial <strong>pathogen</strong>icity or <strong>of</strong> <strong>host</strong> defense (Sinha et al. 2000). The process <strong>of</strong> internalization<br />
implies an active participation <strong>of</strong> <strong>host</strong> cells (Hudson et al. 1995).<br />
S. aureus Virulence Factors<br />
S. aureus has the genetic information to produce a wide range <strong>of</strong> virulence factors, which help<br />
to improve the bacterium’s survival e. g. in infection settings and to fight against the defense <strong>of</strong><br />
its <strong>host</strong>. Some are even required for its ability to establish an infection (Fig. I.4).<br />
S. aureus secretes several enzymes and exotoxins. A direct mode <strong>of</strong> impairing the <strong>host</strong>’s<br />
defense is to lyse <strong>host</strong> cells, which additionally renders nutrients accessible for the <strong>pathogen</strong>. As<br />
first virulence factors secreted enzymes (proteases, lipases, elastases, hyaluronidase and others)<br />
degrade <strong>host</strong> tissue molecules and therefore disintegrate tissue structure and defense barriers<br />
and facilitate first invasion and later spread <strong>of</strong> bacteria (Gordon RJ/Lowy 2008). All bacteria need<br />
iron for their survival. This essential nutrient is not freely available in the <strong>host</strong> but is sequestered<br />
<strong>by</strong> <strong>host</strong> proteins. S. aureus owns iron uptake promoting proteins, which are encoded <strong>by</strong> the ironresponsive<br />
surface determinant locus isd. This system includes binding proteins for different ironcontaining<br />
<strong>host</strong> proteins, transfer and transporter proteins, and proteins which release the iron<br />
into the bacterial metabolism (Maresso/Schneewind 2006).<br />
S. aureus carries different hemolysins which not only act on erythrocyte membranes, but also<br />
on that <strong>of</strong> other cell types. Alpha-hemolysin, which is also named alpha-toxin (encoded <strong>by</strong> the<br />
gene hla), is one <strong>of</strong> the prototypes <strong>of</strong> pore-forming toxins. This toxin has surprising characteristics<br />
<strong>of</strong> being water-soluble, but also able to form pores in hydrophobic membrane surrounding, and it<br />
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