genomewide characterization of host-pathogen interactions by ...

Maren Depke
Introduction
via fibronectin as linker to the host’s α 5 β 1 integrin molecules, which initiates the internalization of
the bacterial cell into the host cell (Hauck/Ohlsen 2006, Peacock et al. 1999, Schwarz-Linek et al.
2004, Sinha et al. 1999). S. aureus strains harboring the SCCmec type I also possess the pls gene
located therein. This gene encodes the plasmin sensitive surface protein Pls, which reduces,
contrarily to the MSCRAMMs, the adherence of S. aureus to host structures and its cellular
invasiveness. Very recently, it has been published that Pls causes this effect by steric hindrance
and blocking adhesin and host factor interaction (Hussain et al. 2009).
An example for a SERAM is the staphylococcal coagulase. The extracellular enzyme is able to
bind prothrombin, which is the enzyme precursor for the coagulation activation by conversion of
fibrinogen to fibrin. Thrombin activation by staphylococcal coagulase does not occur by
proteolysis but by forming an active complex of both molecules in a stoichiometric ratio of 1:1,
which is called staphylothrombin (Kawabata et al. 1985, Kawabata/Iwanaga 1994). Moreover,
coagulase molecules can be attached to the staphylococcal cell surface where it can bind directly
to fibrinogen also without presence of prothrombin (Bodén/Flock 1989).
S. aureus is aiming to evade the immune response, and thus, it has gained several immunemodulating
properties. After the very first steps of infection, the immune response has to be
initiated by chemoattractants which recruit defense cells like neutrophils or macrophages to the
site of infection. The bacterial protein chemotaxis inhibitory protein of staphylococci (CHIPS)
blocks with two different domains the host cell receptors for the host chemoattractant C5a from
the activated complement system and for bacterial formylated peptides, which are secreted by
the pathogen (de Haas et al. 2004, Murdoch/Finn 2000). Tightly associated with interference in
the chemotaxic process is the already mentioned bacterial extracellular adherence protein (Eap).
This protein blocks the endothelial cell receptor ICAM-1. During the normal immune response,
ICAM-1 has receptor function for the leucocyte’s membrane protein LFA-1 and thus allows
leucocyte adhesion at sites of infection. Adhesion is followed by entry of leucocytes into the
tissue in the two steps of diapedesis and extravasation. In cases when ICAM-1 is already occupied
by Eap, not only leucocyte adhesion but also the following steps are impeded (Chavakis et al.
2002).
S. aureus protects and hides its treacherous typical bacterial cell surface structures by a
capsule of polysaccharides. The capsule inhibits binding of opsonic host factors and thus reduces
the phagocytosis of the bacterial cell. An increased production of capsular polysaccharides
increases the virulence of S. aureus (Nilsson et al. 1997, Thakker et al. 1998).
Besides their already mentioned function of MSCRAMMs, clumping factor and protein A also
have anti-phagocytic functions. Clumping factor binds the host molecule fibrinogen which then
serves as camouflage net on the bacterial cell surface. Protein A binds immunoglobulin G (IgG) in
a way beneficial for the bacterium, but not for the host. While the normal antibody-binding with
the antigen-specific F ab part will opsonize the bacterium for recognition by immune defense
mechanisms, the binding of antibodies by protein A occurs via the F c part and thus prevents the
mediation of opsonization signals (Uhlén et al. 1984).
Another protein which interferes with opsonization for phagocytosis is Staphylococcus
complement inhibitor (SCIN). SCIN binds to the C3-convertase complexes from the three
complement activation pathways and inhibits C3b deposition on the pathogen’s surface.
Therefore, the following steps of complement opsonization are impaired. Interestingly, the
complement-inhibitory function of SCIN is specific for the human host (Rooijakkers et al. 2005b).
In a similar function, complement factor C3 is the target of the highly conserved, staphylococcal
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