genomewide characterization of host-pathogen interactions by ...

Maren Depke
Introduction
cathelicidin LL-37 at a special site, which is not recognized by the V8 protease. After aureolysin
cleavage, LL-37 loses its antistaphylococcal activity (Sieprawska-Lupa et al. 2004).
S. aureus cell wall is subjected to modifications of the teichoic acid structure. Dlt proteins
(encoded by the dltABCD operon) lead to D-alanine incorporation. The alanine residues are
further esterified. Without these alanine esters the bacterial surface would carry a strongly
negative net charge, which would attract positively charged cationic antimicrobial molecules.
Therefore, Dlt decreases the vulnerability of the bacterial cell wall via reduction of molecule
charge (Peschel et al. 1999). On the other hand, a stronger negative charge would reduce
S. aureus’ capacity to adhere to polystyrene or glass. Dlt mutants are thus impaired in their
capability of biofilm formation (Gross et al. 2001). Also the MprF protein neutralizes charges of
the cell wall, in this case by linking lysine to phosphatidylglycerol (Peschel et al. 2001).
Biofilm formation, which is often associated with intra-vascular medical devices like catheters,
is another option for S. aureus to protect the bacterial cells from the immune system and
antimicrobials. The material of the medical devices will be covered with host (serum) molecules
like fibrinogen or fibronectin soon after implantation. Therefore, it serves as an ideal attachment
site for the various adhesins of staphylococci (Lowy 1998). In biofilms, S. aureus aggregates in a
multi-cellular structure which already hinders contact between immune cells and substances with
bacterial cells by physical means. Bacterial cells are surrounded by a polysaccharide matrix,
composed of poly-N-acetylglucosamine (PNAG). The ica operon, which is present in almost all
S. aureus strains although not all of them form biofilms in in vitro assays, encodes the proteins
necessary for PNAG biosynthesis. Its expression is regulated by IcaR and TcaR and the
environmental conditions, and SarA and its homologues influence the regulation. Quorum
sensing mechanisms are important in coordination of the individual bacterial cell’s gene
expression, which enables the establishment of the biofilm (Fitzpatrick et al. 2005, Grinholc et al.
2007).
For bacteria, the most effective way of evading the immune response is to hide inside the host
cell. Intracellularly, S. aureus can mask its presence by changing its phenotype into the so-called
small colony variant (SCV). These variants are characterized by physiological adaptation like slow
growth and reduced toxin production, which is caused by alterations of the electron transport
chain. They contribute to persistence and recurrence of staphylococcal infections
(McNamara/Proctor 2000, von Eiff et al. 2006)
Not all staphylococcal strains harbor the information for all virulence factors in their genome,
and they do not necessarily express all virulence factors which are encoded. Virulence factor
expression is limited by strict regulation to avoid wasting of energy or nutrient resources.
Furthermore, the long list of different virulence factors and mechanism underlines the fact that
S. aureus virulence factors are both redundant and multiple in function, with several factors
performing the same or similar function and also one factor harboring several functions
(Gordon RJ/Lowy 2008).
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