Trends in Microbiology
OpinionStaphylococcus aureus as an intracellular pathogen: the role of small colony variants
Section snippets
Small colony variants of Staphylococcus aureus: a link to recurrent infections?
Certain strains of Staphylococcus aureus can produce subpopulations which are phenotypically very different from the parent strain. These naturally occurring subpopulations grow slowly, leading to colonies that are defined as being one-tenth the size of ‘normal’ S. aureus, hence the name ‘small colony variants’ (SCVs) (Figure 1). Prominent features of these SCVs include decreased pigmentation and haemolysis, increased resistance to aminoglycosides and an unstable colony phenotype. The
Intracellular S. aureus: normal colony-size or SCVs?
Recent studies using cell cultures [15] and clinical samples [16] strongly suggest that S. aureus is able to persist intracellularly. Therefore, questions are raised whether all intracellular staphylococci are in fact SCVs, or whether SCVs are an artefact because of the difficulties in culturing intracellular pathogens. No study has fully addressed this question with clinical isolates, most likely because of technical limitations and the ability of SCVs to revert rapidly in the extracellular
SCVs defense strategies to facilitate colonization
In SCVs, a gene coding for an alternate sigma factor, sigB, is upregulated [20]. This gene is recognized as an important regulator of bacterial stress responses and is involved in bacterial strategies to overcome a variety of environmental stress factors, such as pH, temperature and osmolarity [21].
Additionally, SCVs have a thick cell wall [22] and their electrical potential across the cytoplasmic membrane drops immediately when nutrients are expired (e.g. glucose) or do not allow further
Increased uptake and adherence of SCVs?
Bacterial adherence to the host cell is a prerequisite for invasion. The interaction between S. aureus and host cells is believed to occur through a bridging mechanism, in which bacterial adhesion proteins, host proteins (e.g. fibronectin) and cell integrins participate. Integrins mediate communication and adhesion between mammalian cells and the extracellular matrix. S. aureus expresses an array of adhesins, including the ‘microbial surface components recognizing adhesive matrix molecules’
SCVs cause less damage to host cells
In contrast to normal colony-size S. aureus, SCVs have a decreased production of α-toxin and, consequently, do not lyse their host cells [1]. In addition, SCVs produce lower amounts of toxic shock syndrome toxin 1 (TSST-1), which would result in a lower activation of host immune cell-mediated cytotoxicity [31].
Several studies have suggested that normal colony-size intracellular S. aureus mediates apoptosis in epithelial cells [32], endothelial cells [33] and keratinocytes [34], with the
Resistance to intracellular host defenses
As mentioned earlier, a reduced membrane potential can protect SCVs from cationic proteins. Also, because the activity of the tricarboxylic acid cycle is reduced and catabolism of acetate is thus prevented [2], the carboxylate is shunted into the production of polysaccharide intercellular adhesin (PIA), levels of which are elevated in SCVs [45]. PIA is known to contribute to S. aureus resistance against non-oxidative killing mechanisms of neutrophils [46] and thus could enable SCVs to resist
Decreased activation of the host immune system
Bacterial attachment alone is not sufficient to start the signaling process and the inflammatory response. A more intimate connection, such as disruption of normal actin polymerization, is required to set off the cytokine and chemokine alarm system. Infection of endothelial cells with S. aureus leads to induction of cytokines, although different clinical isolates vary greatly in their ability to elicit a proinflammatory response [48], which might reflect their virulence properties. Given that
Proliferation in the cytoplasm of non-professional phagocytes
An assay using human keratinocytes and staphylococci from a patient with Darier's disease revealed that >100-fold more SCVs persisted intracellularly relative to the normal phenotype [18]. Additionally, in a model of endovascular infection used to determine intracellular persistence, >200-fold more SCV (hemB) mutants persisted within cultured endothelial cells relative to the parent strain [47]. Similar results were obtained when endothelial cells were infected with SCVs from cystic fibrosis
Concluding remarks and future directions
Currently, there still is not definitive proof that S. aureus is a (facultative) intracellular pathogen because there are still important questions that need to be addressed (Box 1). Yet, the evidence is accumulating that at least certain strains of S. aureus can persist intracellularly. It is clear that these staphlyococci must adapt their lifestyle to the intracellular milieu. SCVs exhibit many properties that facilitate their attachment to, uptake into and residence and proliferation within
Glossary
- Arginine deiminase pathway
- a part of the bacteria's metabolism that aims to produce ATP. Arginine is degraded (via citrulline) to ornithine and carbamoyl-phosphate. The latter one serves to generate ATP from ADP by a carbamate kinase.
- Auxotrophism
- the requirement of specific compounds in order to grow normally. Auxotrophic organisms are unable to synthesize these essential nutrients and are, therefore, dependent on external sources.
- Clumping factor
- a protein that is excreted by Staphylococcus aureus
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