Abstract
Staphylococcus aureus is a major human pathogen that has evolved very efficient immune evading strategies leading to persistent colonization. During different stages of growth, S. aureus express various surface molecules, which may affect the immune stimulating properties, but very little is known about their role in immune stimulation and evasion. Depending on the growth phase, S. aureus may affect antigen presenting cells differently. Here, the impact of growth phases and the surface molecules lipoteichoic acid, peptidoglycan and poly-N-acetyl glucosamine on the induction of IL-12 imperative for an efficient clearance of S. aureus was studied in dendritic cells (DCs). Exponential phase (EP) S. aureus was superior to stationary phase (SP) bacteria in induction of IL-12, which required actin-mediated endocytosis and endosomal acidification. Moreover, addition of staphylococcal cell wall derived peptidoglycan to EP S. aureus stimulated cells increased bacterial uptake but abrogated IL-12 induction, while addition of lipoteichoic acid increased IL-12 production but had no effect on the bacterial uptake. Depletion of the capability to produce poly-N-acetyl glucosamine increased the IL-12 inducing activity of EP bacteria. Furthermore, the mutant dltA unable to produce D-alanylated teichoic acids failed to induce IL-12 but like peptidoglycan and the toll-like receptor (TLR) ligands LPS and Pam3CSK4 the mutant stimulated increased macropinocytosis. In conclusion, the IL-12 response by DCs against S. aureus is highly growth phase dependent, relies on cell wall D-alanylation, endocytosis and subsequent endosomal degradation, and is abrogated by receptor induced macropinocytosis.
Highlights
The Gram-positive bacterium Staphylococcus aureus often colonizes the human skin and mucosal surfaces without causing any symptoms
IL-12 produced by dendritic cells (DCs) during staphylococcal infection has been shown to be crucial for the activation and regulation of immune cells, and for optimal bacterial clearance [14]
Splenic DCs from S. aureus infected mice were fully capable of producing IL-12 upon ex-vivo stimulation [14], indicating that S. aureus may be capable of inducing a IL-12 stimulating state under in vivo conditions
Summary
The Gram-positive bacterium Staphylococcus aureus often colonizes the human skin and mucosal surfaces without causing any symptoms. Induction of IL-12 by Staphylococcus aureus in Exponential Phase the immune system [1] This may be due to the fact that many staphylococcal strains have evolved mechanisms to circumvent innate immune responses, by expressing cell wall-anchored proteins, extracellular polysaccharides, and toxins such as hemolysins [2]. Many strains secrete extracellular polysaccharides, such as poly-N-acetyl glucosamine (PNAG), which is encoded by the intercellular adhesin (ica) operon and facilitates aggregation of late exponential phase bacteria involved in biofilm formation [10, 11]. All these factors are believed to contribute to the immune evasion; specific mechanisms involved are only poorly understood
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