Abstract
Staphylococcus aureus is one of the clinically most relevant pathogens causing infections. Humans are often exposed to S. aureus. In approximately one-third of the healthy population it can be found on the skin either for long or short periods as colonizing “commensals”, without inducing infections or an inflammatory immune response. While tolerating S. aureus seems to be limited to certain individuals and time periods in most cases, Staphylococcus epidermidis is tolerated permanently on the skin of almost all individuals without activating overwhelming skin inflammation. To investigate this, we co-cultured a keratinocyte cell line (HaCaT) with viable S. aureus or S. epidermidis to study the differences in the immune activation. S. aureus activated keratinocytes depicted by a profound IL-6 and IL-8 response, whereas S. epidermidis did not. Our data indicate that internalization of S. aureus and the subsequent intracellular sensing of bacterial nucleic acid may be essential for initiating inflammatory response in keratinocytes. Internalized dsRNA activates IL-6 and IL-8 release, but not TNF-α or IFNs by human keratinocytes. This is a non-specific effect of dsRNA, which can be induced using Poly(I:C), as well as RNA from S. aureus and S. epidermidis. However, only viable S. aureus were able to induce this response as these bacteria and not S. epidermidis were actively internalized by HaCaT. The stimulatory effect of S. aureus seems to be independent of the TLR3, -7 and -8 pathways.
Highlights
The immunology of the human skin is complex
IL-6 and IL-8 were the most prominent and significantly upregulated cytokines detected by ELISA in the 24-hour supernatant (2-hour co-culture with viable bacteria and another 22-hour after addition of gentamicin/lysostaphin) following stimulation with viable S. aureus (USA300) but were not detected after stimulation with S. epidermidis (Figure 1A) IL-1b and TNF-a were not detected in the supernatants
There were no significant differences in the induction of antimicrobial peptides of the skin, human betadefensins 1 to 3, between S. epidermidis and S. aureus (Supplementary Figure S3)
Summary
The immunology of the human skin is complex. The skin is the largest immune organ of the human body and acts as a physical and immunological barrier against invading pathogens, which can sense invading pathogens and react [1, 2]. As a primary response and innate defense mechanism, keratinocytes respond to stimuli, such as trauma and bacterial invasion, by producing antimicrobial peptides (AMP) to eliminate potentially harmful pathogens. The human skin is constantly exposed to various bacteria as part of the skin microbiome or invading pathogen, some bacteria are tolerated, while others are eliminated. For approximately 20-30% of the healthy population, Staphylococcus aureus is considered part of their microbiome and colonize their nasal cavity and the skin [3]. Others are transiently colonized and can prevent persistent colonization with S. aureus [4]
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