Our current understanding of cutaneous innate immunity states that the skin initially protects against infection by establishing physical and chemical barriers to microbes. These include the stratum corneum, antimicrobial peptides, reactive oxygen species, hostile pH and antimicrobial free fatty acids. Despite a potent constitutive immune defense system however, human skin permits the survival of a unique microbial population on the surface called "the microbiome". Although much recent effort has been applied to defining the components of the microbiome on human skin, its function is unknown. We hypothesize that the microbiome is an important part of the immune shield and that interaction of the microbiome with keratinocytes is critical to this process. Our preliminary data show for the first time that the most commonly cultured bacterium of the human skin microbiome, Staphylococcus epidermidis, can work in three ways to aid skin immune defense. 1. S. epidermidis produces antimicrobial peptides that kill pathogens such as S. aureus and Group A Streptococcus, 2. It releases a factor that enhances endogenous production of antimicrobial peptides by keratinocytes, and 3. It triggers pattern recognition receptors in such a way that it prevents keratinocytes from triggering inflammation under certain conditions. Based on these observations our main hypothesis is that Staphylococcus epidermidis is important to the cutaneous immune defense strategy.
Our specific aims are:
Aim 1. Understand how the antimicrobial peptide(s) produced by S. epidermidis (SE) act to selectively kill skin pathogens.
Aim 2. Discover what molecules produced by SE induce AMP expression by keratinocytes.
Aim 3. Define the molecular mechanisms by which SE inhibits inflammatory cytokine production by keratinocytes. Successful completion of these aims will provide new understanding of skin immunity and move towards developing novel therapeutic approaches to improving treatment of skin disease.
The skin is the first barrier against infection. We have discovered that a bacterial species normally found on the skin helps it prevent infection by producing natural antibiotics and controlling skin inflammation. This proposal will study the molecular mechanisms of these actions, and advance understanding of the beneficial effects of the normal skin microflora.
|Borkowski, Andrew W; Kuo, I-Hsin; Bernard, Jamie J et al. (2015) Toll-like receptor 3 activation is required for normal skin barrier repair following UV damage. J Invest Dermatol 135:569-78|
|Zhang, Ling-juan; Guerrero-Juarez, Christian F; Hata, Tissa et al. (2015) Innate immunity. Dermal adipocytes protect against invasive Staphylococcus aureus skin infection. Science 347:67-71|
|Nakagawa, Yukinobu; Gallo, Richard L (2015) Endogenous intracellular cathelicidin enhances TLR9 activation in dendritic cells and macrophages. J Immunol 194:1274-84|
|MacLeod, Daniel T; Nakatsuji, Teruaki; Wang, Zhenping et al. (2015) Vaccinia virus binds to the scavenger receptor MARCO on the surface of keratinocytes. J Invest Dermatol 135:142-50|
|Muto, Yumiko; Wang, Zhenping; Vanderberghe, Matthieu et al. (2014) Mast cells are key mediators of cathelicidin-initiated skin inflammation in rosacea. J Invest Dermatol 134:2728-36|
|Wang, Yanhan; Kuo, Sherwin; Shu, Muya et al. (2014) Staphylococcus epidermidis in the human skin microbiome mediates fermentation to inhibit the growth of Propionibacterium acnes: implications of probiotics in acne vulgaris. Appl Microbiol Biotechnol 98:411-24|
|Gallo, Richard L; Bernard, Jamie J (2014) Innate immune sensors stimulate inflammatory and immunosuppressive responses to UVB radiation. J Invest Dermatol 134:1508-11|
|Two, Aimee M; Hata, Tissa R; Nakatsuji, Teruaki et al. (2014) Reduction in serine protease activity correlates with improved rosacea severity in a small, randomized pilot study of a topical serine protease inhibitor. J Invest Dermatol 134:1143-5|
|Beaumont, Paula E; McHugh, Brian; Gwyer Findlay, Emily et al. (2014) Cathelicidin host defence peptide augments clearance of pulmonary Pseudomonas aeruginosa infection by its influence on neutrophil function in vivo. PLoS One 9:e99029|
|Santos, JosÃ© Carlos; Silva-Gomes, Sandro; Silva, JoÃ£o Pedro et al. (2014) Endogenous cathelicidin production limits inflammation and protective immunity to Mycobacterium avium in mice. Immun Inflamm Dis 2:1-12|
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