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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Huntley, Clayton C
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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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
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
Santos, José Carlos; Silva-Gomes, Sandro; Silva, João Pedro et al. (2014) Endogenous cathelicidin production limits inflammation and protective immunity to Mycobacterium avium in mice. Immun Inflamm Dis 2:1-12
Borkowski, Andrew W; Gallo, Richard L (2014) UVB radiation illuminates the role of TLR3 in the epidermis. J Invest Dermatol 134:2315-20
Gallo, Richard L; Bernard, Jamie J (2014) Innate immune sensors stimulate inflammatory and immunosuppressive responses to UVB radiation. J Invest Dermatol 134:1508-11
Borkowski, Andrew W; Park, Kyungho; Uchida, Yoshikazu et al. (2013) Activation of TLR3 in keratinocytes increases expression of genes involved in formation of the epidermis, lipid accumulation, and epidermal organelles. J Invest Dermatol 133:2031-40
Afshar, M; Martinez, A D; Gallo, R L et al. (2013) Induction and exacerbation of psoriasis with Interferon-alpha therapy for hepatitis C: a review and analysis of 36 cases. J Eur Acad Dermatol Venereol 27:771-8
Nakatsuji, Teruaki; Chiang, Hsin-I; Jiang, Shangi B et al. (2013) The microbiome extends to subepidermal compartments of normal skin. Nat Commun 4:1431
Morizane, Shin; Yamasaki, Kenshi; Kajita, Ai et al. (2012) TH2 cytokines increase kallikrein 7 expression and function in patients with atopic dermatitis. J Allergy Clin Immunol 130:259-61.e1

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