) ) 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI083358-01
Application #
7841575
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Huntley, Clayton C
Project Start
2009-08-15
Project End
2009-12-07
Budget Start
2009-08-15
Budget End
2009-12-07
Support Year
1
Fiscal Year
2009
Total Cost
$123,319
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Sanford, James A; Gallo, Richard L (2013) Functions of the skin microbiota in health and disease. Semin Immunol 25:370-7
Nakatsuji, Teruaki; Chiang, Hsin-I; Jiang, Shangi B et al. (2013) The microbiome extends to subepidermal compartments of normal skin. Nat Commun 4:1431
Lai, Yuping; Li, Dongqing; Li, Changwei et al. (2012) The antimicrobial protein REG3A regulates keratinocyte proliferation and differentiation after skin injury. Immunity 37:74-84
Gallo, Richard L; Hooper, Lora V (2012) Epithelial antimicrobial defence of the skin and intestine. Nat Rev Immunol 12:503-16
Gallo, Richard L; Nakatsuji, Teruaki (2011) Microbial symbiosis with the innate immune defense system of the skin. J Invest Dermatol 131:1974-80
Borkowski, Andrew W; Gallo, Richard L (2011) The coordinated response of the physical and antimicrobial peptide barriers of the skin. J Invest Dermatol 131:285-7
Lo, Chih-Wei; Lai, Yiu-Kay; Liu, Yu-Tsueng et al. (2011) Staphylococcus aureus hijacks a skin commensal to intensify its virulence: immunization targeting ?-hemolysin and CAMP factor. J Invest Dermatol 131:401-9
Bernard, Jamie J; Gallo, Richard L (2011) Protecting the boundary: the sentinel role of host defense peptides in the skin. Cell Mol Life Sci 68:2189-99
Nakatsuji, Teruaki; Kao, Mandy C; Zhang, Liangfang et al. (2010) Sebum free fatty acids enhance the innate immune defense of human sebocytes by upregulating beta-defensin-2 expression. J Invest Dermatol 130:985-94
Cogen, Anna L; Yamasaki, Kenshi; Sanchez, Katheryn M et al. (2010) Selective antimicrobial action is provided by phenol-soluble modulins derived from Staphylococcus epidermidis, a normal resident of the skin. J Invest Dermatol 130:192-200

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