The surface commensal microbial community has been shown to influence the function and development of the immune system, thus potentially participating in the pathophysiology of several important diseases of the skin, gut, kidney and lung. With increased appreciation that normal microbial communities exist in equilibrium with, and in many cases benefit the host, recent work has sought to better understand the mechanisms by which we permit survival of our skin commensal microbiome and how the microbiome controls mammalian immune responses. We have discovered that it was wrong to assume that bacteria are normally totally separated from us by the epidermis. Strong evidence now shows that microbial communities are in an equilibrium across the basement membrane zone and populate the dermal stroma of normal skin. These observations show that the surface microbiome can get into the position in direct priming with live cells below the epithelial surface therefore influencing cutaneous immunity. Importantly, the observation that microbes enter the dermis is not evidence for infection, rather this findings show that products made by microbes are communicating with various cell types existing in the dermis. The overall goal of this proposal is to understand mechanisms how microbes breakthrough epidermal barrier to enter the dermis, explore the elements of the skin innate immune barrier that regulate microbial entry into the dermis, and begin to test the hypothesis that microbial entry is a rate-limiting step of induction of immunological responses by skin microbiome.
Our aims are as follows:
Aim 1 : Understand how bacteria break through the skin barrier to enter the dermis.
Aim 2 : Understand how innate immune barriers control entry of commensal and pathogenic bacteria Aim 3: Determine if the entry of bacteria into the dermis results in an immunological responses. Successful completion of these aims will provide new information regarding control of an important and novel aspect of the functional interaction between microbiome and cutaneous immunity in homeostatic or pathogenic aspects.
We have discovered that a microbiome exists in equilibrium across the epidermis, and products of these microbes occupy compartments in the dermis of normal skin. This observation permits us to hypothesize that the abundance and identity of microbes below the epidermis will directly influence skin immunological responses. This proposal will study 1) how bacteria penetrate through skin barrier into the dermis, 2) how specific elements of the skin innate immune defense regulate microbial entry into the dermis microbial mechanisms, and 3) if microbiome entry into the dermis is required for the microbiome to exert its immunological functions.
|Nakatsuji, Teruaki; Chen, Tiffany H; Butcher, Anna M et al. (2018) A commensal strain of Staphylococcus epidermidis protects against skin neoplasia. Sci Adv 4:eaao4502|
|O'Neill, Alan M; Gallo, Richard L (2018) Host-microbiome interactions and recent progress into understanding the biology of acne vulgaris. Microbiome 6:177|
|Sato, Emi; Williams, Michael R; Sanford, James A et al. (2017) The parathyroid hormone family member TIP39 interacts with sarco/endoplasmic reticulum Ca2+ - ATPase activity by influencing calcium homoeostasis. Exp Dermatol 26:792-797|
|Lee, Ernest Y; Takahashi, Toshiya; Curk, Tine et al. (2017) Crystallinity of Double-Stranded RNA-Antimicrobial Peptide Complexes Modulates Toll-Like Receptor 3-Mediated Inflammation. ACS Nano 11:12145-12155|
|Williams, Michael R; Nakatsuji, Teruaki; Sanford, James A et al. (2017) Staphylococcus aureus Induces Increased Serine Protease Activity in Keratinocytes. J Invest Dermatol 137:377-384|
|Nakatsuji, Teruaki; Chen, Tiffany H; Narala, Saisindhu et al. (2017) Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Sci Transl Med 9:|
|Adase, Christopher A; Borkowski, Andrew W; Zhang, Ling-Juan et al. (2016) Non-coding Double-stranded RNA and Antimicrobial Peptide LL-37 Induce Growth Factor Expression from Keratinocytes and Endothelial Cells. J Biol Chem 291:11635-46|
|Zhang, Ling-Juan; Sen, George L; Ward, Nicole L et al. (2016) Antimicrobial Peptide LL37 and MAVS Signaling Drive Interferon-? Production by Epidermal Keratinocytes during Skin Injury. Immunity 45:119-30|
|Gallo, Richard L; Hultsch, Thomas; Farnaes, Lauge (2016) Recognizing that the microbiome is part of the human immune system will advance treatment of both cancer and infections. J Am Acad Dermatol 74:772-4|
|Sato, Emi; Muto, Jun; Zhang, Ling-Juan et al. (2016) The Parathyroid Hormone Second Receptor PTH2R and its Ligand Tuberoinfundibular Peptide of 39 Residues TIP39 Regulate Intracellular Calcium and Influence Keratinocyte Differentiation. J Invest Dermatol 136:1449-1459|
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