The primary objective of the studies in this ADRN application is to improve our understanding of mechanisms underlying cutaneous host defense, by determining the cause of different phenotypes of atopic dermatitis (AD) including Staphylococcus aureus (S. aureus) colonization, eczema herpeticum (EH) and severe AD. These studies will include assessment of skin barrier, and adaptive/innate immune system responses to viral and bacterial infections, as well as genetic and epigenetic studies. Three Interventional Clinical Trials Projects with accompanying mechanistic studies are proposed. The first intervention will be aimed at modulating bacterial colonization of the skin and improving the skin host defense by microbiome transplant. The other 2 interventions will assess the effects of Th2/TSLP cytokine blockade in human AD on S. aureus colonization and vaccination responses in different skin compartments (intradermal and transcutaneous). Three Clinical Mechanistic Studies will be aimed at delineating cellular and molecular mechanisms of severe AD phenotypes, and AD subsets prone to recurrent EH, and S. aureus colonization and/or infection. Two animal protocols are also proposed to directly support clinical studies by providing a mechanistic understanding of skin host defense to alterations in microbiome, and comparing cutaneous versus non-cutaneous vaccination immune responses. The proposed protocols are as follows: 1) Targeted Microbiome Transplant in AD; 2) Effect of Dupilumab(r) (anti-IL4Ra) on the Host-Microbe Interface in AD; 3) Randomized Study of Fluzone(r) Immunogenicity after Transcutaneous Vaccination in AD; 4) A Systems Biology Approach to Identify Determinants of S. aureus Colonization in AD; 5) Integrated Extreme Trait Analysis to Understand the Etiology of Eczema Herpeticum; 6) Defining the Determinants of Disease Severity in AD of Different Races and Ethnic Groups; 7) Modulation of the Immune Response to Cutaneous Immunization in a Mouse Model of AD by S. aureus; 8) Control of Microbiome Function by the Barrier in a Mouse Model of AD. Successful completion of these 6 interrelated clinical projects, and 2 animal protocols which directly support the human research, will create a paradigm shift in our understanding of genetics, skin barrier function, microbiome, innate and adaptive immune response underlying host defense mechanisms in the skin of distinct but associated AD phenotypes. At the end of this funding period, these cutting edge mechanistic studies will be translated into new treatment approaches in AD, a disease that remains difficult to treat and that has eluded molecular characterization.
Atopic dermatitis (AD) is the most common skin disease in children and adults. The primary goal of the studies in this application is to improve our understanding of mechanisms causing bacterial and viral skin infections in AD. At the end of this funding period the proposed cutting edge mechanistic and interventional studies will be translated into new treatment approaches in AD, a disease that remains difficult to treat and that has eluded molecular characterization. Project 1: Targeted Microbiome Transplant in Atopic Dermatitis Project Leader (PL): Gallo, R. DESCRIPTION (provided by applicant): Recent work has concluded that some commensal bacteria residing on human skin are beneficial to immune defense. In contrast, colonization by S. aureus of the skin of patients with atopic dermatitis is detrimental. Through high-throughput screening of the normal human skin microbiome we have identified specific strains of commensal coagulase-negative Staphylococcus that kill pathogenic bacteria and enhance skin innate immune defense. Analysis of the function of the skin microbiome from atopic dermatitis patients has further shown that most atopic patients are deficient in these beneficial commensal strains. We therefore hypothesize that increasing the abundance of such commensal bacteria will benefit patients with atopic dermatitis. To test these hypothesis we propose an interventional clinical trial of the topical application of a defined combination of 4 bacteria fro the human skin microbiome. We will confirm that this 'transplant' of beneficial bacteria will kill . aureus on patient skin. We then determine the stability of this transplant in order to design appropriate dosing over a 28-day trial period and evaluate several elements of the host immune response. This intervention will test if transplant of the skin microbiome will benefit subjects wih atopic dermatitis by decreasing S. aureus colonization and/or improve inflammation. Therefore, successful completion of this project will provide answers to key questions about the function of the microbiome on human skin and provide a new approach to treat atopic dermatitis. Our specific aims are: 1: Evaluate the capacity of a microbiome transplant to decrease S. aureus colonization in patients with atopic dermatitis (AD). 2: Determine the stability of the microbiome transplant on lesional and matched non-lesional skin of AD subjects and normal subjects. 3: Evaluate the clinical response to microbiome transplant and identify relevant biomarkers associated with the clinical response.
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