The Role of the Skin Microbiome in Eczema
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1 The Role of the Skin Microbiome in Eczema Niranjan Nagarajan Associate Director and Group Leader Computational & Systems Biology
2 The human skin is an effective barrier Epidermal Hydration Mechanical Barrier Permeability Barrier Waterproof Barrier Anti-microbial Barrier Anti-oxidant Barrier Anti-UV Barrier Initiation of inflammation Slide credit: John Common
3 Infection transmission via skin Conjuctivitis, Acne, Staph/Strep infections, Herpes, Yeast infections, Ebola, RSV, Handfoot-mouth disease, Athlete s foot,
4 Microbial Communities on Skin 10 7 cells/cm 2
5 How do skin bacteria contribute to host health? Skin Microbiome Co-evolved with us Homeostatic and protective function? Gut Microbiome Nutrient Acquisition Drug Metabolism Development of Immune System Credit: Matej Bajzer & Randy J. Seeley. Nature 444, (21 December 2006)
6 Disease Phenotype: Atopic Dermatitis (AD) sa=i&source=images&cd=&docid=79u3nual Dry and itchy skin Inflamed lesions that are WEbBrM&tbnid=3aSgFcIo_0tB0M&ved=0CAg Broken skin barrier prone to bacterial infection QjRw&url=http%3A%2F %2Fwww.dampproofingcyprus.com%2Fstopb asthma-in-children%2f&ei=ntmivozeoadugtv4odocg&psig=afqjcnhqum_ktevpcocdesisvchubk_w&ust= Slide credit: John Common
7 The Atopic Epidemic International study on Asthma and Allergies in childhood sa=i&source=images&cd=&docid=79u3nual WEbBrM&tbnid=3aSgFcIo_0tB0M&ved=0CAg QjRw&url=http%3A%2F %2Fwww.dampproofingcyprus.com%2Fstop- asthma-in-children%2f&ei=ntmivoz- EoadugTV4oDoCg&psig=AFQjCNHQUM_kT- EVpCoCdESIsvcHubK_w&ust= Slide credit: John Common
8 What causes atopic dermatitis? sa=i&source=images&cd=&docid=79u3nual Complex interplay between WEbBrM&tbnid=3aSgFcIo_0tB0M&ved=0CAg Skin Barrier QjRw&url=http%3A%2F Immune system %2Fwww.dampproofingcyprus.com%2Fstop- Environment - Microbiome asthma-in-children%2f&ei=ntmivoz- EoadugTV4oDoCg&psig=AFQjCNHQUM_kT- EVpCoCdESIsvcHubK_w&ust= Slide credit: John Common
9 Microbiome-wide Association study for AD On visually normal, undamaged skin Cohorts Normals no history of AD or allergy SPT+ Allergy, no history of AD AD Active AD patients Analysis Sampling Area: Antecubital fossa High-throughput DNA Sequencing Relative abundance and statistical analysis Chng KR, Tay ASL, Li C, Ng AHQ,, Lane EB, Chew FT, Common JEA#, Nagarajan N# "Whole metagenome profiling reveals skin microbiome-dependent susceptibility to atopic dermatitis flare" Nature Microbiology :16106 doi: /nmicrobiol
10 Bacterial Diversity on Normal Skin Control (Normal) Case (AD) SPT+ 1.0 Yue-Clayton Theta Index Control-Case p-value = Case-Case
11 Enrichment of opportunistic pathogens in AD Relative Abundance (%) 8 Streptococcus ** Control Case SPT Gemella ** 2.0 Haemophilus * Known to cause skin and oral infections. Changes specific to α- hemolytic group Can aggravate symptoms in Cystic Fibrosis Staphylococci produce factors that promote the growth of Haemophilus
12 Depletion of metabolically versatile bacteria Relative Abundance (%) Dermacoccus ** Control Case SPT+ 0.4 Deinococcus * 1.0 Methylobacterium * Actinomycetales are known for producing secondary metabolites with anti-inflammatory and antimicrobial properties Radiation tolerant and metabolically versatile Found commonly on human feet
13 Viruses & Eukaryotes No association for Viruses Significant depletion of Malassezia Lipid dependent and adapted to skin Associated with Dandruff, Seborrhoeic dermatitis, Tinea Versicolor Relative Abundance (%) Malasseziaceae *** Control Case SPT+ Malassezia Genome Database Reference genome and annotation for all 14 species and 24 strains of the genus RESEARCH ARTICLE Genus-Wide Comparative Genomics of Malassezia Delineates Its Phylogeny, Physiology, and Niche Adaptation on Human Skin Guangxi Wu 1, He Zhao 2, Chenhao Li 1, Menaka Priyadarsani Rajapakse 1, Wing Cheong Wong 3, Jun Xu 4, Charles W. Saunders 4, Nancy L. Reeder 4, Raymond A. Reilman 4, Annika Scheynius 5, Sheng Sun 6, Blake Robert Billmyre 6, Wenjun Li 7, Anna Floyd Averette 6, Piotr Mieczkowski 8, Joseph Heitman 6, Bart Theelen 9, Markus S. Schröder 10, Paola Florez De Sessions 1, Geraldine Butler 10, Sebastian Maurer-Stroh 3,11, Teun Boekhout 9, Niranjan Nagarajan 1 *, Thomas L. Dawson, Jr. 12 *
14 Association with specific Malassezia species M. restricta M. sympodialis Relative Abundance (%) Relative Abundance (%) Control Case SPT+ SKP + Control Case SPT+ SKP + M. globosa M. dermatis Relative Abundance (%) ** Relative Abundance (%) * Control Case SPT+ SKP + Control Case SPT+ SKP +
15 HOST-MICROBIOME INTERACTIONS Cause vs Effect in relation to AD 1. Direct cell-to-cell interactions Microbe-human, microbe-microbe 2. By altering the microenvironment 3. Immune-system mediated
16 AD-associated microbiome inhibits S. aureus All Subjects Dermacoccus Methylobacterium Staphylococcus aureus AD Subjects Streptococcus mitis Staphylococcus capitis Bacterial Inhibition Assay S. aureus culture A Streptococcus mitis B Staphylococcus epidermidis C BHI Media
17 AD associated bacteria elicit distinct immune responses SE: Staphylococcus epidermidis SA: Staphylococcus aureus BF: Bacillus firmus DR: Deinococcus radiodurans DN: Dermacoccus nishinomiyaensis DP: Dermacoccus profundi Bacteria 1. Flare associated bacteria (S. epidermidis and S. aureus) induce strong immune response TNF-driven myeloid activating and Th1 polarizing cytokine signature 2. Depleted bacteria (D. nishinomiyaensis and D. radiodurans) elicit minimal response Human cells (NHEKs, MoDCs) Supernatants on Dendritic cells Log 2 Conc SE 0.1% SE 0.01% SE 0.001% SA 0.1% SA 0.01% SA 0.001% BF 0.1% BF 0.01% BF 0.001% DR 0.1% DR 0.01% DR 0.001% DP 0.1% DP 0.01% DP 0.001% DN 0.1% DN 0.01% DN 0.001% MDC MCP-1 MIP-1b IL-8 MIP-1a TNFa TGF-a PDGF-AA IL-10 TNFb EGF Eotaxin G-CSF IP-10 IL-1b IL-6 Flt-3L GRO FGF-2 MCP-3 PDGF-AB/BB IL-12p70 IL-12p10 IL-1a RANTES VEGF IFNa2 scd40l Fractalkine IL-1RA
18 AD skin selects for S. aureus strains Moist Dry geh gene - Lipase gene (glycerol ester hydrolase) is important for virulence. DNA Sequence data Healthy skin Cases vs Controls in our study AD-susceptible skin AD susceptible skin = geh Thr 373 Normal skin = geh Dry skin sites = geh Moist skin sites = geh Arg 373 Thr 373 Arg 373 Dry vs Moist sites in Oh et al, Nature 2014
19 Perturbed microbial metabolism on AD skin Depleted in Cases Enriched in Cases EC Arginine Deaminase EC Ornithine Carbamoyltransferase EC Carbamate Kinase Arginine Citrulline H 2 O Ammonia P i Ornithine Carbamoyl-P ADP ATP + CO 2 Ammonia (ph ) (ph ) Relative Abundance ( 10-4 ) 10 EC Control * Case Control *** Case Control * Case EC EC Combined p- value =
20 Summary Normal Skin 3. Increase in pathobionts Altered microenvironment 2. ph change Risk factors 1. Predisposing microbiome AD flare Skin Immune ac3va3on, Inflamma3on ColonizaCon by opportuniscc pathogens
21
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