Microbial colonisation and canine atopic dermatitis. Dr Tim Nuttall RCVS Specialist in Veterinary Dermatology Head of Dermatology

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1 Microbial colonisation and canine dermatitis Dr Tim Nuttall RCVS Specialist in Veterinary Dermatology Head of Dermatology

2 Staphylococcal colonisation exacerbates canine AD Erythema Hyperpigmentation Lichenification Scaling Papules Seborrhoea * * * * *

3 Malassezia colonisation exacerbates canine AD * * * * * Erythema Hyperpigmentation Lichenification Scaling Papules Seborrhoea

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6 Staphylococcus pseudintermedius Opportunistic pathogen 372% dogs colonised 875% of dogs colonised Infections common Worsen clinical s

7 Isolates from and dogs No association with, or infected status Dice (Tol 20%-20%) (H>00% S>00%) [00%-1000%] PFGE A3Na A3Pa FG4c MSA FG8c MSA FG8c BA FG3c BA BH2c msa FG9c MSA FG9c BA A12Pa A15Pa A15La A15Ea A5Na A5Pa A6Na A13Pa A10Na A10La A10Pa A21Pa A8Pa A8Pb A1Lb A2Na A2Ea A2Sa FG5c msa FG5c BA H8Na H8Nb A8Na A16Pa A16La A16Ea A6Pa BH4b BH4c BH4a H8Pa H8Pb A4Na A4Ea A4Pa H11Pa FG7c MSA A6Ea A6Eb A6Pb FG3b A14La BH7c A9Pa A9La A5Ea A11Nb A11Ea A11Pa A11La H2 A13La A14Na A14Nb A14Pa A20La A20Pa A4La A1Na A1Nb A1Ea A22Na A22Ea A22Pa H6Ea A17Pa A17La A7Pa A7La A1La H10Pa H1 H1Na H1Pa H7Pa A23Ea BH7a A12Nb A12Na A12Eb A12La A9Na A23Pa A23La A23Na FG8a BA FG8a MSA Healthy only = Atopic only = Healthy & Atopic =

8 Staphylococcal adhesion in canine AD Adhere more readily to skin

9 Adhere to al and non-al skin

10 Staphylococcal adhesion in canine AD Isolates from and dogs adhere equally well to fibronectin, fibrinogen and cytokeratin 10

11 Staphylococcal colonisation in AD Associated with host factors Altered cutaneous microenvironment Bind to sites of TH2-inflammation Expression of adhesion molecules

12 Malassezia colonisation in canine AD Malassezia skin and infections common Most dogs are colonised Interdigital skin (70%) and s (63%) Less population diversity on skin?

13 Genotyping of Malassezia isolates Multiple isolates from or affected dogs Most isolated from multiple sites Isolate E2 associated with canine AD Phospholipase is a virulence factor?

14 Malassezia colonisation in canine AD Most if not all dogs colonised with Malassezia Density and population heterogeneity important in infection Role of host factors likely Role of more virulent isolates?

15 Innate immunity and canine AD Antimicrobial peptides (AMPs) β-defensins (BD), cathelicidins (Cath) and others Broad spectrum antimicrobial activity Modulate innate and adaptive responses Cell recruitment and activation Wound healing Coat colour in dogs

16 Human beta-defensins hbd1 hbd2 hbd3 Expression Constitutive Induced Induced Inflammatory stimuli No TNFa, IL-1b, G- ve bacteria (also G+ve and yeasts) TNFa, G+ve and G-ve bacteria Antimicrobial activity G-ve G-ve Yeast G+ve (esp S aureus) G-ve Yeast

17 Innate immunity and human AD Complex pattern of relationships Down-regulation of hbd1 Up-regulation of hbd2, hbd3, RNase7 and psoriasin in al skin Dermcidin expression decreased in al skin No changes in Cath (LL-37) No differences in non-al and skin

18 Antimicrobial peptides in canine AD hbd3 effective against S pseudintermedius

19 Canine beta-defensins in AD Very variable and inconsistent findings for cbd1, cbd3, cbd103, ccath and others in and skin

20 cbds in canine AD and inflammatory dermatoses

21 Staphylococcal exacerbation of AD Staphylococcal proteins can penetrate the stratum corneum following mast cell degranulation Toxins affect the skin barrier and immune system Enterotoxins and exfoliative exotoxins Staphylococcal enterotoxin B (SEB) induces T-cell production of IL-31 in D farinae-sensitized dogs

22 Staphylococcal exacerbation of AD

23 Staphylococcal SAGs in AD Staphylococcal SAGs in humans Induce CLA on T-cells Induce MHCII, IL-1, IL-4, TNFα and IL-12 Up-regulate endothelial ICAM-1 and VCAM-1 S pseudintermedius SAGs stimulate canine PBMCs

24 Staphylococci and TSLP Langerhans cell activation and inflammation Increased expression with TLR3 and TLR4 ligands

25 OD at 405nm x 1000 Malassezia exacerbation of canine AD Intradermal test reactivity, specific IgE serology, passive transfer and PBMC proliferation studies Atopic dogs Atopic dogs with Malassezia overgrowth Non- dogs with Malassezia overgrowth Healthy dogs Bar = sd 0

26 % of positive sera Malassezia major and minor allergens Atopic Healthy MW (kd) Chen and others (2002) Veterinary Dermatology 13:

27 Microbial colonisation in chronic AD

28 Antimicrobial therapy in AD can we do better? Routine use of topical antiseptics May be drying Incorporating anti-adhesives Manage the underlying inflammation Colonisation with less pathogenic species to modify the microbiome?