Arwa Al Kindi1, Helen Williams1, Kenshiro Matsuda2, Abdullah M Alkahtani3, Charis Saville1, Hayley Bennett4, Yasmine Alshammari1, Soo Y Tan5, Catherine O'Neill6, Akane Tanaka7, Hiroshi Matsuda8, Peter D Arkwright9, Joanne L Pennock1. 1. Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom. 2. Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Japan. 3. Department of Medicine, Microbiology and Parasitology, King Khalid University, Abha, Saudi Arabia. 4. Genome Editing Unit, University of Manchester, Manchester, United Kingdom. 5. National University Health System, Singapore. 6. Division of Dermatological and Musculoskeletal Sciences, University of Manchester, Manchester, United Kingdom. 7. Laboratory of Comparative Animal Medicine, Tokyo University of Agriculture & Technology, Tokyo, Japan. 8. Laboratory of Veterinary Molecular Pathology and Therapeutics, Tokyo University of Agriculture & Technology, Tokyo, Japan. 9. Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom. Electronic address: peter.arkwright@manchester.ac.uk.
Abstract
BACKGROUND: Staphylococcus aureus is the dominant infective trigger of atopic dermatitis (AD). How this bacterium drives type 2 allergic pathology in the absence of infection in patients with AD is unclear. OBJECTIVE: We sought to identify the S aureus-derived virulence factor(s) that initiates the cutaneous type 2-promoting immune response responsible for AD. METHODS: In vitro human keratinocyte cell culture, ex vivo human skin organ explants, and the eczema-prone Nishiki-nezumi Cinnamon/Tokyo University of Agriculture and Technology strain mouse were used as model systems to assess type 2-promoting immune responses to S aureus. Identification of the bioactive factor was accomplished using fast protein liquid chromatography and mass spectrometry. Bioactivity was confirmed by cloning and expression in an Escherichia coli vector system, and S aureus second immunoglobulin-binding protein (Sbi) mutant strains confirming loss of activity. RESULTS: S aureus was unique among staphylococcal species in its ability to induce the rapid release of constitutive IL-33 from human keratinocytes independent of the Toll-like receptor pathway. Using the eczema-prone Nishiki-nezumi Cinnamon/Tokyo University of Agriculture and Technology strain mouse model, we showed that IL-33 was essential for inducing the immune response to S aureus in vivo. By fractionation and candidate testing, we identified Sbi as the predominant staphylococcus-derived virulence factor that directly drives IL-33 release from human keratinocytes. Immunohistology of skin demonstrated that corneodesmosin, a component of corneodesmosomes that form key intercellular adhesive structures in the stratum corneum, was disrupted, resulting in reduction of skin barrier function. CONCLUSIONS: S aureus-derived Sbi is a unique type 2-promoting virulence factor capable of initiating the type 2-promoting cytokine activity underlying AD.
BACKGROUND:Staphylococcus aureus is the dominant infective trigger of atopic dermatitis (AD). How this bacterium drives type 2 allergic pathology in the absence of infection in patients with AD is unclear. OBJECTIVE: We sought to identify the S aureus-derived virulence factor(s) that initiates the cutaneous type 2-promoting immune response responsible for AD. METHODS: In vitro human keratinocyte cell culture, ex vivo human skin organ explants, and the eczema-prone Nishiki-nezumi Cinnamon/Tokyo University of Agriculture and Technology strain mouse were used as model systems to assess type 2-promoting immune responses to S aureus. Identification of the bioactive factor was accomplished using fast protein liquid chromatography and mass spectrometry. Bioactivity was confirmed by cloning and expression in an Escherichia coli vector system, and S aureus second immunoglobulin-binding protein (Sbi) mutant strains confirming loss of activity. RESULTS: S aureus was unique among staphylococcal species in its ability to induce the rapid release of constitutive IL-33 from human keratinocytes independent of the Toll-like receptor pathway. Using the eczema-prone Nishiki-nezumi Cinnamon/Tokyo University of Agriculture and Technology strain mouse model, we showed that IL-33 was essential for inducing the immune response to S aureus in vivo. By fractionation and candidate testing, we identified Sbi as the predominant staphylococcus-derived virulence factor that directly drives IL-33 release from human keratinocytes. Immunohistology of skin demonstrated that corneodesmosin, a component of corneodesmosomes that form key intercellular adhesive structures in the stratum corneum, was disrupted, resulting in reduction of skin barrier function. CONCLUSIONS: S aureus-derived Sbi is a unique type 2-promoting virulence factor capable of initiating the type 2-promoting cytokine activity underlying AD.
Authors: Garrett J Patrick; Haiyun Liu; Martin P Alphonse; Dustin A Dikeman; Christine Youn; Jack C Otterson; Yu Wang; Advaitaa Ravipati; Momina Mazhar; George Denny; Roger V Ortines; Emily Zhang; Robert J Miller; Carly A Dillen; Qi Liu; Sabrina J Nolan; Kristine Nguyen; LeeAnn Marcello; Danh C Do; Eric M Wier; Yan Zhang; Gary Caviness; Alexander C Klimowicz; Diane V Mierz; Jay S Fine; Guangping Sun; Raphaela Goldbach-Mansky; Alina I Marusina; Alexander A Merleev; Emanual Maverakis; Luis A Garza; Joshua D Milner; Peisong Gao; Meera Ramanujam; Ernest L Raymond; Nathan K Archer; Lloyd S Miller Journal: J Clin Invest Date: 2021-03-01 Impact factor: 14.808
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