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Staphylococcus aureus second immunoglobulin-binding protein drives atopic dermatitis via IL-33

Published:September 30, 2020DOI:https://doi.org/10.1016/j.jaci.2020.09.023

      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.

      Key words

      Abbreviations used:

      AD (Atopic dermatitis), CDSN (Corneodesmosin), CFU (Colony-forming units), DSC-1 (Desmocollin-1), DSG-1 (Desmoglein-1), FPLC (Fast protein liquid chromatography), FSA (Filtered S aureus supernatant), FSE (Filtered S epidermidis supernatant), LiSA (Live S aureus), NC/Tnd (Nishiki-nezumi Cinnamon/Tokyo University of Agriculture and Technology strain), NHEK (Normal human epidermal keratinocytes), PDHa (Pyruvate dehydrogenase alpha-subunit), Sbi (Second immunoglobulin-binding protein), siRNA (Small-interfering RNA), Spl (Serine-protease-like), TEWL (Transepidermal water loss), TLR (Toll-like receptor), TSLP (Thymic stromal lymphopoietin)
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