ANR-FWF - Appel à projets générique 2020 - FWF

Therapeutic potential of antimicrobial peptides in atopic dermatitis – thera-AMPD

Submission summary

Research Context: Atopic dermatitis (AD) is a common inflammatory skin disease with complex etiopathology linked to abnormal inflammatory pathways, and dysbiotic colonization by Staphylococcus aureus (S. aureus). The microbial dysbiosis is related to failure in expressing antimicrobial peptides (AMPs; small peptides bearing microbiocidal and immunomodulatory functions) in the skin. Phototherapy (using different wavebands of UV radiation) is a widely used treatment for moderate to severe AD and is known to decrease cutaneous inflammation with minimal or no systemic side effects. Intriguingly, UV is known to modulate microbial communities and induce certain AMPs in the skin.

Hypothesis: We hypothesize that the efficacy of phototherapy in AD patients depends on the capacity of UV to (re)induce the expression of AMPs from the host skin or microbe, which can normalize the dysbiotic S. aureus colonization. Furthermore, we hypothesize that such AMPs could be used therapeutically to target S. aureus and improve AD symptoms.

Objectives: The primary objectives of the proposed work are to (i) screen the diversity of AMPs and (ii) investigate impact on S. aureus biology in AD patients undergoing phototherapy; (iii) decipher the complex interplay between S. aureus colonization, UV exposure, and AMP expression; (iv) to establish novel therapeutic strategies by reducing the dysbiotic microbiome/colonization with certain AMPs in an S. aureus-induced AD-like model.

Methods: Overall, the multidisciplinary and translational nature of this proposed work will involve a combination of microbiology, immunology, bioinformatics, and molecular biology. The proposed project will utilize state-of-the-art techniques such as de novo peptide sequencing using mass spectrometry (to detect AMPs), whole genome shotgun sequencing, RNA sequencing, bioinformatics (for AMP database, microbiome analysis and statistics) and biologic samples from patients and pre-clinical models to achieve the objectives.

Level of originality: In this project, we will screen and create for the first time a comprehensive database of the different AMPs produced in the skin of AD patients. Furthermore, we will investigate the effects of UV (phototherapy) on the complex interplay between S. aureus, AMPs and AD. Finally, we attempt to use AMPs as therapeutic agents to target S. aureus in AD inflammation and hereby reduce symptoms of the disease. Such a therapy acting like phototherapy (but without application of UV) might as or even more effective than phototherapy with minimal risk and a good safety profile (avoiding the side effects of UV).

Primary researchers involved: The proposed project will be closely integrated between two teams; Team 1 headed by Prof. Peter Wolf (Austria) and Team 2 headed by Prof. Jean-François Nicolas (France). Dr. Vijaykumar Patra will perform and overlook the experiments while supervising a PhD student (to be employed) and liaising between various teams.

Project coordination

Jean François NICOLAS (CENTRE INTERNATIONAL DE RECHERCHE EN INFECTIOLOGIE)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

MUG = Medical University of Graz Research Unit for Photodermatology, Department of Dermatology, Medical University of Graz
CIRI CENTRE INTERNATIONAL DE RECHERCHE EN INFECTIOLOGIE

Help of the ANR 205,199 euros
Beginning and duration of the scientific project: December 2020 - 24 Months

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