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Description
Atopic dermatitis (AD) is a chronic inflammatory skin condition, characterized by epidermal barrier dysfunction, immune system unbalance and S. aureus overgrowth. Its therapeutic scenario has recently been modified by new biological drugs, including the IL-4 and/or IL-13 antagonists dupilumab and tralokinumab and the Janus Kinase (JAK) inhibitors upadacitinib, abrocitinib and baricitinib. However, some patients remain treatment-resistant and the effect of anti-JAK on S. aureus prevalence/virulence in AD patients is yet unknown. The main objective of this pilot study is to clarify the putative mediator role of S. aureus in molecular mechanisms
underlying IL-4/IL-13/JAK inhibitors resistance in AD patients, regarding the skin areas involved and the consequent microbiota beta diversity. The specific aims are to: i) investigate the presence/relative abundance of S. aureus, based on the various skin areas characteristics, and in relation to the possible different responses to treatment ii) clarify the role of S. aureus in the induction of proinflammatory cytokine expression, through JAK-STAT (IL-22, IFN-?), IL-4 and IL-13 pathways iii) identify specific beta diversity in the skin microbiota, potentially predictive of therapy response iv) set personalized treatment schedules, also for resource optimization. This integrated multidisciplinary research will involve Dermatology, Microbiology, Proteomics, Molecular Biology, Bioinformatics and Statistics specialists. We plan to enroll 20 severe AD adult patients, that will be treated for at least 16 weeks with Dupilumab or Upadacitinib. Skin swabs will be performed both on affected and non-affected areas, before (T0), during (T8), and after (T16) treatment. Swab derived bacterial 16sRNA will be sequenced for skin microbiota diversity identification, and bacterial load will be assessed. S. aureus will be isolated from the swab cultures and biobanked. Genomic DNA extracted from S. aureus colonies isolated from each swab of selected therapy responders and non-responders will be then shotgun metagenome sequenced to build libraries. The metabolic profiles changes in S. aureus culture supernatants and AD patient’s plasma will be characterized in relation to the treatment. S. aureus strains (or their metabolites only) from selected responders/non-responders will be co-cultured in 3D primary epithelial/ Langerhans cell skin models, to in vitro deepen the molecular and inflammatory mechanisms at the basis of AD trigger and progression. Patient's stratification, based on skin microbiota beta diversity, clinical characteristics, and response to treatments could allow to better define personalized therapeutic strategies, increase the likelihood of amelioration, improve the patient's life quality, and optimize the cost-benefit ratio. Results from the in vitro analysis will elucidate the molecular mechanisms at the basis of the interactions among epithelial and immune cells and dysbiotic microbiota.
Stato | Attivo |
---|---|
Data di inizio/fine effettiva | 30/11/23 → 29/11/25 |
Funding
- MUR - Ministero dell'Università e Ricerca
Obiettivi di sviluppo sostenibile dell’ONU
Nel 2015, gli Stati membri dell'ONU hanno sottoscritto 17 obiettivi globali di sviluppo sostenibile (OSS) per porre fine alla povertà, salvaguardare il pianeta e assicurare prosperità a tutti. Il presente lavoro contribuisce al raggiungimento dei seguenti OSS:
Keywords
- skin microbiota/microbioma
- atopic dermatitis
- metabolomic
- IL4/IL13 blockade
- JAK inhibitors
- Staphylococcus aureus
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