A dinâmica dos estafilococos na patogénese da dermatite atópica (DA): rumo à identificação de alvos terapêuticos

Atopic dermatitis (AD) is a pruritic chronic skin inflammatory disease with frequent flares that are associated with comorbidities and systemic inflammation, which may interfere with patients growth, development and mental state. Apart from skin lesions, itch and loss of sleep cause a high burden, reducing patients’ quality of life and ability to work. Furthermore, patients with severe AD usually require systemic therapies, which have varying degrees of success, are more expensive and may have significant side-effects. Additionally, AD can become resistant to currently available treatments, highlighting the need for the development of new and more personalized treatments (1). One of the factors associated with severe forms of disease is the colonization of AD lesions with the bacteria S. aureus (2). Nevertheless, the role of S. aureus in AD pathogenesis is still not clear. We believe that clarifying the molecular mechanisms that link S. aureus and AD will help to identify new therapeutic targets that will allow developing novel and more targeted treatments against severe AD. A few studies have addressed S. aureus pathogenicity in AD. However, these have used targeted approaches, and small cohorts and did not consider the whole genomic content of disease-causing S. aureus or its genetic background. Moreover, most studies considered only the impact of bacteria on the host immune response, disregarding the host effect on S. aureus physiology. The advent of WGS allowed to unravel the bacterial genomic content and gene expression with an unprecedented level of resolution and completeness, which is a compelling opportunity to answer fundamental questions about the relationship between AD and S. aureus. A detailed genome wide analysis of genes and functions present in worldwide collections of AD-associated S. aureus and their response under the typical cutaneous AD microenvironment, may contribute to understand the impact of AD in S. aureus physiology. On the other hand, studies on the impact of S. aureus with different genomic content in skin immunity and skin disruption will contribute to establish a link between specific bacterial genes/mutations and clinical disease expression. This knowledge will provide a better understanding of the S. aureus role in the pathogenesis of AD, namely for its flares. Herein we will use whole-genome wide approaches to address questions regarding S. aureus role in AD, namely: are particular S. aureus genotypes, genetic factors or strains associated with AD? Do S. aureus from AD lesions and healthy skin have identical genomic and functional content? Do S. aureus genome and transcriptome change during AD flares? Are genetic events associated with S. aureus conversion from a mere bystander to an active player in the AD inflammatory reaction? How is S. aureus growth and metabolism affected by exposure to the AD environment? Our specific objectives are to: 1) assess S. aureus genetic background relevance for AD development 2) identify S. aureus clonal types associated to AD in different geographic regions 3) compare S. aureus genomes from anterior nares and AD skin lesions 4) identify S. aureus factors associated to AD and characterize their pathogenicity 5) construct a S. aureus mutant library and establish an AD-targeted screening approach 6) develop and validate a 3D reconstructed human epidermis (3D-RHE) AD model 7) assess the impact of AD-associated microenvironment in S. aureus pathogenicity and physiology