Sunday, May 18, 2025
5/18/2025
Mechanisms of Longitudinal Microbial Colonization in Pediatric Atopic Dermatitis - ABSTRACT Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that affects 15-30% of children worldwide and is characterized by dry, pruritic, and eczematous skin lesions that diminish quality of life. In addition, AD predisposes to other allergic comorbidities including asthma and food allergy that impose considerable morbidity and a significant public health burden. AD is associated with a dysfunctional skin barrier with reduced skin structural protein filaggrin (FLG) expression, Th2 immune dysregulation and microbial dysbiosis including increased Staphylococcus aureus (SA) prevalence. However, current standards of care aimed at reducing SA colonization on AD skin have exhibited minimal benefits and various unintended side effects. Therefore, there is a critical need to elucidate microbial colonization patterns and drivers of SA persistence in early life to guide the development of novel targeted therapies aimed at regulating the microbiome. We are uniquely equipped to address this need by utilizing our established MPAACH (The Mechanisms of Progression of Atopic Dermatitis to Asthma in Children) cohort, the first US-based early-life cohort of children with AD, which includes contact plates and tape strips sampling for microbial data and extensive clinical data at each annual visit. Our novel preliminary studies on the non-lesional skin of MPAACH participants demonstrate: (a) vast microbial diversity on the AD skin surface; (b) an association of persistent SA colonization with increased AD severity, allergen sensitization and low FLG expression; (c) an association of specific SA genes, including lipoprotein-like lipoprotein (lpl) cluster genes, with low FLG expression; and (d) decreased adhesion to keratinocytes in SA lacking the lpl gene cluster, especially in the context of low FLG expression and Th2 cytokines. Together, our findings and existing literature inform our central hypothesis that severe AD will be associated with decreased global microbial diversity, evenness, and richness over time and that persistently SA colonized AD children harbor SA with strain- specific genes that induce increased keratinocyte adhesion, inflammation, and barrier dysfunction. Using additional samples from non-lesional skin over multiple annual visits, we propose to test this hypothesis by (i) identifying longitudinal microbial and SA colonization patterns on non-invasive skin tapes (Aim 1), (ii) identifying SA genes involved in binding to AD skin (Aim 2) and (iii) identifying the mechanisms of SA adhesion and invasion on WT and FLG deficient primary human keratinocytes (Aim 3). Our studies will enhance our understanding of microbial patterns and identify mechanisms of SA adhesion, invasion and persistence over time in early life. More broadly, these studies will give crucial insight into novel therapeutic targets to mitigate skin dysbiosis and attenuate disease severity, which may have biological and clinical significance that extends far beyond AD.
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