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.