Contributions of gastrointestinal Staphylococcus aureus and other gut microbiota to pediatric atopic dermatitis

PROJECT SUMMARY Atopic dermatitis (AD) is the most common inflammatory skin disease in children worldwide and has a substantial detrimental impact on patients’ quality of life. Staphylococcus aureus is known to contribute to AD pathogenesis and is also found at high rates in the gut of infants. However, the contribution of gastrointestinal (GI)-colonizing

S. aureus to AD, remains largely unexplored. In this proposal, we will determine whether and how S. aureus in concert with other microbiota from the GI tract, contributes to AD. Our preliminary data suggest an association of S. aureus rectal colonization, a surrogate measure for GI colonization, with pediatric AD. Further, within hosts,

S. aureus colonization density in the rectum correlates with AD flare and remission, mirroring cutaneous colonization. Comparative genomic analysis of S. aureus isolates from the nares, lesional skin, and rectum in an AD subject demonstrates identical mutations shared exclusively between rectal and cutaneous S. aureus,

providing evidence of transmission from gut to skin. Several of these mutations were observed within the agr locus, a regulator of virulence thought to promote AD, but only in combination with wild-type agr strains. This observation of both wild-type S. aureus and isolates with mutations in this important gene regulator suggests

evolutionary pressures may have selected for the cooperative effects of these mixed S. aureus populations. We will test whether the GI tract is a source of cutaneous S. aureus in AD using advanced sequencing techniques to perform comparative genomic analysis on S. aureus isolates from human subjects (Aim 1). We will further

characterize the effects of other gut microbiota on S. aureus GI and cutaneous colonization and, by consequence, on AD (Aim 2). Finally, we will determine whether cooperative effects of agr wild-type and mutant variants contribute to S. aureus colonization fitness and AD in GI and skin colonization mouse models (Aim 3).

Our central hypothesis is that GI-colonizing S. aureus contributes to AD through interactions with other gut microbiota and effects on cutaneous S. aureus colonization. These effects may be mediated by the mixed populations of S. aureus present in the GI reservoir. The rationale for this research is that improved

understanding of the colonization dynamics of S. aureus beyond the nares and skin in AD will allow for improved therapeutic strategies targeting the microbiome in AD. To achieve these aims, I will be supported by my primary mentor, Dr. Bo Shopsin (NYU), a scientific leader in the study of S. aureus molecular epidemiology and

translation of genetic features in bacterial field isolates to relevant clinical phenotypes. Dr. Shopsin’s guidance will be complemented by a committee of investigators with expertise in cutaneous biology, microbiome analysis, and physician-scientist training. This proposal includes training in microbiology, sequencing techniques, in vivo

models, and coursework in advanced genomic and microbiome analysis. NYU offers outstanding faculty with well-supported core facilities to provide an optimal environment to support my transition to an independent investigator studying the impact of microbes on skin health.