Defining the Role of Commensal-Specific Immunity in the Etiology of Psoriasis
Grant Abstract: The skin is the body’s most exposed environmental interface and acts as a first line of physical and immunological defense. The skin is a complex and dynamic ecosystem that is inhabited by bacteria, archaea, fungi, and viruses. These microbes—collectively referred to as the skin microbiota—are fundamental to skin physiology and immunity. Notably, it has previously been shown that defined commensals such as Staphylococcus epidermidis or Candida albicans can promote skin T cell responses, particularly IL-17A production. These findings have obvious relevance to the etiology of psoriasis, a disease characterized by a massive influx of lymphocytes and in which IL-17A acts as the central inflammatory cytokine. This disease is also characterized by major defects in barrier integrity and function, a phenomenon that can have a profound impact on the sensing of otherwise innocuous microbes. Furthermore, alteration of the microbiota composition has been observed during psoriatic flares. Of particular interest, studies focusing on skin fungal species in psoriasis have shown distinct composition of the fungal microbiome on lesional skin of psoriasis patients compared to healthy controls. Together these observations support the idea that defined skin microbes, particularly those that promote IL-17 production, such as fungi, may play an important role in the etiology of psoriasis. Supporting this hypothesis, our preliminary data obtained in mice revealed that defined members of the skin microbiota promote inflammation during experimental psoriasis. Notably, we found that the presence of C. albicans prior to the induction of skin inflammation was associated with aberrant anti-fungal Th17 responses and these responses promoted massive neutrophil recruitment and activation.
The aim of the proposed project is to assess aberrant responses to the skin microbiota during psoriasis with the ultimate goal to understand the role of commensal-specific immunity in the etiology of human psoriasis. We hope that this work will not only validate, in humans, our hypothesis based on experimental models, but will also allow the development of novel therapies directed toward the management of the microbiota.