Regulatory T cells limit opportunistic colonization of Staphylococcus aureus to promote lesion resolution in cutaneous leishmaniasis

Abstract The severity and responsiveness to treatment in L. braziliensis patients is influenced by a variety of factors, including microbiota and cytolytic T cells. Recently, we studied the skin microbiome in patients and demonstrated that high levels of S. aureus are associated with delayed healing in patients. To understand how S. aureus might influence cutaneous leishmaniasis, we studied the immune responses in mice following colonization with a S. aureus isolate from a L. braziliensis patient. Colonization of the skin with S. aureus alone induced a dominant type-17 response as well as an accumulation of Foxp3 T regulatory cells, and subsequent infection of mice with L. braziliensis led to increased IL-17 dependent pathology. Unexpectedly, transient depletion of total Tregs or RORγtin Foxp3 Tregs in S. aureus colonized mice increased IFN-γ and decreased the IL-17A response in skin. These mice exhibited increased pathology, which was accompanied by epidermal cell death and loss of barrier integrity. Additionally, the mice had substantially more S. aureus in the skin, and in the lymph nodes. In mice colonized with S. aureus and infected with L. braziliensis partial reduction led to a substantial increase in disease and a higher burden of S. aureus. Consistent with these results, in a transcriptional analysis of lesions from L. braziliensis patients, we found that low Foxp3 expression in patients had increased expression of cytolytic genes and IFN-γ, increased S. aureus in the lesions and had a delay in lesion resolution compared to patients with high Foxp3. Taken, together, these results suggest that in L. braziliensis patients Tregs are critical to regulate type-1 responses that in the context of S. aureus can promote more severe disease.