The skin microbiome enhances disease through IL-1b and delays healing in cutaneous leishmaniasis patients

Abstract

SUMMARYLeishmania braziliensisinfection results in inflammation and skin injury, with highly variable and unpredictable clinical outcomes. Here, we investigated the potential impact of microbiota on infection-induced inflammatory responses and disease resolution by conducting an integrated analysis of the skin microbiome and host transcriptome on a cohort of 62L. braziliensis-infected patients. We found that overall bacterial burden and microbiome configurations dominated withStaphylococcusspp. were associated with delayed healing and enhanced inflammatory responses, especially by IL-1 family members. Dual RNA-seq of human lesions revealed that high lesionalS. aureustranscript abundance was associated with delayed healing and increased expression of IL-1β. This cytokine was critical for modulating disease outcome inL. braziliensis-infected mice colonized withS. aureus, as its neutralization reduced pathology and inflammation. These results implicate the microbiome in cutaneous leishmaniasis disease outcomes in humans and suggest host-directed therapies to mitigate the inflammatory consequences.