Staphylococcus aureus promotes increase IL-1 mediated immunopathology and delayed healing in cutaneous leishmaniasis

Abstract The chronic infection by Leishmania braziliensis causes a skin barrier (ulcer) breach and is susceptible to secondary bacterial infections. The development of the ulcer is associated with a dysregulation of the skin microbiome, which we hypothesized impacts host gene expression, exacerbates the inflammatory response, and prolongs the resolution of the disease. We conducted an integrative multi-omics meta-analysis of the skin microbiome, host gene expression, and clinical metadata of patients. We found that a high bacterial burden was associated with an increased inflammatory response and delayed healing. 16S-seq analysis of lesion swabs revealed that while patients exhibit several distinct skin microbiomes, a microbiome dominated by Staphylococcus is the most common. Furthermore, the patients with a dominant lesional Staphylococcus microbiome were delayed in healing compared to those with a heterogeneous microbiome. Since we found that S. aureus was a common isolate from the ulcers, we carried out dual RNA-seq analysis on the lesion biopsies to quantify S. aureus transcriptional abundances and associated them with host gene expression. High S. aureus transcript abundance was associated with delayed healing and increased expression of IL-1α and IL-1β. These cytokines were critical for modulating disease outcome since pathology was reduced when we neutralized either in L. braziliensis-infected mice colonized with S. aureus. These results indicate that an altered skin microbiome develops in cutaneous leishmaniasis, influencing responsiveness to anti-parasitic drug treatment. They suggest that host-directed therapies designed to reduce the bacterial burden in leishmanial lesions may be therapeutic. NIH (AI143790)