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https://www.arca.fiocruz.br/handle/icict/61763
THE SKIN MICROBIOME ENHANCES TRANSCRIPTIONAL INFLAMMATORY SIGNATURES AND DELAYS CLINICAL RESOLUTION IN CUTANEOUS LEISHMANIASIS
Author
Affilliation
Department of Pathobiology. School of Veterinary Medicine. University of Pennsylvania. Philadelphia, United States.
Department of Dermatology. Perelman School of Medicine. University of Pennsylvania. Philadelphia, United States.
Department of Microbial Infection and Immunity. College of Medicine. The Ohio State University. Philadelphia, United States.
Department of Dermatology. Perelman School of Medicine. University of Pennsylvania. Philadelphia, United States.
Fundação Oswaldo Cruz. Instituto Gonçalo Muniz. Laboratório de Pesquisas Clínicas. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Muniz. Laboratório de Pesquisas Clínicas. Salvador, BA, Brasil.
Department of Pathobiology. School of Veterinary Medicine. University of Pennsylvania. Philadelphia, United States.
Department of Dermatology. Perelman School of Medicine. University of Pennsylvania. Philadelphia, United States.
Department of Pathobiology. School of Veterinary Medicine. University of Pennsylvania. Philadelphia, United States.
Department of Dermatology. Perelman School of Medicine. University of Pennsylvania. Philadelphia, United States.
Department of Microbial Infection and Immunity. College of Medicine. The Ohio State University. Philadelphia, United States.
Department of Dermatology. Perelman School of Medicine. University of Pennsylvania. Philadelphia, United States.
Fundação Oswaldo Cruz. Instituto Gonçalo Muniz. Laboratório de Pesquisas Clínicas. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Muniz. Laboratório de Pesquisas Clínicas. Salvador, BA, Brasil.
Department of Pathobiology. School of Veterinary Medicine. University of Pennsylvania. Philadelphia, United States.
Department of Dermatology. Perelman School of Medicine. University of Pennsylvania. Philadelphia, United States.
Department of Pathobiology. School of Veterinary Medicine. University of Pennsylvania. Philadelphia, United States.
Abstract
Cutaneous leishmaniasis (CL) caused by Leishmania braziliensis is associated with chronic lesions that are often difficult to drug treat. We previously found that treatment failure is associated with increased expression of cytolytic genes, including GZMB, GNLY and PRF1, as well as IL1B. Here we investigate how the skin microbiome influences host gene expression in lesions and treatment outcome. We carried out an integrative multi-omics study from 64 L. braziliensis patients including RNA-seq from lesion biopsies, 16 seq from skin swabs collection of bacterial isolates prior to treatment. We first assessed the total bacterial burden in lesions by qPCR of the 16S ribosomal subunit and found that patients with higher bacterial burdens exhibited delayed healing. To identify the bacteria, we performed 16S sequencing of lesion swabs and found that Staphylococcus was the most frequent dysbiosis observed in patients and was associated with delayed lesion resolution. Since 50% of the Staphylococcus isolates, we collected were S. aureus, and S. aureus can be associated with severe infections, we asked whether lesions with high levels of S. aureus might be associated with inflammatory gene expression. We generated an in-house Staphylococcus aureus pangenome from our clinical isolates and known public references to quantify S. aureus transcript abundances through dual RNA-seq mapping analysis. We found that lesions with increased S. aureus transcripts exhibited high expression of inflammatory-related genes, such as CXCL5/8, CCL3/4, IL1A, IFNG, as wells as genes we previously reported as biomarkers for treatment failure including PRF1, GNLY, GZMB and IL1B. Together, these results suggest that the skin microbiome influences immune responses in lesions of CL patients, affecting how patients respond to therapy with antimony leading to a delay in healing. These studies suggest that antibiotics or probiotic therapies given in conjunction with anti-parasitic drugs might augment healing.
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