Genetic and Functional Analyses of Cutibacterium Acnes Isolates Reveal the Association of a Linear Plasmid with Skin Inflammation
Alan M. O’Neill, Kellen Cavagnero, Jason S. Seidman, Lívia S. Zaramela, Yang Chen, Fengwu Li, Teruaki Nakatsuji, J Cheng, Yun Tong, Tran Do, S. Brinton, Tissa Hata, Robert L. Modlin, Richard L. Gallo
Abstract
Cutibacterium acnes (C. acnes) is a commensal bacterium on skin that is generally well tolerated but different strain-types have been hypothesized to contribute to the disease acne vulgaris. To understand how some strain-types might contribute to skin inflammation we generated a repository of C. acnes isolates from skin swabs of healthy and acne subjects and assessed their strain-level identity and capacity to stimulate cytokine release. Phylotype II K-type strains were more frequent on healthy and non-lesional skin of acne subjects compared to those isolated from lesions. Phylotype IA-1 C-type strains were increased on lesional skin compared to healthy skin. The capacity to induce cytokines from cultured monocyte-derived dendritic cells was opposite to this action on sebocytes and keratinocytes and did not correlate with the strain-types associated with disease. Whole genome sequencing revealed a linear plasmid in high-inflammatory isolates within similar strain-types that had different proinflammatory responses. Single-cell RNA sequencing of mouse skin following intradermal injection showed strains containing this plasmid induced a higher inflammatory response in dermal fibroblasts. These findings revealed that C. acnes strain-type is insufficient to predict inflammation and that carriage of a plasmid could contribute to disease. Cutibacterium acnes (C. acnes) is a commensal bacterium on skin that is generally well tolerated but different strain-types have been hypothesized to contribute to the disease acne vulgaris. To understand how some strain-types might contribute to skin inflammation we generated a repository of C. acnes isolates from skin swabs of healthy and acne subjects and assessed their strain-level identity and capacity to stimulate cytokine release. Phylotype II K-type strains were more frequent on healthy and non-lesional skin of acne subjects compared to those isolated from lesions. Phylotype IA-1 C-type strains were increased on lesional skin compared to healthy skin. The capacity to induce cytokines from cultured monocyte-derived dendritic cells was opposite to this action on sebocytes and keratinocytes and did not correlate with the strain-types associated with disease. Whole genome sequencing revealed a linear plasmid in high-inflammatory isolates within similar strain-types that had different proinflammatory responses. Single-cell RNA sequencing of mouse skin following intradermal injection showed strains containing this plasmid induced a higher inflammatory response in dermal fibroblasts. These findings revealed that C. acnes strain-type is insufficient to predict inflammation and that carriage of a plasmid could contribute to disease.