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Engineered skin microbiome-assisted delivery to the pilosebaceous unit

ABSTRACT: Microbes are fascinating molecular machines which can be equipped with synthetic genetic programs that allow them to produce therapeutic molecules targeted on demand upon disease sensing. Cutibacterium acnes engraftment capacity and its living habitat close to important pharmacological targets makes it an attractive chassis to create skin-delivered therapeutics. Here, we report the engineering of this bacterium, the most abundant commensal of the human skin, to produce and secrete the therapeutic molecule neutrophil gelatinase-associated lipocalin in vivo, known to modulate cutaneous sebum production.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Eduard Sabidó

LAB HEAD: Eduard Sabido

PROVIDER: PXD044802 | Pride | 2023-11-10

REPOSITORIES: Pride

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			Action	DRS
	2023LZ018_NAKN_001_01_45pto.raw	Raw
	2023LZ018_NAKN_001_human.msf	Msf
	2023LZ018_NAKN_001_human.pdResult	Other
	2023MW001_NAKN_001_01_45pto.raw	Raw
	2023MW001_NAKN_002_01_45pto.raw	Raw

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Molecular typing and functional profiling of acne-derived Cutibacterium acnes isolates reveal determinants of skin inflammation

Project description:Cutibacterium acnes (C. acnes) is a ubiquitous skin commensal bacterium that is generally well tolerated by the immune system. Different strain-types of C. acnes have been reported to be enriched on patients with acne. To understand if these strain-types contribute to skin inflammation, we generated a library of over 200 C. acnes isolates from skin swabs of healthy and acne subjects and assessed their strain-level identity and inflammatory potential. Phylotype II K-type strains were more frequent on healthy and acne non-lesional skin compared to lesional. Phylotype IA-1 C-type strains were dominant on acne lesional skin but absent from healthy. Measurement of host cytokine responses from C. acnes supernatant revealed neither strain-type nor skin-type association predicted inflammatory potential. However, differential proinflammatory responses were induced from identical strain-types, but these differences were not attributable to protease, short chain fatty acid or porphyrin production. Instead, whole genome sequencing revealed the presence of a linear plasmid in high inflammatory strain-types. Intradermal injection of C. acnes in mouse skin revealed a plasmid-associated inflammatory response in dermal fibroblasts, revealed by single-cell RNA sequencing. We conclude that C. acnes strain-type is not sufficient to predict inflammation but other virulence factors including a plasmid may contribute to disease.

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