Project description:The skin is the human body’s largest organ and is in contact with a diverse community of microorganisms that includes both resident and pathogenic bacteria. Skin immune defenses include the production of antimicrobial proteins that kill bacteria directly. However, we still have an incomplete understanding of how skin antimicrobial proteins promote homeostasis with resident bacterial communities and limit infection. Here, we show that resistin-like molecule α (RELMα) is an antibacterial protein that is produced by keratinocytes and sebocytes in the mouse skin. RELMα expression was induced in mouse skin by resident and pathogenic skin bacteria and was bactericidal for several bacterial species found on the skin, including Streptococcus pyogenes. Mice lacking RELMα had altered resident skin bacterial communities and were more susceptible to bacterial infection, indicating that RELMα controls bacterial colonization of the skin. RELMα expression required dietary vitamin A and could be induced by therapeutic retinoids that protected against bacterial infection in a RELMα-dependent manner. Resistin, another member of the RELM family, was expressed in human skin, required retinoids for expression, and killed skin bacteria, indicating a conserved function for RELM proteins in skin innate immunity. Our findings thus identify members of the RELM family as antibacterial proteins that provide vitamin A-dependent antimicrobial protection of the skin, and provide insight into why skin immunity requires adequate dietary vitamin A.
Project description:<p>Studies have emphasized the importance of disease-associated microorganisms in perturbed communities, however, the protective roles of commensals are largely under recognized and poorly understood. Using acne as a model disease, we investigated the determinants of the overall virulence property of the skin microbiota when disease- and health-associated organisms coexist in the community. By ultra-deep metagenomic shotgun sequencing, we revealed higher relative abundances of propionibacteria and Propionibacterium acnes phage in healthy skin. In acne patients, the microbiome composition at the species level and at P. acnes strain level was more diverse than in healthy individuals, with enriched virulence-associated factors and reduced abundance of metabolic synthesis genes. Based on the abundance profiles of the metagenomic elements, we constructed a quantitative prediction model, which classified the clinical states of the host skin with high accuracy in both our study cohort (85%) and an independent sample set (86%). Our results suggest that the balance between metagenomic elements, not the mere presence of disease-associated strains, shapes the overall virulence property of the skin microbiota. This study provides new insights into the microbial mechanism of acne pathogenesis and suggests probiotic and phage therapies as potential acne treatments to modulate the skin microbiota and to maintain skin health.</p>