The skin harbors a diverse population of microbiota with important functions in cutaneous health and disease. The role of host-microbe interactions is well appreciated in multiple skin disorders. However, very little is known regarding host modulation of skin microbiota, and microbial regulation of host cutaneous immunity. We have previously shown that disrupting complement signaling alters the diversity and composition of skin microbiota in parallel with changing the cutaneous inflammatory milieu. Further, our RNA-seq studies indicate that genes related to complement signaling and activation are upregulated in conventionally raised mouse skin as compared to germ free mouse skin, suggesting that the commensal microbiota regulate their expression. Our overarching hypothesis is that there is a mechanistic link between the skin microbiota and complement. We posit that the skin microbiota are shaped and maintained by complement, and conversely, that the commensal microbiota modulate complement at the gene expression level. To test our hypothesis we propose the following aims: 1) Determine how commensals and pathogens differentially induce complement gene expression in skin. We will also determine if commensal microbiota reconstitution can tune complement gene expression and improve infection outcome in a model of skin and soft tissue infection. 2) Establish the complement effector pathways that impact cutaneous microbial composition, diversity, and quantity. Following up on preliminary data indicating that complement deficiency accelerates excisional wound healing in mouse models in parallel with shifting the colonizing microbiota, we will test the necessity and the sufficiency of the microbiot in this phenotype. Completion of the proposed studies will fill a gap in our fundamental knowledge of skin-microbe interactions, the functional consequences of disrupting these interactions, while facilitating future research questions regarding the role of skin microbiota in disease, wound healing, and infection.

Public Health Relevance

The skin, our interface to the outside world, is colonized by a diversity of microbiota that have important functions in skin health and disease. The goal of this project is to examine the interactions of complement, an arm of innate immunity, with the skin microbiota. The proposed research will advance our understanding of skin host-microbe interactions and provide a foundation for novel preventative and therapeutic approaches in skin disorders, wound healing, and infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR066663-01A1
Application #
8882659
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Dermatology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Loesche, Michael; Gardner, Sue E; Kalan, Lindsay et al. (2017) Temporal Stability in Chronic Wound Microbiota Is Associated With Poor Healing. J Invest Dermatol 137:237-244
SanMiguel, Adam J; Meisel, Jacquelyn S; Horwinski, Joseph et al. (2017) Topical Antimicrobial Treatments Can Elicit Shifts to Resident Skin Bacterial Communities and Reduce Colonization by Staphylococcus aureus Competitors. Antimicrob Agents Chemother 61:
Meisel, Jacquelyn S; Hannigan, Geoffrey D; Tyldsley, Amanda S et al. (2016) Skin Microbiome Surveys Are Strongly Influenced by Experimental Design. J Invest Dermatol 136:947-56
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Kalan, Lindsay; Loesche, Michael; Hodkinson, Brendan P et al. (2016) Redefining the Chronic-Wound Microbiome: Fungal Communities Are Prevalent, Dynamic, and Associated with Delayed Healing. MBio 7:
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