Th17 extracellular trap-mediated antimicrobial host defense in acne vulgaris

PROJECT SUMMARY
Acne vulgaris, or acne, is a disease of the pilosebaceous unit (PSU). Acne is ranked third among
chronic skin diseases for causing disability and medical expense and is a major cause of psychological stress
in young people. One factor contributing to acne is Cutibacterium acnes, the major bacterial species in the
PSU. Using C. acnes as a model to study the interaction between the microbiome and the host immune
response, we: 1) previously demonstrated the presence of IL-17 in acne skin lesions and 2) recently
discovered that C. acnes phylotypes associated with acne (CA) or healthy skin (CH) differentially regulate the
fate of TH17 cells to develop into non-antimicrobial (n-AMTH17) and antimicrobial (AMTH17) subsets. AMTH17 cells
release T cell extracellular traps (TETs) and directly kill C. acnes and other bacteria pathogens.
To date, the mechanisms by which C. acnes phylotypes induce TETs and their biological impact in
acne are unknown. Therefore, our proposed research is innovative because we will define the immune
landscape of the acne lesions, provide mechanistic insights into the biological impact of TH17-TET formation in
acne, and identify novel immune pathways and potential biomarkers that can be targeted for acne therapy.
This is important as future strategies could be developed to modulate TH17 function. Additionally, maintaining
the balance among the different phylotypes of C. acnes may represent a strategy for novel probiotic design.
The identification of C. acnes ligands will further elucidate the specificity of host receptors involved in microbial
surveillance and lead to the development of novel therapeutic approaches
skin diseases caused by dysbiosis.
to control acne and other human
Our central hypothesis is that innate activation of TH17 cells leads to induction of antimicrobial
mechanisms, including TETs, which contribute to host defense against C. acnes and other bacteria. To
elucidate this, we will determine the antimicrobial mechanisms of AMTH17 cells against C. acnes (Aim 1),
investigate the role of AMTH17 cells in acne inflammation (Aim 2), and identify the C. acnes ligands that induce
AMTH17 differentiation (Aim 3). Our preliminary findings support the premise that healthy skin commensals are
critical to the education of our immune system and our overall defense against pathogens. Our strategy will
include: classical immunological techniques involving T cell cloning to dissect the immune effector functions
that underlie TH17-mediated antimicrobial host defense; microbiome sequencing of C. acnes phylotypes that
inhabit donor biopsies to define how interactions within the skin microbiome and the host immune response
influences acne development; high-resolution time-lapse imaging to define mechanisms of TET release and
chromatin dynamics that occur during TET formation; scanning electron microscopy to delimit extracellular trap
formation in human T cells; and state-of-the-art single cell RNA-seq experiments to compute T cell gene
signatures and to define the T cell types and immune circuits present in acne lesions. Additional state-of-the-
art methodologies include the use of high affinity capture of cellular interactomes, coupled with mass
spectrometry-based proteomics, lipidomics and carbohydrate HPAEC-PAD analysis to identify C. acnes
ligands and endogenous complexes. This contribution is significant as, our studies will make significant
conceptual advances in our understanding of T cell–antimicrobial defense mechanisms, and allow major
advances in the understanding of the immune networks in acne that can be targeted for therapy

Grant Number: 5R01AR081337-04
NIH Institute/Center: NIH
Principal Investigator: George Agak