A small subgroup of atopic dermatitis (AD) patients, suffer from life-threatening disseminated herpes simplex virus (HSV) skin infections, termed eczema herpeticum (ADEH+). The manifestation of ADEH+ is not simply a consequence of HSV-1 infection, as latent infection of both the AD and general population is near universal (90%). Most importantly, there is a remarkable bimodality in the `recurrence' of EH episodes; most individuals have only a single episode, but a subgroup of ADEH+ have more than five (5+) lifetime episodes. Based on this, we hypothesize recurrent ADEH+ is characterized by unique: (1) genetic profiles, (2) dysregulated skin tissue transcriptional signatures, and (3) skin cell responses to HSV-1 infection, which collectively underlie ADEH+ disease development. We suggest these profiles, signatures, and responses will be most pronounced among AD patients with 5+ EH episodes as they represent the extreme of AD severity. Therefore we propose an extreme trait study, investigating recurrent ADEH+ (5+ episodes) vs. ADEH-, using genetic, transcriptomic, and cellular function analyses.
The specific aims will be: 1) To use whole genome sequencing (WGS) to identify rare deleterious genetic variants that determine recurrent ADEH+. Deep WGS data will be generated on 50 ADEH+ subjects with >5 EH episodes. We will leverage the ADRN DNA repository and expertise on WGS data from 500 ADEH- individuals through our ongoing ADRN protocol on S. aureus colonization as a control group; 2) To identify differences in the transcriptional signatures of recurrent ADEH+ vs. ADEH- in disease-relevant tissue and cells under baseline and HSV-1 stimulated conditions. We will isolate dermal and epidermal tissue from uninvolved skin biopsies of recurrent ADEH+ versus ADEH- subjects. We will also isolate plasmacytoid dendritic cells from the peripheral blood of these subjects. Paired tissues and cells from these subjects will be sham- and HSV-1-infected. Whole transcriptome RNA-sequencing (RNA-seq) will be performed on these samples. We will determine tissue/cell specific genes regulated by HSV-1 infection and whether this regulation differs by ADEH status. Differential and allele-specific expression data will be used to filter Aim 1 risk variants; 3) Compare primary cell responses to HSV-1 infection between recurrent ADEH+ vs. ADEH- and determine biological function of risk genes and genetic variants identified from WGS and RNA-seq analyses. We will culture skin primary keratinocytes and fibroblasts from the same subjects examined in Aims 1 and 2. Part 1: Paired sham and HSV-1 infected cultures will be analyzed to determine differences in the infection rates and anti-viral, inflammatory, and differentiation responses between ADEH+ and ADEH- subjects. Part 2: We will functionally characterize the effect of genes and genetic risk variants (identified in Aims 1 and 2) on these cellular HSV-1 responses by a suite of genetic modification techniques applied to these primary cells, including CRISPR/Cas9 mediated gene-editing. Our novel, integrated, multi-disciplinary extreme trait design will allow a powerful examination of the etiology of ADEH+.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI117673-05
Application #
9688054
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Minnicozzi, Michael
Project Start
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
Li, Jin; Zheng, Le; Uchiyama, Akihiko et al. (2018) A data mining paradigm for identifying key factors in biological processes using gene expression data. Sci Rep 8:9083
Malhotra, Nidhi; Leyva-Castillo, Juan Manuel; Jadhav, Unmesh et al. (2018) ROR?-expressing T regulatory cells restrain allergic skin inflammation. Sci Immunol 3:
Bin, Lianghua; Li, Xiaozhao; Richers, Brittany et al. (2018) Ankyrin repeat domain 1 regulates innate immune responses against herpes simplex virus 1: A potential role in eczema herpeticum. J Allergy Clin Immunol 141:2085-2093.e1
Dyjack, Nathan; Goleva, Elena; Rios, Cydney et al. (2018) Minimally invasive skin tape strip RNA sequencing identifies novel characteristics of the type 2-high atopic dermatitis disease endotype. J Allergy Clin Immunol 141:1298-1309
Archer, Nathan K; Jo, Jay-Hyun; Lee, Steven K et al. (2018) Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through keratinocyte IL-1? release. J Allergy Clin Immunol :
Leyva-Castillo, Juan Manuel; Yoon, Juhan; Geha, Raif S (2018) IL-22 promotes allergic airway inflammation in epicutaneously sensitized mice. J Allergy Clin Immunol :
Nakatsuji, Teruaki; Chen, Tiffany H; Butcher, Anna M et al. (2018) A commensal strain of Staphylococcus epidermidis protects against skin neoplasia. Sci Adv 4:eaao4502
Simpson, Eric L; Villarreal, Miguel; Jepson, Brett et al. (2018) Patients with Atopic Dermatitis Colonized with Staphylococcus aureus Have a Distinct Phenotype and Endotype. J Invest Dermatol 138:2224-2233
O'Neill, Alan M; Gallo, Richard L (2018) Host-microbiome interactions and recent progress into understanding the biology of acne vulgaris. Microbiome 6:177
Berdyshev, Evgeny; Goleva, Elena; Bronova, Irina et al. (2018) Lipid abnormalities in atopic skin are driven by type 2 cytokines. JCI Insight 3:

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