Ankyrin repeat domain 1 regulates innate immune responses against herpes simplex virus 1: A potential role in eczema herpeticum

• Published in: Journal of allergy and clinical immunology Vol. 141; no. 6; pp. 2085 - 2093.e1
• Main Authors: Bin, Lianghua, Li, Xiaozhao, Richers, Brittany, Streib, Joanne E., Hu, Jack W., Taylor, Patricia, Leung, Donald Y.M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2018; Elsevier Limited
• Subjects: Acids; Adolescent; Adult; Aged; ankyrin repeat domain 1; Ankyrins; Antigen-presenting cells; Atopic dermatitis; Cells, Cultured; Child; Cytokines; Demographics; Dendritic cells; Dermatitis; Eczema; Eczema herpeticum; Female; Gene expression; Genes; Herpes simplex; Herpes simplex virus; Herpes viruses; Herpesvirus 1, Human - immunology; Human subjects; Humans; IFN-β1; IL-29; Immune response; Immunity, Innate - immunology; Immunoprecipitation; Infections; Innate immunity; interferon regulatory 3; Interferon regulatory factor; Interferon regulatory factor 3; Interferon regulatory factor 7; Interferon Regulatory Factor-3 - immunology; Kaposi Varicelliform Eruption - immunology; Laboratories; Leukocytes, Mononuclear; Lymphocytes B; Lymphocytes T; Male; Middle Aged; Monocytes; Muscle Proteins - immunology; Natural killer cells; nuclear factor κB1; Nuclear Proteins - immunology; Pattern recognition; Pattern recognition receptors; Polymerase chain reaction; Proteins; Repressor Proteins - immunology; Signal transduction; siRNA; Skin diseases; Studies; Transcription factors; Viral infections; Young Adult; atopic dermatitis; Poly I:C-LMW; Herpes simplex virus; eczema herpeticum; HPV; NF-κB; PRR; Poly dA:dT; innate immunity; IL-29; ADEH; ANKRD1; nuclear factor κB1; TLR; interferon regulatory 3; AD; MOI; qRT-PCR; HSV; siRNA; IFN-β1; NA; APC; HA; HCV; ankyrin repeat domain 1; IRF; NK
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2018.01.001

Atopic dermatitis (AD) is a common inflammatory skin disease. A subset of patients with AD are susceptible to disseminated herpes simplex virus (HSV) infection, a complication termed eczema herpeticum (ADEH+). The immune mechanisms causing ADEH+ remain elusive. Using RNA sequencing, we recently found that ankyrin repeat domain 1 (ANKRD1) was significantly induced in human PBMCs upon HSV-1 stimulation, and its induction in patients with ADEH+ was significantly reduced compared with that seen in AD patients without a history of eczema herpeticum (ADEH−). We sought to validate ANKRD1 gene expression in nonatopic (NA) subjects, patients with ADEH−, and patients with ADEH+ and to delineate the biological function of ANKRD1 and the signaling pathway or pathways involved. Purification of human PBMCs, monocytes, B cells, dendritic cells, T cells, and natural killer cells; RNA extraction and quantitative RT-PCR; small interfering RNA technique; co-immunoprecipitation; and Western blot assays were used. ANKRD1 expression was significantly reduced in PBMCs from patients with ADEH+ after HSV-1 stimulation compared with PBMCs from patients with ADEH−. We found that the induction of ANKRD1 by HSV-1 and multiple pattern recognition receptor agonists are mediated by inflammatory cytokines. Silencing ANKRD1 gene expression in antigen-presenting cells led to increased viral load and reduced IFNB1 and IL29 production. Using co-immunoprecipitation methods, we demonstrated that ANKRD1 formed protein complexes with interferon regulatory factor (IRF) 3 and IRF7, which are important transcription factors regulating signaling transduction of pattern recognition receptors. Overexpression of ANKRD1 enhanced the IRF3-mediated signaling pathways. ANKRD1 is involved in IRF3-mediated antiviral innate immune signaling pathways. Its reduced expression in patients with ADEH+ might contribute to the pathogenesis of ADEH+.