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

Background: 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 (ADEH1). The immune mechanisms causing ADEH1 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 ADEH1 was significantly reduced compared with that seen in AD patients without a history of eczema herpeticum (ADEH2). Objective: We sought to validate ANKRD1 gene expression in nonatopic (NA) subjects, patients with ADEH2, and patients with ADEH1 and to delineate the biological function of ANKRD1 and the signaling pathway or pathways involved. Methods: 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; coimmunoprecipitation; and Western blot assays were used. Results: ANKRD1 expression was significantly reduced in PBMCs from patients with ADEH1 after HSV-1 stimulation compared with PBMCs from patients with ADEH2. 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 antigenpresenting 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. Conclusion: ANKRD1 is involved in IRF3-mediated antiviral innate immune signaling pathways. Its reduced expression in patients with ADEH1 might contribute to the pathogenesis of ADEH1.