BACKGROUND: Eczema herpeticum (EH) is a rare complication of atopic dermatitis (AD) caused by disseminated herpes simplex virus (HSV) infection. The role of rare and/or deleterious genetic variants in disease etiology is largely unknown. This study aimed to identify genes that harbor damaging genetic variants associated with HSV infection in AD with a history of recurrent eczema herpeticum (ADEH+). METHODS: Whole genome sequencing (WGS) was performed on 49 recurrent ADEH+ (≥3 EH episodes), 491 AD without a history of eczema herpeticum (ADEH-) and 237 non-atopic control (NA) subjects. Variants were annotated, and a gene-based approach (SKAT-O) was used to identify genes harboring damaging genetic variants associated with ADEH+. Genes identified through WGS were studied for effects on HSV responses and keratinocyte differentiation. RESULTS: Eight genes were identified in the comparison of recurrent ADEH+to ADEH-and NA subjects: SIDT2, CLEC7A, GSTZ1, TPSG1, SP110, RBBP8NL, TRIM15, and FRMD3. Silencing SIDT2 and RBBP8NL in normal human primary keratinocytes (NHPKs) led to significantly increased HSV-1 replication. SIDT2-silenced NHPKs had decreased gene expression of IFNk and IL1b in response to HSV-1 infection. RBBP8NL-silenced NHPKs had decreased gene expression of IFNk, but increased IL1b. Additionally, silencing SIDT2 and RBBP8NL also inhibited gene expression of keratinocyte differentiation markers keratin 10 (KRT10) and loricrin (LOR). CONCLUSION: SIDT2 and RBBP8NL participate in keratinocyte's response to HSV-1 infection. SIDT2 and RBBP8NL also regulate expression of keratinocyte differentiation genes of KRT10 and LOR.
BACKGROUND: Eczema herpeticum (EH) is a rare complication of atopic dermatitis (AD) caused by disseminated herpes simplex virus (HSV) infection. The role of rare and/or deleterious genetic variants in disease etiology is largely unknown. This study aimed to identify genes that harbor damaging genetic variants associated with HSV infection in AD with a history of recurrent eczema herpeticum (ADEH+). METHODS: Whole genome sequencing (WGS) was performed on 49 recurrent ADEH+ (≥3 EH episodes), 491 AD without a history of eczema herpeticum (ADEH-) and 237 non-atopic control (NA) subjects. Variants were annotated, and a gene-based approach (SKAT-O) was used to identify genes harboring damaging genetic variants associated with ADEH+. Genes identified through WGS were studied for effects on HSV responses and keratinocyte differentiation. RESULTS: Eight genes were identified in the comparison of recurrent ADEH+to ADEH-and NA subjects: SIDT2, CLEC7A, GSTZ1, TPSG1, SP110, RBBP8NL, TRIM15, and FRMD3. Silencing SIDT2 and RBBP8NL in normal human primary keratinocytes (NHPKs) led to significantly increased HSV-1 replication. SIDT2-silenced NHPKs had decreased gene expression of IFNk and IL1b in response to HSV-1 infection. RBBP8NL-silenced NHPKs had decreased gene expression of IFNk, but increased IL1b. Additionally, silencing SIDT2 and RBBP8NL also inhibited gene expression of keratinocyte differentiation markers keratin 10 (KRT10) and loricrin (LOR). CONCLUSION: SIDT2 and RBBP8NL participate in keratinocyte's response to HSV-1 infection. SIDT2 and RBBP8NL also regulate expression of keratinocyte differentiation genes of KRT10 and LOR.
Authors: Anna De Benedetto; Mark K Slifka; Nicholas M Rafaels; I-Hsin Kuo; Steve N Georas; Mark Boguniewicz; Tissa Hata; Lynda C Schneider; Jon M Hanifin; Richard L Gallo; David C Johnson; Kathleen C Barnes; Donald Y M Leung; Lisa A Beck Journal: J Allergy Clin Immunol Date: 2011-04-13 Impact factor: 10.793
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Authors: Anna V Mikhaylova; Caitlin P McHugh; Linda M Polfus; Laura M Raffield; Meher Preethi Boorgula; Thomas W Blackwell; Jennifer A Brody; Jai Broome; Nathalie Chami; Ming-Huei Chen; Matthew P Conomos; Corey Cox; Joanne E Curran; Michelle Daya; Lynette Ekunwe; David C Glahn; Nancy Heard-Costa; Heather M Highland; Brian D Hobbs; Yann Ilboudo; Deepti Jain; Leslie A Lange; Tyne W Miller-Fleming; Nancy Min; Jee-Young Moon; Michael H Preuss; Jonathon Rosen; Kathleen Ryan; Albert V Smith; Quan Sun; Praveen Surendran; Paul S de Vries; Klaudia Walter; Zhe Wang; Marsha Wheeler; Lisa R Yanek; Xue Zhong; Goncalo R Abecasis; Laura Almasy; Kathleen C Barnes; Terri H Beaty; Lewis C Becker; John Blangero; Eric Boerwinkle; Adam S Butterworth; Sameer Chavan; Michael H Cho; Hélène Choquet; Adolfo Correa; Nancy Cox; Dawn L DeMeo; Nauder Faraday; Myriam Fornage; Robert E Gerszten; Lifang Hou; Andrew D Johnson; Eric Jorgenson; Robert Kaplan; Charles Kooperberg; Kousik Kundu; Cecelia A Laurie; Guillaume Lettre; Joshua P Lewis; Bingshan Li; Yun Li; Donald M Lloyd-Jones; Ruth J F Loos; Ani Manichaikul; Deborah A Meyers; Braxton D Mitchell; Alanna C Morrison; Debby Ngo; Deborah A Nickerson; Suraj Nongmaithem; Kari E North; Jeffrey R O'Connell; Victor E Ortega; Nathan Pankratz; James A Perry; Bruce M Psaty; Stephen S Rich; Nicole Soranzo; Jerome I Rotter; Edwin K Silverman; Nicholas L Smith; Hua Tang; Russell P Tracy; Timothy A Thornton; Ramachandran S Vasan; Joe Zein; Rasika A Mathias; Alexander P Reiner; Paul L Auer Journal: Am J Hum Genet Date: 2021-09-27 Impact factor: 11.043