期刊
ALLERGY
卷 76, 期 8, 页码 2510-2523出版社
WILEY
DOI: 10.1111/all.14762
关键词
atopic dermatitis; eczema herpeticum; genetics; herpes simplex virus; SIDT2; whole genome sequencing
资金
- National Institute of Allergy and Infectious Diseases [1U19AI117673-01, 1UM1AI151958]
- National Center for Advancing Translational Sciences [UL1 TR000154]
- National Center for Research Resources [UL1 RR025780]
This study identified damaging genetic variants associated with HSV infection in atopic dermatitis patients with a history of recurrent eczema herpeticum. Genes SIDT2 and RBBP8NL were found to play crucial roles in keratinocyte response to HSV-1 infection and regulation of keratinocyte differentiation.
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.
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