期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：48
页码：E7818-E7827
DOI：10.1073/pnas.1611711113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceInfection with human cytomegalovirus (HCMV) is a growing health problem, creating diagnostic and therapeutic challenges. Biomarkers for risk of infection are lacking, and the limited drugs that inhibit HCMV have major side effects. New strategies for virus control are needed. We report on the role of nucleotide-binding oligomerization domain 1 (NOD1), a cytoplasmic pattern recognition receptor, in HCMV suppression. NOD1 activation (through IKK and IRF3) resulted in IFN response and HCMV inhibition. Specific mutations in NOD1 showed differential effects on HCMV replication in vitro. In a nested study of HCMV vaccine, specific polymorphisms in NOD1 were detected in HCMV-infected women compared with noninfected women. Our work provides direction for studies of innate immune response to HCMV and genetic susceptibility through NOD1. Induction of nucleotide-binding oligomerization domain 2 (NOD2) and downstream receptor-interacting serine/threonine-protein kinase 2 (RIPK2) by human cytomegalovirus (HCMV) is known to up-regulate antiviral responses and suppress virus replication. We investigated the role of nucleotide-binding oligomerization domain 1 (NOD1), which also signals through RIPK2, in HCMV control. NOD1 activation by Tri-DAP (NOD1 agonist) suppressed HCMV and induced IFN-{beta}. Mouse CMV was also inhibited through NOD1 activation. NOD1 knockdown (KD) or inhibition of its activity with small molecule ML130 enhanced HCMV replication in vitro. NOD1 mutations displayed differential effects on HCMV replication and antiviral responses. In cells overexpressing the E56K mutation in the caspase activation and recruitment domain, virus replication was enhanced, but in cells overexpressing the E266K mutation in the nucleotide-binding domain or the wild-type NOD1, HCMV was inhibited, changes that correlated with IFN-{beta} expression. The interaction of NOD1 and RIPK2 determined the outcome of virus replication, as evidenced by enhanced virus growth in NOD1 E56K mutant cells (which failed to interact with RIPK2). NOD1 activities were executed through IFN-{beta
