title: Role of nucleotide-binding oligomerization domain 1 (NOD1) and its variants in human cytomegalovirus control in vitro and in vivo.
abstract: 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-β. 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-β 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-β, given that IFN-β KD reduced the inhibitory effect of Tri-DAP on HCMV. Signaling through NOD1 resulting in HCMV suppression was IKKα-dependent and correlated with nuclear translocation and phosphorylation of IRF3. Finally, NOD1 polymorphisms were significantly associated with the risk of HCMV infection in women who were infected with HCMV during participation in a glycoprotein B vaccine trial. Collectively, our data indicate a role for NOD1 in HCMV control via RIPK2- IKKα-IRF3 and suggest that its polymorphisms predict the risk of infection.
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Fan
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
authors.forename: Sujayita
authors.initials: S
authors.lastname: Roy
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
authors.forename: Rupkatha
authors.initials: R
authors.lastname: Mukhopadhyay
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
authors.forename: Arun
authors.initials: A
authors.lastname: Kapoor
authors.affiliation: Department of Genetic Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21231.
authors.forename: Priya
authors.initials: P
authors.lastname: Duggal
authors.affiliation: Department of Genetic Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21231.
authors.forename: Genevieve L
authors.initials: GL
authors.lastname: Wojcik
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Pass
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287; boger@jhmi.edu.
authors.forename: Ravit
authors.initials: R
authors.lastname: Arav-Boger
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D008807:Mice, Inbred BALB C; D053474:Nod1 Signaling Adaptor Protein / Q000502:physiology*; D053473:Nod2 Signaling Adaptor Protein / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000378:metabolism; D015398:Signal Transduction; D014779:Virus Replication
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D016899:Interferon-beta; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D051550:I-kappa B Kinase
keywords: NOD1; RIPK2; cytomegalovirus; innate immune response; polymorphisms