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Role of nucleotide-binding oligomerization domain 1 (NOD1) and its variants in human cytomegalovirus control in vitro and in vivo.
Fan, Yi-Hsin; Roy, Sujayita; Mukhopadhyay, Rupkatha; Kapoor, Arun; Duggal, Priya; Wojcik, Genevieve L; Pass, Robert F; Arav-Boger, Ravit.
Afiliação
  • Fan YH; Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
  • Roy S; Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
  • Mukhopadhyay R; Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
  • Kapoor A; Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
  • Duggal P; Department of Genetic Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21231.
  • Wojcik GL; Department of Genetic Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21231.
  • Pass RF; Division of Infectious Diseases, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294.
  • Arav-Boger R; Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287; boger@jhmi.edu.
Proc Natl Acad Sci U S A ; 113(48): E7818-E7827, 2016 11 29.
Article em En | MEDLINE | ID: mdl-27856764
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-ß. 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-ß 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-ß, given that IFN-ß 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Infecções por Citomegalovirus / Citomegalovirus / Proteína Adaptadora de Sinalização NOD1 Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Infecções por Citomegalovirus / Citomegalovirus / Proteína Adaptadora de Sinalização NOD1 Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article