Back to Search
Start Over
Role of nucleotide-binding oligomerization domain 1 (NOD1) and its variants in human cytomegalovirus control in vitro and in vivo.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2016 Nov 29; Vol. 113 (48), pp. E7818-E7827. Date of Electronic Publication: 2016 Nov 16. - Publication Year :
- 2016
-
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.<br />Competing Interests: Two US applications are currently pending in connection with this paper: US application 15/026,863, Compositions and Methods for Prediction and Treatment of Human Cytomegalovirus Infections, and US Application 15/215,711, Vaccine Adjuvants for Cytomegalovirus Prevention and Treatment.
- Subjects :
- Animals
Cells, Cultured
Cytomegalovirus Infections genetics
Cytomegalovirus Infections virology
Female
Gene Expression
Genetic Association Studies
Genetic Predisposition to Disease
Humans
I-kappa B Kinase metabolism
Interferon Regulatory Factor-3 metabolism
Interferon-beta metabolism
Mice, Inbred BALB C
Nod2 Signaling Adaptor Protein physiology
Polymorphism, Single Nucleotide
Receptor-Interacting Protein Serine-Threonine Kinase 2 metabolism
Signal Transduction
Virus Replication
Cytomegalovirus physiology
Cytomegalovirus Infections metabolism
Nod1 Signaling Adaptor Protein physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 113
- Issue :
- 48
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 27856764
- Full Text :
- https://doi.org/10.1073/pnas.1611711113