PMID- 27856764 OWN - NLM STAT- MEDLINE DCOM- 20180330 LR - 20181113 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 113 IP - 48 DP - 2016 Nov 29 TI - Role of nucleotide-binding oligomerization domain 1 (NOD1) and its variants in human cytomegalovirus control in vitro and in vivo. PG - E7818-E7827 AB - 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, given that IFN-beta KD reduced the inhibitory effect of Tri-DAP on HCMV. Signaling through NOD1 resulting in HCMV suppression was IKKalpha-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- IKKalpha-IRF3 and suggest that its polymorphisms predict the risk of infection. FAU - Fan, Yi-Hsin AU - Fan YH AD - Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287. FAU - Roy, Sujayita AU - Roy S AD - Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287. FAU - Mukhopadhyay, Rupkatha AU - Mukhopadhyay R AD - Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287. FAU - Kapoor, Arun AU - Kapoor A AD - Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287. FAU - Duggal, Priya AU - Duggal P AD - Department of Genetic Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21231. FAU - Wojcik, Genevieve L AU - Wojcik GL AD - Department of Genetic Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21231. FAU - Pass, Robert F AU - Pass RF AD - Division of Infectious Diseases, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294. FAU - Arav-Boger, Ravit AU - Arav-Boger R AD - Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287; boger@jhmi.edu. LA - eng GR - N01HV48195/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20161116 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (IRF3 protein, human) RN - 0 (Interferon Regulatory Factor-3) RN - 0 (NOD1 protein, human) RN - 0 (NOD2 protein, human) RN - 0 (Nod1 Signaling Adaptor Protein) RN - 0 (Nod2 Signaling Adaptor Protein) RN - 77238-31-4 (Interferon-beta) RN - EC 2.7.11.1 (RIPK2 protein, human) RN - EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinase 2) RN - EC 2.7.11.10 (I-kappa B Kinase) SB - IM MH - Animals MH - Cells, Cultured MH - Cytomegalovirus/*physiology MH - Cytomegalovirus Infections/genetics/*metabolism/virology MH - Female MH - Gene Expression MH - Genetic Association Studies MH - Genetic Predisposition to Disease MH - Humans MH - I-kappa B Kinase/metabolism MH - Interferon Regulatory Factor-3/metabolism MH - Interferon-beta/metabolism MH - Mice, Inbred BALB C MH - Nod1 Signaling Adaptor Protein/*physiology MH - Nod2 Signaling Adaptor Protein/physiology MH - Polymorphism, Single Nucleotide MH - Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism MH - Signal Transduction MH - Virus Replication PMC - PMC5137695 OTO - NOTNLM OT - NOD1 OT - RIPK2 OT - cytomegalovirus OT - innate immune response OT - polymorphisms COIS- 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. EDAT- 2016/11/20 06:00 MHDA- 2018/03/31 06:00 PMCR- 2017/05/29 CRDT- 2016/11/19 06:00 PHST- 2016/11/20 06:00 [pubmed] PHST- 2018/03/31 06:00 [medline] PHST- 2016/11/19 06:00 [entrez] PHST- 2017/05/29 00:00 [pmc-release] AID - 1611711113 [pii] AID - 201611711 [pii] AID - 10.1073/pnas.1611711113 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2016 Nov 29;113(48):E7818-E7827. doi: 10.1073/pnas.1611711113. Epub 2016 Nov 16.