title: Bacterial Muramyl Dipeptide (MDP) Restricts Human Cytomegalovirus Replication via an IFN-β-Dependent Pathway.
abstract: We recently reported that induction of NOD2 by human Cytomegalovirus (HCMV) resulted in virus inhibition and upregulation of antiviral and inflammatory cytokines. Here we investigated the effects of muramyl dipeptide (MDP), a bacterial cell wall component that activates NOD2, on HCMV replication and antiviral responses. HCMV infection of human foreskin fibroblasts induced NOD2, the downstream receptor-interacting serine/threonine-protein kinase 2 (RIPK2), resulting in phosphorylation of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3). MDP treatment following infection at low multiplicity (MOI = 0.1 PFU/cell) inhibited HCMV in a dose-dependent manner and further induced phosphorylation of TBK1, IRF3 and expression of IFN-β. None of these effects of MDP were observed following infection at multiplicity of 1. In infected NOD2 knocked-down cells MDP did not induce IFN-β, irrespective of MOI. Treatment with MDP before infection also inhibited HCMV, an effect augmented with treatment duration. Treatment with an IFN-β receptor blocking antibody or knockdown of IFN-β significantly attenuated the inhibitory effect of MDP on HCMV. MDP treatment before or after infection with herpesvirus 1 did not inhibit its replication. Summarized, NOD2 activation exerts anti-HCMV activities predominantly via IFN-β. Since MDP is a bacterial cell wall component, ongoing microbial exposure may influence HCMV replication.
authors.affiliation: Department of Pediatrics, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Kapoor
authors.affiliation: Department of Pediatrics, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Fan
authors.affiliation: Department of Pediatrics, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Ravit
authors.initials: R
authors.lastname: Arav-Boger
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003587:Cytomegalovirus / Q000187:drug effects*; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology*; D005347:Fibroblasts; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D016207:Cytokines; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D016899:Interferon-beta; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human
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