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.
Highlights
Recognition of human Cytomegalovirus (HCMV) by the innate immune system can set the cell for an effective response and is counteracted by HCMV to allow for productive replication and generation of latency
Since induction of nucleotide binding oligomerization domain 2 (NOD2) by HCMV resulted in consequential virus inhibition[11], and since muramyl dipeptide (MDP) is known to bind to and activate NOD222, we investigated the effects of MDP on HCMV replication and the pathway through which MDP exerts anti-HCMV activities
We reported on NOD2 induction by HCMV which triggered an antiviral cytokine response and suppressed virus replication, it remains to be determined whether NOD2 acts as a true pattern recognition receptors (PRRs) for HCMV11,20
Summary
Recognition of HCMV by the innate immune system can set the cell for an effective response and is counteracted by HCMV to allow for productive replication and generation of latency. When added to infected cells after 48 h, MDP could still induce NOD2 and RIPK2 expression (Fig. 1F), HCMV replication (by protein expression and plaque reduction) was not inhibited, indicating virus replication took over signaling for its benefit. We investigated the effect of MDP on expression of NOD2 downstream signaling proteins in HCMV-infected cells at 36 hpi (Fig. 2E,F).
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