Abstract
Nucleotide-binding oligomerization domain 2 (NOD2) is an important innate immune sensor of bacterial pathogens. Its induction results in activation of the classic NF-κB pathway and alternative pathways including type I IFN and autophagy. Although the importance of NOD2 in recognizing RNA viruses has recently been identified, its role in sensing DNA viruses has not been studied. We report that infection with human cytomegalovirus (HCMV) results in significant induction of NOD2 expression, beginning as early as 2 hours post infection and increasing steadily 24 hours post infection and afterwards. Infection with human herpesvirus 1 and 2 does not induce NOD2 expression. While the HCMV-encoded glycoprotein B is not required for NOD2 induction, a replication competent virion is necessary. Lentivirus-based NOD2 knockdown in human foreskin fibroblasts (HFFs) and U373 glioma cells leads to enhanced HCMV replication along with decreased levels of interferon beta (IFN-β) and the pro-inflammatory cytokine, IL8. NOD2 induction in HCMV-infected cells activates downstream NF-κB and interferon pathways supported by reduced nuclear localization of NF-κB and pIRF3 in NOD2 knockdown HFFs. Stable overexpression of NOD2 in HFFs restricts HCMV replication in association with increased levels of IFN-β and IL8. Similarly, transient overexpression of NOD2 in U373 cells or its downstream kinase, RIPK2, results in decreased HCMV replication and enhanced cytokine responses. However, overexpression of a mutant NOD2, 3020insC, associated with severe Crohn's disease, results in enhanced HCMV replication and decreased levels of IFN-β in U373 cells. These results show for the first time that NOD2 plays a significant role in HCMV replication and may provide a model for studies of HCMV recognition by the host cell and HCMV colitis in Crohn's disease.
Highlights
Infection with human CMV (HCMV), a member of the herpesvirus family, is common in humans
HCMV infection results in significant induction of Nucleotide-binding oligomerization domain 2 (NOD2) expression mRNA levels of NOD1 and NOD2 were measured by qRTPCR in HCMV-infected human foreskin fibroblasts (HFFs)
In contrast to NOD2, NOD1 was already expressed in non-infected HFFs, and there was a modest increase (,3–7 fold) in NOD1 transcripts at 12 and 72 hpi (Fig. 1A–E), depending on the HCMV strain and cell type used
Summary
Infection with human CMV (HCMV), a member of the herpesvirus family, is common in humans. While infection in the normal host is usually asymptomatic, HCMV is a major pathogen in immunocompromised patients and the congenitally-infected newborns [2,3,4]. In these cohorts infection can be severe, persistent, recurrent, or resistant to anti-viral therapy. Despite being a very common pathogen, around 10–15% of individuals remain HCMV negative for life. HCMV seronegativity may reflect lack of exposure to the virus; alternatively, host genetics may contribute to susceptibility to HCMV infection. Host genetics can influence susceptibility to human infection and cytokine production by the innate immune system [5,6,7,8]
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