Activation of nucleotide oligomerization domain 2 (NOD2) by human cytomegalovirus initiates innate immune responses and restricts virus replication. PLoS One 2014;9(3):e92704
Date
03/29/2014Pubmed ID
24671169Pubmed Central ID
PMC3966837DOI
10.1371/journal.pone.0092704Scopus ID
2-s2.0-84899922475 (requires institutional sign-in at Scopus site) 46 CitationsAbstract
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.
Author List
Kapoor A, Forman M, Arav-Boger RAuthor
Ravit Boger MD Chief, Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Cell LineCytokines
Cytomegalovirus
Cytomegalovirus Infections
Fibroblasts
Gene Knockdown Techniques
Herpesviridae
Humans
Immunity, Innate
Inflammation Mediators
Interferons
Kinetics
Male
Mutant Proteins
NF-kappa B
Nod2 Signaling Adaptor Protein
RNA, Messenger
Ultraviolet Rays
Viral Envelope Proteins
Virus Inactivation
Virus Replication
