The Type I Interferon System and Its Effects on CMV Replication Induction of IFN

Interferons (IFNs) are powerful antimicrobial cytokines that induce the expression of numerous IFN-stimulated genes (ISGs). The actual antiviral effects are conferred by ISG products that target different stages of virus replication (Samuel 2001). CMV replication is susceptible to the effects of ISGs and IFN-induced cellular states in vitro (Gribaudo et al. 1993; Torigoe et al. 1993; Chin and Cresswell 2001; Sainz et al. 2005; DeFilippis et al. 2006) and in vivo for murine CMV (MCMV) (Yeow et al. 1998; Cull et al. 2002; Salazar-Mather et al. 2002).

IFN-dependent ISG transcription is induced by signal transduction triggered by IFNa or ß binding to the type I IFN receptor, resulting in phosphorylation of tyrosine kinase 2 (Tyk2) and Janus kinase 1 (JAK1) that subsequently phosphorylate STAT (signal transducers and activators of transcription) 2 (Fig. 1). STAT2 phosphorylation leads to its heterodimerization with STAT1, association with IFN regulatory factor 9 (IRF9), and nuclear accumulation of the complex (termed IFN-stimulated gene factor 3; ISGF3). ISGF3 binds to IFN-stimulated response elements (ISREs) contained in the promoters of numerous ISGs, resulting in their transcriptional upregulation (Shuai and Liu 2003).

Induction of IFNß itself (reviewed in Hiscott et al. 2003) occurs following stimulation of pattern recognition receptors (PRRs) and involves signaling separate from the JAK/STAT pathway. PRRs detect molecular components of pathogens such as LPS and double-stranded RNA (dsRNA). The best-studied PRRs, Toll-like receptors (TLRs), are expressed predominantly in immune surveillance cells such as DCs and macrophages (Martin and Wesche 2002; Kawai and Akira 2006). TLR activation triggers secretion of inflammatory cytokines and expression of co-stimulatory molecules that activate innate and adaptive immune responses (Takeuchi and Akira 2001). A separate class of cytoplasmic PRRs detects virus-specific molecules and is also capable of inducing IFNß (Kato et al. 2005). These include retinoic acid inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5) (Andrejeva et al. 2004; Yoneyama et al. 2004), which react to dsRNA (Gitlin et al. 2006; Kato et al.

2006). The recently identified receptor DAI also recognizes dsDNA (Takaoka et al.

2007). Two ubiquitous transcription factors, IFN regulatory factor 3 (IRF3) and nuclear factor kappa B (NFkB), are terminal in the PRR-triggered signaling cascades and are both required for transcription of the IFNß gene. Both reside in the cytoplasm but accumulate in the nucleus upon activation, where they bind to the IFNß promoter. IRF3 also induces a subset of ISGs (Wathelet et al. 1998; Hiscott et al. 2003).

Fig. 1 Induction of IFNp and ISG expression by CMV. Virus entry triggers the activation of NFkB and IRF3 by way of TLRs (NFkB) and an unknown pattern recognition receptor (IRF3). Following association with other proteins these transcription factors accumulate in the nucleus and bind to promoter elements upstream of IFNp and specific ISGs, thereby stimulating their expression. HCMV IE2 is known to block binding of NFkB to DNA, while RhCMV has been shown to block IRF3 activation via and unknown mechanism. Expression and secretion of IFNp further induces expression of ISGs by binding to the IFN receptor, which leads to dimerization of the receptor subunits 1 and 2, resulting in phosphorylation of tyrosine kinase 2 (Tyk2) and Janus kinase 1 (JAK). Tyk2 and JAK phosphorylate signal transducer and activator of transcription (STAT) 2. STAT2 phosphorylation leads to its heterodimerization with STAT1 followed by nuclear accumulation and association with IFN regulatory factor 9 (IRF9). This complex (termed IFN-stimulated gene factor 3; ISGF3) binds to IFN stimulated response elements (ISREs) upstream of numerous ISGs. Both the MCMV M27 protein and HCMV IE1 protein have been shown to impair DNA binding of this complex

Fig. 1 Induction of IFNp and ISG expression by CMV. Virus entry triggers the activation of NFkB and IRF3 by way of TLRs (NFkB) and an unknown pattern recognition receptor (IRF3). Following association with other proteins these transcription factors accumulate in the nucleus and bind to promoter elements upstream of IFNp and specific ISGs, thereby stimulating their expression. HCMV IE2 is known to block binding of NFkB to DNA, while RhCMV has been shown to block IRF3 activation via and unknown mechanism. Expression and secretion of IFNp further induces expression of ISGs by binding to the IFN receptor, which leads to dimerization of the receptor subunits 1 and 2, resulting in phosphorylation of tyrosine kinase 2 (Tyk2) and Janus kinase 1 (JAK). Tyk2 and JAK phosphorylate signal transducer and activator of transcription (STAT) 2. STAT2 phosphorylation leads to its heterodimerization with STAT1 followed by nuclear accumulation and association with IFN regulatory factor 9 (IRF9). This complex (termed IFN-stimulated gene factor 3; ISGF3) binds to IFN stimulated response elements (ISREs) upstream of numerous ISGs. Both the MCMV M27 protein and HCMV IE1 protein have been shown to impair DNA binding of this complex

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