Human Cytomegalovirus Elicits a Coordinated Cellular Antiviral Response via Envelope Glycoprotein B

Boehme, Karl W.; Singh, Jasbir; Perry, Stuart T.; Compton, Teresa

doi:10.1128/jvi.78.3.1202-1211.2004

Cited by 103 publications

(112 citation statements)

References 52 publications

(77 reference statements)

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“…In contrast to paramyxoviruses and retroviruses, CMV is extremely structurally complex, displaying at least 12 envelope glycoproteins. Soluble forms of envelope glycoprotein B (gB) activate NF-B (80) and IRF3, induce IFN-␤ secretion, and render an antiviral state in cells (11,12,16,71). More recently, we have found that soluble gB also induces inflammatory cytokine secretion in a TLR2-dependent manner.…”

Section: Molecular Basis Of Tlr Activationmentioning

confidence: 82%

Innate Sensing of Viruses by Toll-Like Receptors

Boehme

Compton

2004

J Virol

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199

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Section: Molecular Basis Of Tlr Activationmentioning

confidence: 82%

Innate Sensing of Viruses by Toll-Like Receptors

Boehme

Compton

2004

J Virol

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234

199

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“…HCMV and a soluble version of gB are able to activate IRF3 and the transcription of ISGs (32)(33)(34). Recent evidence using several strategies to deplete cellular IRF3 confirms its requirement and proposes that IRF3 is the primary transcription factor mediating HCMV-induced IFN signaling (35).…”

mentioning

confidence: 96%

Differential Initiation of Innate Immune Responses Induced by Human Cytomegalovirus Entry into Fibroblast Cells

Juckem

Boehme

Feire

et al. 2008

The Journal of Immunology

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Infection of permissive fibroblasts with human CMV (HCMV, AD169) is accompanied by a robust activation of innate immune defense. In this study, we show that inflammatory cytokine (IC) secretion and activation of the type I IFN pathway (αβ IFN) are initiated through distinct mechanisms. HCMV is recognized by TLR2 leading to the NF-κB activation and IC secretion. However, the IFN response to HCMV is not a TLR2-dependent process, as a dominant negative TLR2 does not affect the antiviral response to infection. Additionally, bafilomycin, an endosomal acidification inhibitor, has no effect on HCMV-induced IFN responses suggesting that IFN signaling is independent of endosomal resident TLRs. By contrast, disruption of lipid rafts by depletion of cellular cholesterol inhibits both HCMV entry as well as IFN responses. Cholesterol depletion had no effect on the induction of ICs by HCMV, illustrating a biological distinction at the cellular level with the initiation of innate immune pathways. Furthermore, HCMV entry inhibitors block IFN responses but not IC signaling. In particular, blocking the interaction of HCMV with β1 integrin diminished IFN signaling, suggesting that this virus-cell interaction or subsequent downstream steps in the entry pathway are critical for downstream signal transduction events. These data show that HCMV entry and IFN signaling are coordinated processes that require cholesterol-rich microdomains, whereas IC signaling is activated through outright sensing via TLR2. These findings further highlight the complexity and sophistication of innate immune responses at the earliest points in HCMV infection.

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“…The recently identified cytosolic DNA sensor DAI (Takaoka et al, 2007) could be involved in the TLRindependent recognition of MCMV. For HCMV, several components including gB and gH (Yurochko et al, 1995(Yurochko et al, , 1997, the TNF-receptor homologue UL144 (Poole et al, 2006) and virion-associated activated casein kinase (Nogalski et al, 2007) were reported to induce an extended activation of NF-kB and IRF3 (Yurochko et al, 1997;Boehme et al, 2004). HCMV stimulates NF-kB activity binding to HCMV promoter elements (Sambucetti et al, 1989;Sun et al, 2001), and complete repression of NF-kB signalling was found only in the late phase of HCMV replication (Jarvis et al, 2006).…”

Section: Infection Activates Ifn-a/b Inducing Signalling Pathwaysmentioning

confidence: 99%

Mouse cytomegalovirus inhibits beta interferon (IFN-β) gene expression and controls activation pathways of the IFN-β enhanceosome

Trilling

Zimmermann

et al. 2008

Journal of General Virology

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We have investigated beta interferon (IFN-b) and IFN-a4 gene expression and activation of related transcription factors in mouse cytomegalovirus (MCMV)-infected fibroblasts. mRNA analysis demonstrated an initial phase of IFN gene induction upon MCMV infection, which was followed by a sustained MCMV-mediated simultaneous downregulation of IFN-b and IFN-a4 gene expression. The induction of IFN transcription resulted from the activation of the components of the IFN-b enhanceosome, i.e. IFN regulatory factor (IRF) 3, nuclear factor (NF)-kB, activating transcription factor (ATF)-2 and c-Jun. Activation of the transcription factors occurred rapidly and in a sequential order upon infection, but only lasted a while. As a consequence, IFN-a/b gene expression became undetectable 6 h post-infection and throughout the MCMV replication cycle. This effect is based on an active interference since restimulation of IFN gene induction by further external stimuli (e.g. Sendai virus infection) was completely abolished. This inhibition required MCMV gene expression and was not observed in cells infected with UV-inactivated MCMV virions. The efficiency of inhibition is achieved by a concerted blockade of IkBa degradation and a lack of nuclear accumulation of IRF3 and ATF-2/c-Jun. Using an MCMV mutant lacking pM27, a signal transducer and activator of transcription (STAT) 2-specific inhibitor of Jak/STAT signalling, we found that the initial phase of IFN induction and the subsequent inhibition does not depend on the positive-IFN feedback loop. Our findings indicate that the MCMV-mediated downregulation of IFN transcription in fibroblasts relies on a large arsenal of inhibitory mechanisms targeting each pathway that contributes to the multiprotein enhanceosome complex. INTRODUCTIONUpon virus infection the type I interferon (IFN-a/b) response is one of the earliest innate host defence mechanisms, and many viruses have found means to avoid IFN gene expression Haller et al., 2006). Production of IFN-a/b is induced by the recognition of pathogen-associated molecular patterns (PAMP) (Medzhitov & Janeway, 2002) and initiates transcriptional upregulation of IFN-stimulated genes (ISGs) to establish an antiviral state. IFN-a/b synthesized by virus-infected cells bind to the IFN-a/b receptor complex, termed IFNAR, and activates the Jak/STAT signal transduction cascade, leading to the formation of the IFN-stimulated gene factor 3 (ISGF3). ISGF3 binds to IFN-stimulated response elements (ISRE), located in the promoter region of IFNinducible target genes mediating IFN effector functions (Darnell et al., 1994).Initiation of IFN transcription and its subsequent autocrine and paracrine amplification is a prerequisite for efficient IFN effector responses. IFN-b gene transcription is controlled by a higher order transcription enhancer complex, known as enhanceosome (Maniatis, 1986;Maniatis et al., 1998). The multi-component complex includes three distinct transcription factors binding cooperatively to the IFN-b promoter and the architectural high mobili...

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Human Cytomegalovirus Elicits a Coordinated Cellular Antiviral Response via Envelope Glycoprotein B

Cited by 103 publications

References 52 publications

Innate Sensing of Viruses by Toll-Like Receptors

Innate Sensing of Viruses by Toll-Like Receptors

Differential Initiation of Innate Immune Responses Induced by Human Cytomegalovirus Entry into Fibroblast Cells

Mouse cytomegalovirus inhibits beta interferon (IFN-β) gene expression and controls activation pathways of the IFN-β enhanceosome

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