A Mouse Model for Cytomegalovirus Infection

Brune, Wolfram; Hengel, Hartmut; Koszinowski, Ulrich H.

doi:10.1002/0471142735.im1907s43

Cited by 131 publications

(148 citation statements)

References 42 publications

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“…Primary mouse embryonic fibroblasts (MEF) were prepared as described previously (Brune et al, 1999). MEF were cultured in complete medium [Dulbecco's modified Eagle's medium supplemented with 10 % fetal calf serum (FCS), 2 mM glutamine, 200 mg penicillin and streptomycin ml 21 ] and used for experiments within three passages.…”

Section: Methodsmentioning

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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Section: Methodsmentioning

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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“…Mice were infected intranasally with 10 3 50% tissue culture-infective dose under general anesthesia. Bacterial artificial chromosome-derived mCMV strain MW97.01, which was experimentally shown to be identical to the WT Smith strain (22), was generated in primary mouse embryonic fibroblasts according to standard protocol (23). PFUs were determined by standard plaque assay on mouse embryonic fibroblasts, and 5 3 10 5 PFUs per mouse were injected i.p.…”

Section: Viral Infectionmentioning

confidence: 99%

Pro-Apoptotic Protein Noxa Regulates Memory T Cell Population Size and Protects against Lethal Immunopathology

Wensveen

Gisbergen

et al. 2013

The Journal of Immunology

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Memory T cells form a highly specific defense layer against reinfection with previously encountered pathogens. In addition, memory T cells provide protection against pathogens that are similar, but not identical to the original infectious agent. This is because each T cell response harbors multiple clones with slightly different affinities, thereby creating T cell memory with a certain degree of diversity. Currently, the mechanisms that control size, diversity, and cross-reactivity of the memory T cell pool are incompletely defined. Previously, we established a role for apoptosis, mediated by the BH3-only protein Noxa, in controlling diversity of the effector T cell population. This function might positively or negatively impact T cell memory in terms of function, pool size, and cross-reactivity during recall responses. Therefore, we investigated the role of Noxa in T cell memory during acute and chronic infections. Upon influenza infection, Noxa−/− mice generate a memory compartment of increased size and clonal diversity. Reinfection resulted in an increased recall response, whereas cross-reactive responses were impaired. Chronic infection of Noxa−/− mice with mouse CMV resulted in enhanced memory cell inflation, but no obvious pathology. In contrast, in a model of continuous, high-level T cell activation, reduced apoptosis of activated T cells rapidly led to severe organ pathology and premature death in Noxa-deficient mice. These results establish Noxa as an important regulator of the number of memory cells formed during infection. Chronic immune activation in the absence of Noxa leads to excessive accumulation of primed cells, which may result in severe pathology.

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“…Recombinant MCMV-Dm157 (m157 deletion mutant) was described previously [26]. MCMV was grown on C57BL/6 mouse embryonic fibroblasts and titrated by plaque-forming assays as described previously [27]. [141][142][143][144][145][146][147][148][149][150][151][152][153][154][155] .…”

Section: Batf3mentioning

confidence: 99%

Batf3 transcription factor‐dependent DC subsets in murine CMV infection: Differential impact on T‐cell priming and memory inflation

Torti¹,

Walton²,

Murphy³

et al. 2011

Eur J Immunol

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Priming of CD81 T cells specific for viruses that interfere with the MHC class I presentation pathway is a challenge for the immune system and is believed to rely on cross-presentation. Cytomegalovirus (CMV) infection induces vigorous CD8 1 T-cell responses despite its potent immune evasion strategies. Furthermore, CD8 1 T cells specific for a subset of viral epitopes accumulate and are maintained at high levels exhibiting an activated phenotype -referred to as ''inflationary T cells''. Taking advantage Batf3 À/À mice in which the development of cross-presenting CD8a 1 and CD103 1 DCs is severely compromised, we analyzed their role in the induction and inflation of murine (M)CMV-specific CD8 1 T-cell responses. We found that priming of MCMV-specific CD8 1 T cells was severely impaired in the absence of cross-presenting DCs. However, inflation of two immuno-dominant MCMVspecific CD8 1 T-cell populations was largely normal in the absence of cross-presenting DCs, indicating that inflation during latency was mainly dependent on direct antigen presentation. These results highlight differential antigen presentation requirements during acute and latent MCMV infection.

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A Mouse Model for Cytomegalovirus Infection

Cited by 131 publications

References 42 publications

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

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

Pro-Apoptotic Protein Noxa Regulates Memory T Cell Population Size and Protects against Lethal Immunopathology

Batf3 transcription factor‐dependent DC subsets in murine CMV infection: Differential impact on T‐cell priming and memory inflation

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