subject:(murine cytomegalovirus)

Georgia State University

1. Alston, Christine I. Suppressor of Cytokine Signaling (SOCS)1 and SOCS3 Stimulation during Experimental Cytomegalovirus Retinitis: Virologic, Immunologic, or Pathologic Mechanisms.

Degree: PhD, Biology, 2017, Georgia State University

URL: https://scholarworks.gsu.edu/biology_diss/172

► AIDS-related human cytomegalovirus (HCMV) retinitis remains the leading cause of blindness among untreated HIV/AIDS patients worldwide. Understanding the pathogenesis of this disease is essential… (more)

▼ AIDS-related human cytomegalovirus (HCMV) retinitis remains the leading cause of blindness among untreated HIV/AIDS patients worldwide. Understanding the pathogenesis of this disease is essential for developing new, safe, and effective treatments for its prevention or management, yet much remains unknown about the virologic and immunologic mechanisms contributing to its pathology. To study such mechanisms, we use a well-established, reproducible, and clinically relevant animal model with retrovirus-induced murine acquired immunodeficiency syndrome (MAIDS) that mimics in mice the symptoms and progression of AIDS in humans. Over 8 to 12 weeks, MAIDS mice become susceptible to experimental murine cytomegalovirus (MCMV) retinitis. We have found in this model that MCMV infection significantly stimulates ocular suppressor of cytokine signaling (SOCS)1 and SOCS3, host proteins which dampen immune-related signaling by cytokines, including antiviral interferons. Herein we investigated virologic and/or immunologic mechanisms involved in this stimulation and how virally-modulated SOCS1 and/or SOCS3 proteins may contribute to MCMV infection or experimental MAIDS-related MCMV retinitis. Through pursuit of two specific aims, we tested the central hypothesis that MCMV stimulates and employs SOCS1 and/or SOCS3 to induce the onset and development of MCMV retinal disease. MCMV-related SOCS1 and SOCS3 stimulation in vivo occurred with intraocular infection, was dependent on method and stage of immune suppression and severity of ocular pathology, was associated with stimulation of SOCS-inducing cytokines, and SOCS1 and SOCS3 were differentially sensitive to antiviral treatment. In vitro studies further demonstrated that SOCS1 and SOCS3 stimulation during MCMV infection occurred with expected immediate early kinetics, required viral gene expression in cell-type-dependent and virus origin-dependent patterns of expression, and displayed differential sensitivity to antiviral treatment. These data suggest that SOCS1 and SOCS3 are stimulated by divergent virologic, immunologic, and/or pathologic mechanisms during MCMV infection, and that they contribute to the pathogenesis of retinal disease, revealing new insights into the pathophysiology of AIDS-related HCMV retinitis. Advisors/Committee Members: Richard D. Dix, PhD, Julia K. Hilliard, PhD, Yuan Liu, PhD, Homayon Ghiasi, PhD.

Subjects/Keywords: Cytomegalovirus retinitis; human cytomegalovirus (HCMV); HIV/AIDS; suppressors of cytokine signaling (SOCS); murine cytomegalovirus (MCMV); murine AIDS (MAIDS)

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APA (6^th Edition):

Alston, C. I. (2017). Suppressor of Cytokine Signaling (SOCS)1 and SOCS3 Stimulation during Experimental Cytomegalovirus Retinitis: Virologic, Immunologic, or Pathologic Mechanisms. (Doctoral Dissertation). Georgia State University. Retrieved from https://scholarworks.gsu.edu/biology_diss/172

Chicago Manual of Style (16^th Edition):

Alston, Christine I. “Suppressor of Cytokine Signaling (SOCS)1 and SOCS3 Stimulation during Experimental Cytomegalovirus Retinitis: Virologic, Immunologic, or Pathologic Mechanisms.” 2017. Doctoral Dissertation, Georgia State University. Accessed December 11, 2019. https://scholarworks.gsu.edu/biology_diss/172.

MLA Handbook (7^th Edition):

Alston, Christine I. “Suppressor of Cytokine Signaling (SOCS)1 and SOCS3 Stimulation during Experimental Cytomegalovirus Retinitis: Virologic, Immunologic, or Pathologic Mechanisms.” 2017. Web. 11 Dec 2019.

Vancouver:

Alston CI. Suppressor of Cytokine Signaling (SOCS)1 and SOCS3 Stimulation during Experimental Cytomegalovirus Retinitis: Virologic, Immunologic, or Pathologic Mechanisms. [Internet] [Doctoral dissertation]. Georgia State University; 2017. [cited 2019 Dec 11]. Available from: https://scholarworks.gsu.edu/biology_diss/172.

Council of Science Editors:

Alston CI. Suppressor of Cytokine Signaling (SOCS)1 and SOCS3 Stimulation during Experimental Cytomegalovirus Retinitis: Virologic, Immunologic, or Pathologic Mechanisms. [Doctoral Dissertation]. Georgia State University; 2017. Available from: https://scholarworks.gsu.edu/biology_diss/172

2. Fries, Anissa. Etude de la différenciation et des fonctions des monocytes classiques au cours de l'infection par le cytomégalovirus murin : Study of classical monocytes differentiation and functions during murine cytomegalovirus infection.

Degree: Docteur es, Biologie, 2016, Aix Marseille Université

URL: http://www.theses.fr/2016AIXM4047

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Les monocytes classiques (cMo) sont des phagocytes mononucléés circulant dans le sang et capables de migrer vers les tissus enflammés pour s’y différencier en monocytes… (more)

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Les monocytes classiques (cMo) sont des phagocytes mononucléés circulant dans le sang et capables de migrer vers les tissus enflammés pour s’y différencier en monocytes inflammatoires, cellules dendritiques dérivées de monocytes (MoDC), macrophages (MoM) ou cellules myéloïdes suppressives. Selon le contexte physiopathologique, les cellules dérivées de cMo peuvent être bénéfiques ou néfastes. Dans l’infection par le cytomégalovirus murin (MCMV) leur rôle est controversé. Les divergences apparentes dans la littérature pourraient s’expliquer par l’utilisation de souches distinctes de souris ou de virus, l’étude d’organes différents, et la confusion existante sur l’identité et la plasticité de différents sous-types de cellules dérivées de cMo. Par des analyses transcriptionnelles, morphologiques et fonctionnelles, mon travail de thèse montre que, dans la rate de souris infectées par MCMV, les cMo se différencient simultanément en monocytes inflammatoires, MoDC et MoM. Cette différenciation est abrogée lorsque les cMo sont incapables de répondre aux interférons de type I (IFN-I), massivement produits dans les infections virales, qui boostent l’immunité intrinsèque antivirale et promeuvent l’activation des cellules immunitaires innées et adaptatives. La déplétion des cMo compromet le contrôle de l’infection et les réponses des cellules Natural Killer et des lymphocytes T CD8+. Mon travail montre que, dans les souris infectées par MCMV, les cMo se différencient, de manière dépendante de l’IFN-I, en trois sous-types cellulaires distincts qui contribuent à la fois au contrôle de la réplication virale et à la promotion de réponses immunitaires innées et adaptatives protectrices.

Classical monocytes (cMo) are mononuclear phagocytes mainly localized in the blood at steady state. Upon inflammation cMo migrate into inflamed tissues where they can differentiate in inflammatory monocytes, monocyte-derived dendritic cells (MoDC), monocyte-derived macrophages (MoM) or myeloid derived suppressor cells (MDSC). Depending on the physiopathological context, cMo-derived cells can be beneficial or detrimental. There are major discrepancies between published reports on the role of cMo during MCMV infection. This may be due to the use of distinct strains of mice or of virus, to the study of different organs, or to the confusion existing in the field regarding the identity and the plasticity of the different types of cMo-derived cells. During my PhD, by combining gene expression profiling, morphological, phenotypical and functional studies, I have shown that splenic cMo in MCMV-infected mice encompass cells that had simultaneously differentiated in vivo into either inflammatory monocytes, MoDC or MoM. This cMo differentiation is abrogated in the absence of responsiveness to type I interferons (IFN-I), which are highly produced during viral infections and boosting cell-intrinsic anti-viral immunity as well as promoting the activation of innate and adaptive immune responses. cMo depletion compromises the control of MCMV replication and the…

Advisors/Committee Members: Tomasello, Elena (thesis director).

Subjects/Keywords: Monocytes classiques; Cytomégalovirus murin; Interférons de type I; Cellules dendritiques dérivées de monocytes; Macrophages; Classical monocytes; Murine cytomegalovirus; Type I interferons; Monocyte derived dendritic cells; Macrophages; 570

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Fries, A. (2016). Etude de la différenciation et des fonctions des monocytes classiques au cours de l'infection par le cytomégalovirus murin : Study of classical monocytes differentiation and functions during murine cytomegalovirus infection. (Doctoral Dissertation). Aix Marseille Université. Retrieved from http://www.theses.fr/2016AIXM4047

Chicago Manual of Style (16^th Edition):

Fries, Anissa. “Etude de la différenciation et des fonctions des monocytes classiques au cours de l'infection par le cytomégalovirus murin : Study of classical monocytes differentiation and functions during murine cytomegalovirus infection.” 2016. Doctoral Dissertation, Aix Marseille Université. Accessed December 11, 2019. http://www.theses.fr/2016AIXM4047.

MLA Handbook (7^th Edition):

Fries, Anissa. “Etude de la différenciation et des fonctions des monocytes classiques au cours de l'infection par le cytomégalovirus murin : Study of classical monocytes differentiation and functions during murine cytomegalovirus infection.” 2016. Web. 11 Dec 2019.

Vancouver:

Fries A. Etude de la différenciation et des fonctions des monocytes classiques au cours de l'infection par le cytomégalovirus murin : Study of classical monocytes differentiation and functions during murine cytomegalovirus infection. [Internet] [Doctoral dissertation]. Aix Marseille Université 2016. [cited 2019 Dec 11]. Available from: http://www.theses.fr/2016AIXM4047.

Council of Science Editors:

Fries A. Etude de la différenciation et des fonctions des monocytes classiques au cours de l'infection par le cytomégalovirus murin : Study of classical monocytes differentiation and functions during murine cytomegalovirus infection. [Doctoral Dissertation]. Aix Marseille Université 2016. Available from: http://www.theses.fr/2016AIXM4047

3. Fogel, Leslie Abigail. The Resolution Phase of NK Cell Proliferation and IFN Production Following Viral Infection Are Highly Regulated Processes.

Degree: PhD, Biology & Biomedical Sciences (Immunology), 2016, Washington University in St. Louis

URL: https://openscholarship.wustl.edu/art_sci_etds/760

► In response to MCMV infection, NK cells undergo three distinct phases of proliferation: the non-specific phase mediated by pro-proliferative cytokines; the specific phase mediated… (more)

Subjects/Keywords: Apoptosis, Interferon gamma, Murine cytomegalovirus, Natural killer cells, Proliferation; Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Fogel, L. A. (2016). The Resolution Phase of NK Cell Proliferation and IFN Production Following Viral Infection Are Highly Regulated Processes. (Doctoral Dissertation). Washington University in St. Louis. Retrieved from https://openscholarship.wustl.edu/art_sci_etds/760

Chicago Manual of Style (16^th Edition):

Fogel, Leslie Abigail. “The Resolution Phase of NK Cell Proliferation and IFN Production Following Viral Infection Are Highly Regulated Processes.” 2016. Doctoral Dissertation, Washington University in St. Louis. Accessed December 11, 2019. https://openscholarship.wustl.edu/art_sci_etds/760.

MLA Handbook (7^th Edition):

Fogel, Leslie Abigail. “The Resolution Phase of NK Cell Proliferation and IFN Production Following Viral Infection Are Highly Regulated Processes.” 2016. Web. 11 Dec 2019.

Vancouver:

Fogel LA. The Resolution Phase of NK Cell Proliferation and IFN Production Following Viral Infection Are Highly Regulated Processes. [Internet] [Doctoral dissertation]. Washington University in St. Louis; 2016. [cited 2019 Dec 11]. Available from: https://openscholarship.wustl.edu/art_sci_etds/760.

Council of Science Editors:

Fogel LA. The Resolution Phase of NK Cell Proliferation and IFN Production Following Viral Infection Are Highly Regulated Processes. [Doctoral Dissertation]. Washington University in St. Louis; 2016. Available from: https://openscholarship.wustl.edu/art_sci_etds/760

4. Cocita, Clément. Etude de redondances mises en place par le système immunitaire pour lutter contre l'infection par le cytomégalovirus murin : Study of redundancies established by the immune system for the protection during murine cytomegalovirus infection.

Degree: Docteur es, Immunologie, 2015, Aix Marseille Université

URL: http://www.theses.fr/2015AIXM4061

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Chez la souris, les cellules dendritiques plasmacytoïdes (pDC) et natural killer (NK) contribuent à la résistance contre les infections systémiques par les virus herpétiques tels… (more)

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Chez la souris, les cellules dendritiques plasmacytoïdes (pDC) et natural killer (NK) contribuent à la résistance contre les infections systémiques par les virus herpétiques tels que le cytomégalovirus murin (MCMV). Les pDC représentent la source majeure d’interférons de type I (IFN-I) lors d’une infection par le MCMV. Cette réponse est dépendante de MyD88 et des récepteurs de type Toll 7 et 9. D’autre part, les cellules NK, qui expriment le récepteur d’activation Ly49H, peuvent détecter et lyser les cellules infectées par le MCMV. La perte de l’une de ces réponses augmente la sensibilité à l’infection. Cependant, la façon dont ces réponses antivirales interagissent est mal connue. Chez l’homme, bien que les réponses dépendantes des IFN-I soient essentielles, MyD88 semble superflu pour l’immunité antivirale. Cependant, les mécanismes susceptibles de compenser l’absence de MyD88 chez l’homme sont inconnus. Il a été supposé que les souris déficientes pour MyD88 ne parvenaient pas à monter de réponse protectrice dépendante des IFN-I lors d’infections par le MCMV. Afin d’évaluer cela, nous avons comparé la résistance de souris déficientes pour MyD88, les récepteurs aux IFN-I (IFNAR) et/ou Ly49H lors de cette infection. La déplétion sélective des pDC ou l’absence de MyD88 diminue drastiquement la production d’IFN-I, mais n’empêche pas l’établissement d’une forte réponse aux IFN-I dans la rate. De plus, l’absence de MyD88, mais pas celle d’IFNAR, peut être compensée par l’activité antivirale des cellules NK dépendant de Ly49H. Par conséquent, chez la souris, MyD88 est redondant pour l’établissement d’une réponse splénique aux IFN-I lors d’une infection systémique par le MCMV.

In mice, plasmacytoid dendritic cells (pDC) and natural killer (NK) cells both contribute to resistance to systemic infections with herpes viruses including mouse Cytomegalovirus (MCMV). pDCs are the major source of type I IFN (IFN-I) during MCMV infection. This response requires pDC-intrinsic MyD88-dependent signaling by Toll-Like Receptors 7 and 9. Provided that they express appropriate recognition receptors such as Ly49H, NK cells can directly sense and kill MCMV-infected cells. The loss of any one of these responses has been reported to increase susceptibility to infection. However, the relative importance of these antiviral immune responses and how they are related remain unclear. In humans, while IFN-I responses are essential, MyD88 appears to be dispensable for antiviral immunity. However, the mechanisms that could compensate MyD88 deficiency in humans have not been elucidated. Moreover, it has been assumed, but not proven, that MyD88-deficient mice fail to mount protective IFN-I responses to systemic herpes virus infections. To address these issues, we compared resistance to MCMV infection between mouse strains deficient for MyD88, the IFN-I receptor (IFNAR) and/or Ly49H. We show that selective depletion of pDC or genetic deficiencies for MyD88 drastically decreased production of IFN-I, but not the protective antiviral responses mediated by…

Advisors/Committee Members: Dalod, Marc (thesis director).

Subjects/Keywords: Cytomégalovirus murin; Cellule dendritique plasmacytoïde; Cellule natural killer; Interféron de type I; MyD88; Rate; Foie; Redondance; Murine cytomegalovirus; Plasmacytoid dendritic cell; Natural killer cell; Type I interferon; MyD88; Spleen; Liver; Redundancy; 571

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Cocita, C. (2015). Etude de redondances mises en place par le système immunitaire pour lutter contre l'infection par le cytomégalovirus murin : Study of redundancies established by the immune system for the protection during murine cytomegalovirus infection. (Doctoral Dissertation). Aix Marseille Université. Retrieved from http://www.theses.fr/2015AIXM4061

Chicago Manual of Style (16^th Edition):

Cocita, Clément. “Etude de redondances mises en place par le système immunitaire pour lutter contre l'infection par le cytomégalovirus murin : Study of redundancies established by the immune system for the protection during murine cytomegalovirus infection.” 2015. Doctoral Dissertation, Aix Marseille Université. Accessed December 11, 2019. http://www.theses.fr/2015AIXM4061.

MLA Handbook (7^th Edition):

Cocita, Clément. “Etude de redondances mises en place par le système immunitaire pour lutter contre l'infection par le cytomégalovirus murin : Study of redundancies established by the immune system for the protection during murine cytomegalovirus infection.” 2015. Web. 11 Dec 2019.

Vancouver:

Cocita C. Etude de redondances mises en place par le système immunitaire pour lutter contre l'infection par le cytomégalovirus murin : Study of redundancies established by the immune system for the protection during murine cytomegalovirus infection. [Internet] [Doctoral dissertation]. Aix Marseille Université 2015. [cited 2019 Dec 11]. Available from: http://www.theses.fr/2015AIXM4061.

Council of Science Editors:

Cocita C. Etude de redondances mises en place par le système immunitaire pour lutter contre l'infection par le cytomégalovirus murin : Study of redundancies established by the immune system for the protection during murine cytomegalovirus infection. [Doctoral Dissertation]. Aix Marseille Université 2015. Available from: http://www.theses.fr/2015AIXM4061

5. Bittencourt, Fabiola M. Examination of the Function of the Murine Cytomegalovirus Encoded G Protein-Coupled Receptor M33 in vivo.

Degree: PhD, Medicine: Molecular Genetics, Biochemistry, and Microbiology, 2014, University of Cincinnati

URL: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1397234044

► The betaherpesvirus Human Cytomegalovirus (HCMV) is estimated to be present in 40-80% of world population. HCMV infection in a healthy person causes mild symptoms, although… (more)

▼ The betaherpesvirus Human Cytomegalovirus (HCMV) is estimated to be present in 40-80% of world population. HCMV infection in a healthy person causes mild symptoms, although the virus persists in the host in the latent form. Immunocompromised patients such as HIV and organ transplant patients as well as fetuses and neonatal babies with underdeveloped immune system are most affected by HCMV infection. CMVs are characterized by their strict species specifity; therefore humans are the only host for HCMV. The mouse cytomegalovirus (MCMV) has been the most useful animal model to explore HCMV spread and disease. CMVs encode G Protein-Coupled Receptors (GPCR) and these viral GPCRs are increasingly recognized as important regulators of pathogenesis and disease. HCMV for example encodes four of these GPCRs, whereas MCMV expresses two: M33 and M78. M33 shows constitutive signaling properties and activates various signaling pathways. M33 stimulates the PLC-&beta/PKC pathway via G&alphaq/11, however activation of NF-&kappaB and p38 MAP-kinase is independent of G-proteins. Importantly, M33 is essential for dissemination to or growth in salivary glands of immunocompetent mice and the G-protein signaling ability of M33 is necessary for viral growth at this site. Here we used the non-obese diabetic (NOD) and the immunocompromised NOD scid gamma (NSG) mouse models to assess a potential role for M33 as an immunomodulator and to further investigate the mechanism(s) by which M33 promotes viral growth in vivo. We are able to detect replication of &DeltaM33 viruses in the salivary glands of immunocompromised NSG mice; however it exhibited a 400x defect compared to wildtype MCMV. Since the growth phenotype is not completely reverted in the NSG mice, we conclude that M33 is not solely functioning to modulate the immune system. We also showed that M33 is dispensable for hematogenous dissemination within the host and that activation of G&alphaq signaling pathways alone is not sufficient to promote salivary gland growth as neither HCMV US28 nor a constitutively active form of G&alphaq are able to complement the unique functions of M33. We also describe here the generation and characterization of an in vitro cell culture model with cells extracted from mouse salivary glands. Specialized growth conditions resulted in cells that express markers of salivary gland epithelium, but none resulted in maintenance of epithelial markers similar to those expressed by the organ in vivo. Despite growth conditions that enable sustained expression of at least low levels of the salivary epithelial markers, M33 was not required for viral growth in these primary cells. Taken together, these studies suggest that M33 is necessary to allow viral growth within the three-dimensional structure of the gland in vivo but that this activity is not required once the structure of the gland is disrupted. An understanding of CMV replication in the salivary gland and how M33 modulates salivary gland function to promote viral replication will provide insights into mechanisms that… Advisors/Committee Members: Miller, William (Committee Chair).

Subjects/Keywords: Virology; Murine Cytomegalovirus; Viral GPCR; M33

…disease. Among them, murine cytomegalovirus (MCMV) has been well characterized as a… …Table 1: GPCRs encoded by herpesviruses. MCMV: murine cytomegalovirus; RCMV: rat… …reason, murine cytomegalovirus (MCMV) has been commonly used as a model system to… …CMV: Cytomegalovirus CRE: Cyclization Recombinase CREB: cAMP response element binding DAG… …regulated kinase FACS: Fluorescence activated cell sorting HCMV: Human cytomegalovirus IFN…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Bittencourt, F. M. (2014). Examination of the Function of the Murine Cytomegalovirus Encoded G Protein-Coupled Receptor M33 in vivo. (Doctoral Dissertation). University of Cincinnati. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=ucin1397234044

Chicago Manual of Style (16^th Edition):

Bittencourt, Fabiola M. “Examination of the Function of the Murine Cytomegalovirus Encoded G Protein-Coupled Receptor M33 in vivo.” 2014. Doctoral Dissertation, University of Cincinnati. Accessed December 11, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1397234044.

MLA Handbook (7^th Edition):

Bittencourt, Fabiola M. “Examination of the Function of the Murine Cytomegalovirus Encoded G Protein-Coupled Receptor M33 in vivo.” 2014. Web. 11 Dec 2019.

Vancouver:

Bittencourt FM. Examination of the Function of the Murine Cytomegalovirus Encoded G Protein-Coupled Receptor M33 in vivo. [Internet] [Doctoral dissertation]. University of Cincinnati; 2014. [cited 2019 Dec 11]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1397234044.

Council of Science Editors:

Bittencourt FM. Examination of the Function of the Murine Cytomegalovirus Encoded G Protein-Coupled Receptor M33 in vivo. [Doctoral Dissertation]. University of Cincinnati; 2014. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1397234044

Johannes Gutenberg Universität Mainz

6. Fink, Annette. Molekulare Grundlagen der Immunkontrolle des murinen Cytomegalovirus in Gegenwart viruskodierter Immunevasine.

Degree: 2014, Johannes Gutenberg Universität Mainz

URL: http://ubm.opus.hbz-nrw.de/volltexte/2014/3708/

► Die Kontrolle der Infektion mit dem humanen Cytomegalovirus (HCMV) wird primär durch antivirale CD8 T-Zellen vermittelt. Während der Koevolution zwischen Virus und Wirt wurden Immunevasionsmechanismen… (more)

▼ Die Kontrolle der Infektion mit dem humanen Cytomegalovirus (HCMV) wird primär durch antivirale CD8 T-Zellen vermittelt. Während der Koevolution zwischen Virus und Wirt wurden Immunevasionsmechanismen entwickelt, die direkt die Expression der Peptid-MHC-Klasse-I-Komplexe an der Zelloberfläche beeinflussen und es dem Virus ermöglichen, der Immunkontrolle des Wirtes zu entkommen. Da HCMV und das murine CMV (mCMV) zum Teil analoge Strategien zur Modulation des MHC-Klasse-I-Antigen-Präsentationswegs entwickelt haben, wurde in der vorliegenden Arbeit auf das experimentelle Modell mit mCMV zurückgegriffen. Die für die Immunevasion verantwortlichen Genprodukte m04/gp34, m06/gp48 und m152/gp40 werden aufgrund ihres regulatorischen Einflusses auf die Antigenpräsentation als vRAPs (viral regulators of antigen presentation) bezeichnet. Diese interferieren mit dem Transport Peptid-beladener MHC-Klasse-I-Moleküle und reduzieren in ihrer konzertierten Wirkung die Präsentation viraler Peptide an der Zelloberfläche.rnDie Transplantation hämatopoietischer Zellen nach Immunoablation stellt eine etablierte Therapieform bei malignen hämatologischen Erkrankungen dar. Zwischen Immunoablation und der Rekonstitution des Immunsystems sind die Empfänger der transferierten Zellen stark immunsupprimiert und anfällig für eine CMV-Erkrankung bei Reaktivierung des Virus. Neben der Gabe antiviraler Medikamente ist der adoptive Transfer antiviraler CD8 T-Zellen eine vielversprechende Therapiemöglichkeit, um reaktivierende CMV zu kontrollieren, bis das körpereigene Immunsystem wieder funktionsfähig ist. Obwohl im murinen Modell sehr wohl etabliert, stellen im humanen System die eingeschränkte Wirkung und die Notwendigkeit der konsequenten Gabe hoher Zellzahlen gewisse logistische Schwierigkeiten dar, welche die Methode bisher von der klinischen Routine ausschließen.rnDas murine Modell sagte eine Rolle von IFN-γ voraus, da Depletion dieses Zytokins zu einer verminderten Schutzwirkung gegen die mCMV-Infektion führt.rnIm ersten Teil dieser Arbeit sollte ein möglicher inhibitorischer Effekt von m04 auf m152 untersucht werden, der bei der Rekombinanten Δm06W beobachtet wurde. Mit neu generierten Viren (Δm06L1+2) konnte dieser Effekt allerdings nicht bestätigt werden. Bei Δm06W fehlte jedoch eine höher N-glykosylierte Isoform des m152-Proteins. Um zu untersuchen, ob die N-Glykosylierung von m152 für seine Funktion notwendig ist, wurde ein rekombinantes Virus generiert, das in Folge einer Deletion aller 3 N-Glykosylierungssequenzen nur eine nicht-glykosylierte Isoform des m152-Proteins bilden kann. In Übereinstimmung mit der zwischenzeitlich publizierten Kristallstruktur das Komplexes von m152 und dem Liganden RAE-1 des aktivierenden NK-Zellrezeptors NKG2D konnte erstmals gezeigt werden, dass die Funktionen von m152 in der adaptiven und in der angeborenen Immunität auch von der nicht N-glykosylierten Isoform wahrgenommen werden können.rnIm zweiten Teil der Arbeit sollte mit Hilfe eines Sets an vRAP Deletionsmutanten der Einfluss von IFN γ auf die einzeln…

Subjects/Keywords: murines Cytomegalovirus, Immunevasion, Interferon-gamma, N-Glykosylierung; murine cytomegalovirus, immunoevasion, Interferon-gamma, N-Glycosylation; Life sciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Fink, A. (2014). Molekulare Grundlagen der Immunkontrolle des murinen Cytomegalovirus in Gegenwart viruskodierter Immunevasine. (Doctoral Dissertation). Johannes Gutenberg Universität Mainz. Retrieved from http://ubm.opus.hbz-nrw.de/volltexte/2014/3708/

Chicago Manual of Style (16^th Edition):

Fink, Annette. “Molekulare Grundlagen der Immunkontrolle des murinen Cytomegalovirus in Gegenwart viruskodierter Immunevasine.” 2014. Doctoral Dissertation, Johannes Gutenberg Universität Mainz. Accessed December 11, 2019. http://ubm.opus.hbz-nrw.de/volltexte/2014/3708/.

MLA Handbook (7^th Edition):

Fink, Annette. “Molekulare Grundlagen der Immunkontrolle des murinen Cytomegalovirus in Gegenwart viruskodierter Immunevasine.” 2014. Web. 11 Dec 2019.

Vancouver:

Fink A. Molekulare Grundlagen der Immunkontrolle des murinen Cytomegalovirus in Gegenwart viruskodierter Immunevasine. [Internet] [Doctoral dissertation]. Johannes Gutenberg Universität Mainz; 2014. [cited 2019 Dec 11]. Available from: http://ubm.opus.hbz-nrw.de/volltexte/2014/3708/.

Council of Science Editors:

Fink A. Molekulare Grundlagen der Immunkontrolle des murinen Cytomegalovirus in Gegenwart viruskodierter Immunevasine. [Doctoral Dissertation]. Johannes Gutenberg Universität Mainz; 2014. Available from: http://ubm.opus.hbz-nrw.de/volltexte/2014/3708/

Johannes Gutenberg Universität Mainz

7. Wilhelmi, Vanessa. An interferon regulatory factor element controls the major immune modulator of murine cytomegalovirus.

Degree: 2012, Johannes Gutenberg Universität Mainz

URL: http://ubm.opus.hbz-nrw.de/volltexte/2012/3057/

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Immune modulation by herpesviruses, such as cytomegalovirus, is critical for the establishment of acute and persistent infection confronting a vigorous antiviral immune response of the… (more)

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Immune modulation by herpesviruses, such as cytomegalovirus, is critical for the establishment of acute and persistent infection confronting a vigorous antiviral immune response of the host. Therefore, the action of immune-modulatory proteins has long been the subject of research, with the final goal to identify new strategies for antiviral therapy.rnIn the case of murine cytomegalovirus (mCMV), the viral m152 protein has been identified to play a major role in targeting components of both the innate and the adaptive immune system in terms of infected host-cell recognition in the effector phase of the antiviral immune response. On the one hand, it inhibits cell surface expression of RAE-1 and thereby prevents ligation of the activating natural killer (NK)-cell receptor NKG2D. On the other hand, it decreases cell surface expression of peptide-loaded MHC class I molecules thereby preventing antigen presentation to CD8 T cells. Ultimately, the outcome of CMV infection is determined by the interplay between viral and cellular factors.rnIn this context, the work presented here has revealed a novel and intriguing connection between viral m152 and cellular interferon (IFN), a key cytokine of the immune system: rnthe m152 promoter region contains an interferon regulatory factor element (IRFE) perfectly matching the consensus sequence of cellular IRFEs.rnThe biological relevance of this regulatory element was first suggested by sequence comparisons revealing its evolutionary conservation among various established laboratory strains of mCMV and more recent low-passage wild-derived virus isolates. Moreover, search of the mCMV genome revealed only three IRFE sites in the complete sequence. Importantly, the functionality of the IRFE in the m152 promoter was confirmed with the use of a mutant virus, representing a functional deletion of the IRFE, and its corresponding revertant virus. In particular, m152 gene expression was found to be inhibited in an IRFE-dependent manner in infected cells. Essentially, this inhibition proved to have a severe impact on the immune-modulatory function of m152, first demonstrated by a restored direct antigen presentation on infected cells for CD8 T-cell activation. Even more importantly, this effect of IRFE-mediated IFN signaling was validated in vivo by showing that the protective antiviral capacity of adoptively-transferred, antigen-specific CD8 T cells is also significantly restored by the IRFE-dependent inhibition of m152. Somewhat curious and surprising, the decrease in m152 protein simultaneously prevented an enhanced activation of NK cells in acute-infected mice, apparently independent of the RAE-1/NKG2D ligand/receptor interaction but rather due to reduced ‘missing-self’ recognition.rnTaken together, this work presents a so far unknown mechanism of IFN signaling to control mCMV immune modulation in acute infection.rnrn

Die Immunmodulation durch Herpesviren, wie das Cytomegalovirus, ist wichtig für die Etablierung akuter und persistenter Infektion, im Zuge einer starken antiviralen…

Subjects/Keywords: murines Cytomegalovirus; Immunmodulation; IRFE; murine cytomegalovirus; immune modulation; IRFE; Life sciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Wilhelmi, V. (2012). An interferon regulatory factor element controls the major immune modulator of murine cytomegalovirus. (Doctoral Dissertation). Johannes Gutenberg Universität Mainz. Retrieved from http://ubm.opus.hbz-nrw.de/volltexte/2012/3057/

Chicago Manual of Style (16^th Edition):

Wilhelmi, Vanessa. “An interferon regulatory factor element controls the major immune modulator of murine cytomegalovirus.” 2012. Doctoral Dissertation, Johannes Gutenberg Universität Mainz. Accessed December 11, 2019. http://ubm.opus.hbz-nrw.de/volltexte/2012/3057/.

MLA Handbook (7^th Edition):

Wilhelmi, Vanessa. “An interferon regulatory factor element controls the major immune modulator of murine cytomegalovirus.” 2012. Web. 11 Dec 2019.

Vancouver:

Wilhelmi V. An interferon regulatory factor element controls the major immune modulator of murine cytomegalovirus. [Internet] [Doctoral dissertation]. Johannes Gutenberg Universität Mainz; 2012. [cited 2019 Dec 11]. Available from: http://ubm.opus.hbz-nrw.de/volltexte/2012/3057/.

Council of Science Editors:

Wilhelmi V. An interferon regulatory factor element controls the major immune modulator of murine cytomegalovirus. [Doctoral Dissertation]. Johannes Gutenberg Universität Mainz; 2012. Available from: http://ubm.opus.hbz-nrw.de/volltexte/2012/3057/

Johannes Gutenberg Universität Mainz

8. Gergely, Kerstin Marlene. Präklinische Evaluierung von therapeutischer Vakzinierung zur Effizienzsteigerung der adoptiven Immuntherapie von Cytomegalovirus-Erkrankungen.

Degree: 2012, Johannes Gutenberg Universität Mainz

URL: http://ubm.opus.hbz-nrw.de/volltexte/2013/3312/

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Klinische Manifestationen einer Cytomegalovirus (CMV)-Infektion gefährden den therapeutischen Erfolg der hämatopoetischen Stammzelltransplantation (HSCT). Dabei stellt insbesondere die Reaktivierung von latentem CMV im HSCT-Rezipienten das häufigste… (more)

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Klinische Manifestationen einer Cytomegalovirus (CMV)-Infektion gefährden den therapeutischen Erfolg der hämatopoetischen Stammzelltransplantation (HSCT). Dabei stellt insbesondere die Reaktivierung von latentem CMV im HSCT-Rezipienten das häufigste Infektionsrisiko dar. Die Inzidenz der CMV-Erkrankung kann durch Rekonstitution adoptiv transferierter CMV-spezifischer CD8 T-Zellen im HSCT-Rezipienten reduziert werden. Das Modell der sogenannten adoptiven Immuntherapie wurde zunächst im murinen Modell entwickelt und bereits in klinischen Studien bestätigt. Jedoch ist der adoptive Transfer (AT) aufgrund der nur limitiert zur Verfügung stehenden therapeutisch effektiven Zellzahlen zurzeit in der klinischen Routine nicht einsetzbar.rnZiel dieser Arbeit war daher die präklinische Evaluierung einer Kombinationstherapie aus AT einer limitierten Anzahl CMV-spezifischer T-Zellen und deren in vivo Expansion durch therapeutische Vakzinierung nach HSCT. Zur Testung dieser Therapie wurde ein murines Modell auf der Grundlage von rekombinanten murinen CMV (mCMV) und rekombinanten HCMV Dense Bodies (DB) etabliert. Beide exprimieren das gut charakterisierte MHC-Klasse-I Kb-restringierte SIINFEKL-Peptid (OVA257-264) des Ovalbumins (OVA) bzw. die Funktions-verlustmutante SIINFEKA als Modellantigen. In den rekombinanten mCMV, mCMV-Δm157Luc/m164-SIINFEKL/-A (mCMV-SIINFEKL/-A), wurde mittels orthotopen Peptid-austauschs das m164257-265 Peptid des gp36,5/m164 Proteins deletiert und durch das SIINFEKL- bzw. SIINFEKA-Peptid ersetzt. Anhand von Priming-Analysen konnte gezeigt werden, dass nach Infektion von C57BL/6 Mäusen mit mCMV-SIINFEKL SIINFEKL-spezifische T-Zellen nachweisbar sind und das im CMV-Genom integrierte SIINFEKL funktional prozessiert und präsentiert wird. Parallel hierzu konnte nach Immunisierung mit DB-SIINFEKL in vivo ein SIINFEKL-spezifisches CD8 T-Zell-Priming induziert werden. In weiteren Experimenten konnte nach DB-SIINFEKL-Immunisierung im poplitealen Lymphknoten sowie in der Milz eine Proliferation von adoptiv transferierten CD8 T-Zellen beobachtet werden. Die anschließenden Challenge-Versuche zeigten, dass eine DB-SIINFEKL-Immunisierung epitopspezifisch vor einer hoch dosierten Challenge-Infektion mit mCMV-SIINFEKL schützt. Im AT-Modell konnte gezeigt werden, dass adoptiv transferierte OT-I Zellen hämatoablativ behandelte Rezipienten epitopspezifisch vor einer mCMV-SIINFEKL-Infektion schützen können, wobei der erzielte Schutz durch zusätzliche Vakzinierung mit DB-SIINFEKL deutlich verbessert werden konnte. Im Anschluss konnte im HSCT-Rezipienten erstmals eine durch zusätzliche Vakzinierung signifikante Verbesserung des protektiven Potenzials adoptiv transferierter OT-I Zellen bestätigt werden. Diese Verstärkung der Protektion ermöglicht die Reduktion der Anzahl der für den Schutz benötigten Zellzahl und erhöht damit die Effizienz der adoptiven Immuntherapie.

Clinical manifestations of cytomegalovirus (CMV)-infection compromise the therapeutic success of hematopoietic stem cell transplantation (HSCT). The…

Subjects/Keywords: therapeutische Vakzinierung, adoptive Immuntherapie, mCMV, murine Cytomegalovirus, Dense Bodies; therapeutic vaccination, adoptive immunotherapy, mCMV, murine cytomegalovirus, dense bodies; Life sciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Gergely, K. M. (2012). Präklinische Evaluierung von therapeutischer Vakzinierung zur Effizienzsteigerung der adoptiven Immuntherapie von Cytomegalovirus-Erkrankungen. (Doctoral Dissertation). Johannes Gutenberg Universität Mainz. Retrieved from http://ubm.opus.hbz-nrw.de/volltexte/2013/3312/

Chicago Manual of Style (16^th Edition):

Gergely, Kerstin Marlene. “Präklinische Evaluierung von therapeutischer Vakzinierung zur Effizienzsteigerung der adoptiven Immuntherapie von Cytomegalovirus-Erkrankungen.” 2012. Doctoral Dissertation, Johannes Gutenberg Universität Mainz. Accessed December 11, 2019. http://ubm.opus.hbz-nrw.de/volltexte/2013/3312/.

MLA Handbook (7^th Edition):

Gergely, Kerstin Marlene. “Präklinische Evaluierung von therapeutischer Vakzinierung zur Effizienzsteigerung der adoptiven Immuntherapie von Cytomegalovirus-Erkrankungen.” 2012. Web. 11 Dec 2019.

Vancouver:

Gergely KM. Präklinische Evaluierung von therapeutischer Vakzinierung zur Effizienzsteigerung der adoptiven Immuntherapie von Cytomegalovirus-Erkrankungen. [Internet] [Doctoral dissertation]. Johannes Gutenberg Universität Mainz; 2012. [cited 2019 Dec 11]. Available from: http://ubm.opus.hbz-nrw.de/volltexte/2013/3312/.

Council of Science Editors:

Gergely KM. Präklinische Evaluierung von therapeutischer Vakzinierung zur Effizienzsteigerung der adoptiven Immuntherapie von Cytomegalovirus-Erkrankungen. [Doctoral Dissertation]. Johannes Gutenberg Universität Mainz; 2012. Available from: http://ubm.opus.hbz-nrw.de/volltexte/2013/3312/

Johannes Gutenberg Universität Mainz

9. Scheller, Sabine. In vivo konditionale Depletion von latentem murinen Cytomegalovirus.

Degree: 2011, Johannes Gutenberg Universität Mainz

URL: http://ubm.opus.hbz-nrw.de/volltexte/2012/3013/

► Die Lunge stellt einen Hauptort der CMV-Latenz dar. Die akute CMV-Infektion wird durch infiltrierende antivirale CD8 T-Zellen terminiert. Das virale Genom verbleibt jedoch im Lungengewebe… (more)

▼ Die Lunge stellt einen Hauptort der CMV-Latenz dar. Die akute CMV-Infektion wird durch infiltrierende antivirale CD8 T-Zellen terminiert. Das virale Genom verbleibt jedoch im Lungengewebe in einem nicht replikativen Zustand, der Latenz, erhalten. Es konnte bereits gezeigt werden, dass während der Latenz die Major Immediate Early- (MIE) Gene ie1- und ie2 sporadisch transkribiert werden. Bisher konnte diese beginnende Reaktivierung latenter CMV-Genome nur in einer Momentaufnahme gezeigt werden (Kurz et al., 1999; Grzimek et al., 2001; Simon et al., 2005; zur Übersicht: Reddehase et al., 2008). Die sporadische Expression der MIE-Gene führt jedoch zur Präsentation eines antigenen IE1-Peptids und somit zur Stimulation antiviraler IE1-Peptid-spezifischer CD8 T-Zellen, die durch ihre Effektorfunktion die beginnende Reaktivierung wieder beenden. Dies führte uns zu der Hypothese, dass MIE-Genexpression über einen Zeitraum betrachtet (period prevalence) häufiger stattfindet als es in einer Momentaufnahme (point prevalence) beobachtet werden kann.rnrnUm die Häufigkeit der MIE-Genexpression in der Dynamik in einem definierten Zeitraum zu erfassen, sollte eine Methode entwickelt werden, welche es erstmals ermöglicht, selektiv und konditional transkriptionell aktive Zellen sowohl während der akuten Infektion als auch während der Latenz auszulöschen. Dazu wurde mit Hilfe der Zwei-Schritt BAC-Mutagenese ein rekombinantes death-tagged Virus hergestellt, welches das Gen für den Diphtherie Toxin Rezeptor (DTR) unter Kontrolle des ie2-Promotors (P2) enthält. Ist der P2 transkriptionell aktiv, wird der DTR an der Zelloberfläche präsentiert und die Zelle wird suszeptibel für den Liganden Diphtherie Toxin (DT). Durch Gabe von DT werden somit alle Zellen ausgelöscht, in denen virale Genome transkriptionell aktiv sind. Mit zunehmender Dauer der DT-Behandlung sollte also die Menge an latenten viralen Genomen abnehmen.rnrnIn Western Blot-Analysen konnte das DTR-Protein bereits 2h nach der Infektion nachgewiesen werden. Die Präsentation des DTR an der Zelloberfläche wurde indirekt durch dessen Funktionalität bewiesen. Das rekombinante Virus konnte in Fibroblasten in Gegenwart von DT nicht mehr replizieren. In akut infizierten Tieren konnte die virale DNA-Menge durch eine einmalige intravenöse (i.v.) DT-Gabe signifikant reduziert werden. Verstärkt wurde dieser Effekt durch eine repetitive i.v. DT-Gabe. Auch während der Latenz gelang es, die Zahl der latenten viralen Genome durch repetitive i.v. und anschließende intraperitoneale (i.p.) DT-Gabe zu reduzieren, wobei wir abhängig von der Dauer der DT-Gabe eine Reduktion um 60% erreichen konnten. Korrespondierend zu der Reduktion der DNA-Menge sank auch die Reaktivierungshäufigkeit des rekombinanten Virus in Lungenexplantatkulturen. rnrnrnUm die Reaktivierungshäufigkeit während der Latenz berechnen zu können, wurde durch eine Grenzverdünnungsanalyse die Anzahl an latenten viralen Genomen pro Zelle bestimmt. Dabei ergab sich eine Kopienzahl von 9 (6 bis 13). Ausgehend von diesen Ergebnissen lässt…

Subjects/Keywords: Latenz, Diphtherie Toxin Rezeptor, murines Cytomegalievirus, transkriptionelle Aktivität, period prevalence; latency, diphtheria toxin receptor, murine Cytomegalovirus, transcriptional activity, period prevalence; Life sciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Scheller, S. (2011). In vivo konditionale Depletion von latentem murinen Cytomegalovirus. (Doctoral Dissertation). Johannes Gutenberg Universität Mainz. Retrieved from http://ubm.opus.hbz-nrw.de/volltexte/2012/3013/

Chicago Manual of Style (16^th Edition):

Scheller, Sabine. “In vivo konditionale Depletion von latentem murinen Cytomegalovirus.” 2011. Doctoral Dissertation, Johannes Gutenberg Universität Mainz. Accessed December 11, 2019. http://ubm.opus.hbz-nrw.de/volltexte/2012/3013/.

MLA Handbook (7^th Edition):

Scheller, Sabine. “In vivo konditionale Depletion von latentem murinen Cytomegalovirus.” 2011. Web. 11 Dec 2019.

Vancouver:

Scheller S. In vivo konditionale Depletion von latentem murinen Cytomegalovirus. [Internet] [Doctoral dissertation]. Johannes Gutenberg Universität Mainz; 2011. [cited 2019 Dec 11]. Available from: http://ubm.opus.hbz-nrw.de/volltexte/2012/3013/.

Council of Science Editors:

Scheller S. In vivo konditionale Depletion von latentem murinen Cytomegalovirus. [Doctoral Dissertation]. Johannes Gutenberg Universität Mainz; 2011. Available from: http://ubm.opus.hbz-nrw.de/volltexte/2012/3013/

University of California – Berkeley

10. Umamoto, Sean. Global Analysis of Murine Cytomegalovirus Open Reading Frames Using Yeast Two-Hybrid and Growth Phenotype Analysis.

Degree: Comparative Biochemistry, 2011, University of California – Berkeley

URL: http://www.escholarship.org/uc/item/0177z7vw

► Human cytomegalovirus (HCMV), a beta-herpesvirus, is an important opportunistic pathogen that primarily affects individuals with compromised or immature immune systems. It is of great significance… (more)

▼ Human cytomegalovirus (HCMV), a beta-herpesvirus, is an important opportunistic pathogen that primarily affects individuals with compromised or immature immune systems. It is of great significance in AIDS patients where it can cause serious morbidity through retinitis-associated blindness, and other complications, such as pneumonia and enteritis. In developed nations, it is a leading viral cause of congenital disease, where in-utero infection manifests in mental and behavioral disorders. In order to control infection and HCMV associated disease, new compounds and novel strategies must be developed. Understanding the role viral proteins play during the course of infection will help elucidate the mechanisms of HCMV pathogenesis and provide important information on potential targets for new treatments. However, the strict species specificity of HCMV prevents any studies into the pathogenesis of the virus in an animal host. This limitation can be overcome through the use of murine cytomegalovirus (MCMV). MCMV, like HCMV, is a betaherpesvirus that exhibits similar pathogenesis in mice to HCMV infection in the human host. The genetic structure of MCMV contains significant sequence homology to HCMV AD169 in at least 78 ORFs and can thereby be used as an important tool in elucidating the functions of these ORFs in a complete in vivo system. In our study, we have conducted a comprehensive YTH screen to identify potential interactions between approximately 170 MCMV ORFs. Growth phenotype analysis were also conducted using five different cell lines potentially involved in various aspects of CMV infection. Between these 170 predicted proteins we have identified 94 potential interactions that exhibit varying levels of essentiality depending on the type of cell infected. We aim to understand the nature of the interactions between the viral particle and proteins encoded by the virus in order to elucidate potential mechanisms by which these proteins help to assemble and create new progeny viruses. The interactions that we have identified in this study provide a framework to predict the functions of uncharacterized viral proteins. And understanding the importance of each protein in the context of infection can further help to determine the nature of these unknown viral proteins. Together using information about known viral proteins that interact with these unknown elements, we can develop a better understanding of how all of these components contribute to viral infection which can be used to determine more effective methods to treat or prevent CMV associated diseases.

Subjects/Keywords: Virology; Molecular Biology; CMV; cytomegalovirus; MCMV; murine cytomegalovirus; yeast two-hybrid

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Umamoto, S. (2011). Global Analysis of Murine Cytomegalovirus Open Reading Frames Using Yeast Two-Hybrid and Growth Phenotype Analysis. (Thesis). University of California – Berkeley. Retrieved from http://www.escholarship.org/uc/item/0177z7vw

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Umamoto, Sean. “Global Analysis of Murine Cytomegalovirus Open Reading Frames Using Yeast Two-Hybrid and Growth Phenotype Analysis.” 2011. Thesis, University of California – Berkeley. Accessed December 11, 2019. http://www.escholarship.org/uc/item/0177z7vw.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Umamoto, Sean. “Global Analysis of Murine Cytomegalovirus Open Reading Frames Using Yeast Two-Hybrid and Growth Phenotype Analysis.” 2011. Web. 11 Dec 2019.

Vancouver:

Umamoto S. Global Analysis of Murine Cytomegalovirus Open Reading Frames Using Yeast Two-Hybrid and Growth Phenotype Analysis. [Internet] [Thesis]. University of California – Berkeley; 2011. [cited 2019 Dec 11]. Available from: http://www.escholarship.org/uc/item/0177z7vw.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Umamoto S. Global Analysis of Murine Cytomegalovirus Open Reading Frames Using Yeast Two-Hybrid and Growth Phenotype Analysis. [Thesis]. University of California – Berkeley; 2011. Available from: http://www.escholarship.org/uc/item/0177z7vw

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Edinburgh

11. Martín, Sara Rodríguez. Investigation of MCMV-induced suppression of TNF production in vitro and in vivo.

Degree: PhD, 2010, University of Edinburgh

URL: http://hdl.handle.net/1842/4426

► The murine cytomegalovirus (MCMV) immediate early 1 (IE1) protein has been described as a trans-activator of viral and host gene expression. However, the precise role… (more)

▼ The murine cytomegalovirus (MCMV) immediate early 1 (IE1) protein has been described as a trans-activator of viral and host gene expression. However, the precise role that IE1 plays in the viral life cycle, and in particular its effect on the host immune response is not known. This thesis investigates the functional relationship of the IE1 protein and the immune response induced after infection. By using an ie1-deletion mutant MCMV (MCMVdie1) it was demonstrated that, early after infection, tumor necrosis factor (tnf ) gene activation and protein production was significantly induced in infected-primary macrophages (M ) to a much greater extent than its wild type counterpart. In addition, preliminary studies on the signalling pathways activated upon infection were carried out in order to gain information about the pathways that might be involved in MCMVinduced modulation of tnf activation. Initial observations on the MAPK family members Erk1/2, p38 and JNK did not revealed any differential activation in the absence of IE1. However, due to a number of limitations, it was not possible to draw any firm conclusions from this study. Investigation of the role of IE1 in the in vivo production of TNF were also performed in both susceptible (BALB/c) and resistant (C57Bl/6) mice. These experiments confirmed the attenuated phenotype of MCMVdie1 in vivo, whereby the mutant strain grew to much lower titers than wild type. When cytokine production was assessed in relation to PFU levels a significant production of TNF after infection is observed in different organs of both mice strains. This raises the question whether IE1 contributes to MCMV modulation of TNF production in the natural host. Although, because it is still unclear whether the phenotype of MCMVdie1 in vivo is due to a defect in the virus or the result of a immune response, it was not possible to conclude unequivocally that IE1 is responsible for dampening this cytokine response. This thesis also tested whether the attenuated replication of MCMVdie1 in vivo was due to the increased TNF production induced after infection. An initial investigation in tnf depleted mice revealed that the MCMVdie1 growth phenotype is not due to TNF response. Overall, this study has provided insight into a potential immune modulatory function by MCMV associated with IE1 protein and the regulation of TNF in vivo and in vitro.

Subjects/Keywords: 579.2; murine cytomegalovirus; macrophages; tumor necrosis factor; immediate early 1 protein; IE1

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Martín, S. R. (2010). Investigation of MCMV-induced suppression of TNF production in vitro and in vivo. (Doctoral Dissertation). University of Edinburgh. Retrieved from http://hdl.handle.net/1842/4426

Chicago Manual of Style (16^th Edition):

Martín, Sara Rodríguez. “Investigation of MCMV-induced suppression of TNF production in vitro and in vivo.” 2010. Doctoral Dissertation, University of Edinburgh. Accessed December 11, 2019. http://hdl.handle.net/1842/4426.

MLA Handbook (7^th Edition):

Martín, Sara Rodríguez. “Investigation of MCMV-induced suppression of TNF production in vitro and in vivo.” 2010. Web. 11 Dec 2019.

Vancouver:

Martín SR. Investigation of MCMV-induced suppression of TNF production in vitro and in vivo. [Internet] [Doctoral dissertation]. University of Edinburgh; 2010. [cited 2019 Dec 11]. Available from: http://hdl.handle.net/1842/4426.

Council of Science Editors:

Martín SR. Investigation of MCMV-induced suppression of TNF production in vitro and in vivo. [Doctoral Dissertation]. University of Edinburgh; 2010. Available from: http://hdl.handle.net/1842/4426

University of Oxford

12. Hutchinson, Sarah Louise. Role of the immuno-proteasome in CD8 responses to MCMV.

Degree: PhD, 2009, University of Oxford

URL: http://ora.ox.ac.uk/objects/uuid:e3bbf79a-95b1-41fd-9f3e-ce55d42fb16c ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.504483

Subjects/Keywords: 579.2; Immunology; Viruses; Infectious diseases; Murine cytomegalovirus; immuno-proteasome

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Hutchinson, S. L. (2009). Role of the immuno-proteasome in CD8 responses to MCMV. (Doctoral Dissertation). University of Oxford. Retrieved from http://ora.ox.ac.uk/objects/uuid:e3bbf79a-95b1-41fd-9f3e-ce55d42fb16c ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.504483

Chicago Manual of Style (16^th Edition):

Hutchinson, Sarah Louise. “Role of the immuno-proteasome in CD8 responses to MCMV.” 2009. Doctoral Dissertation, University of Oxford. Accessed December 11, 2019. http://ora.ox.ac.uk/objects/uuid:e3bbf79a-95b1-41fd-9f3e-ce55d42fb16c ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.504483.

MLA Handbook (7^th Edition):

Hutchinson, Sarah Louise. “Role of the immuno-proteasome in CD8 responses to MCMV.” 2009. Web. 11 Dec 2019.

Vancouver:

Hutchinson SL. Role of the immuno-proteasome in CD8 responses to MCMV. [Internet] [Doctoral dissertation]. University of Oxford; 2009. [cited 2019 Dec 11]. Available from: http://ora.ox.ac.uk/objects/uuid:e3bbf79a-95b1-41fd-9f3e-ce55d42fb16c ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.504483.

Council of Science Editors:

Hutchinson SL. Role of the immuno-proteasome in CD8 responses to MCMV. [Doctoral Dissertation]. University of Oxford; 2009. Available from: http://ora.ox.ac.uk/objects/uuid:e3bbf79a-95b1-41fd-9f3e-ce55d42fb16c ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.504483

University of Western Australia

13. Khong, Andrea. Effect of murine cytomegalovirus infection on haematopoiesis and myeloid cell differentiation and function.

Degree: PhD, 2008, University of Western Australia

URL: http://repository.uwa.edu.au:80/R/?func=dbin-jump-full&object_id=10770&local_base=GEN01-INS01

► Cytomegalovirus (CMV) is a ubiquitous pathogen affecting over 95% of the world’s population. While infection is typically asymptomatic in healthy individuals, the virus persists life-long… (more)

▼ Cytomegalovirus (CMV) is a ubiquitous pathogen affecting over 95% of the world’s population. While infection is typically asymptomatic in healthy individuals, the virus persists life-long in its host and can be reactivated following withdrawal of immune control. As such, it remains a serious clinical concern in individuals who are immunocompromised, such as newborns and neonates, transplant and/or chemotherapy recipients, and HIV/AIDS patients. CMV also has the ability to cause immunosuppression, the mechanisms of which include defective antigen presentation to T cells and interference with haematopoiesis in the bone marrow (BM). Due to strict species specificity, murine CMV (MCMV) provides a relevant model for the study of CMV modulation of the immune system in vivo in its natural host. The type I interferons (IFNs) represent a major family of cytokines involved in the early response to MCMV infection. Their anti-viral activity and regulation of NK cell activation and cytotoxicity are of significant interest in the context of MCMV infection, as genetic resistance to MCMV is mediated by the ability of Ly49H+ NK cells to directly recognise and lyse infected cells. Chapter 2 comprises an analysis of acute MCMV infection in the absence of type I IFN activity. These studies were conducted in IFNAR1 and IFNAR2 deficient mice, which lack components of the type I IFN receptor. Data obtained from these studies confirmed the essential requirement for type I IFN in controlling viral titres, promoting expansion of splenic Ly49H+ NK cells, and inducing early activation of NK cell cytotoxicity. In addition, our data depicted an accumulation of infected myeloid cells in the absence of effective NK cell-mediated control. This was paralleled by a significant increase in the level of serum TNF-α and IFN-γ, an effect which in some cases has been linked to serious pathological disease. Thus, the data described in this chapter provide an insight into the consequences arising from delayed NK cell responses to MCMV infection in the absence of type I IFN. vii Type I IFN can also potentially affect BM haematopoiesis. BM atrophy and impairment of myelopoiesis are serious consequences of CMV infection. During acute MCMV infection we consistently observed a profound loss of splenic dendritic cells (DCs) in BALB/c mice. Since all DC subsets are derived from BM haematopoietic progenitor cells, the possibility that MCMV might interfere with BM haematopoiesis and DC differentiation was explored. Chapters 3 and 4 describe the impact of acute MCMV infection on BM progenitors, with particular emphasis on the differentiation capabilities of these cells in ex vivo culture systems. Chapter 3 focuses on the effect of MCMV infection on BM cellularity and frequency of specific BM progenitor populations. A thorough analysis of contributing factors, such as viral infection of BM cells, involvement of type I and II IFNs, progenitor cell trafficking and NK cell activity in the BM compartment, was conducted. Our results showed that a severe loss of BM…

Subjects/Keywords: Cytomegalovirus infections; Cytomegaloviruses; Dendritic cells; Hematopoiesis; Immune response; Immunosuppressive agents; Interferon; Tumour model; Cytokine response; Dendritic cells; Murine cytomegalovirus

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Khong, A. (2008). Effect of murine cytomegalovirus infection on haematopoiesis and myeloid cell differentiation and function. (Doctoral Dissertation). University of Western Australia. Retrieved from http://repository.uwa.edu.au:80/R/?func=dbin-jump-full&object_id=10770&local_base=GEN01-INS01

Chicago Manual of Style (16^th Edition):

Khong, Andrea. “Effect of murine cytomegalovirus infection on haematopoiesis and myeloid cell differentiation and function.” 2008. Doctoral Dissertation, University of Western Australia. Accessed December 11, 2019. http://repository.uwa.edu.au:80/R/?func=dbin-jump-full&object_id=10770&local_base=GEN01-INS01.

MLA Handbook (7^th Edition):

Khong, Andrea. “Effect of murine cytomegalovirus infection on haematopoiesis and myeloid cell differentiation and function.” 2008. Web. 11 Dec 2019.

Vancouver:

Khong A. Effect of murine cytomegalovirus infection on haematopoiesis and myeloid cell differentiation and function. [Internet] [Doctoral dissertation]. University of Western Australia; 2008. [cited 2019 Dec 11]. Available from: http://repository.uwa.edu.au:80/R/?func=dbin-jump-full&object_id=10770&local_base=GEN01-INS01.

Council of Science Editors:

Khong A. Effect of murine cytomegalovirus infection on haematopoiesis and myeloid cell differentiation and function. [Doctoral Dissertation]. University of Western Australia; 2008. Available from: http://repository.uwa.edu.au:80/R/?func=dbin-jump-full&object_id=10770&local_base=GEN01-INS01

Johannes Gutenberg Universität Mainz

14. Simon, Christian Oliver. Generierung und Charakterisierung von rekombinanten Cytomegaloviren mit Punktmutationen in antigenen Peptiden.

Degree: 2005, Johannes Gutenberg Universität Mainz

URL: http://ubm.opus.hbz-nrw.de/volltexte/2006/937/

► Die Kontrolle der produktiven Cytomegalovirus- (CMV) Infektion ist von der effizienten Rekonstitution antiviraler CD8 T-Zellen abhängig. Dies führt jedoch nicht zur vollständigen Eliminierung des viralen… (more)

▼ Die Kontrolle der produktiven Cytomegalovirus- (CMV) Infektion ist von der effizienten Rekonstitution antiviraler CD8 T-Zellen abhängig. Dies führt jedoch nicht zur vollständigen Eliminierung des viralen Genoms aus den Zielorganen, sondern das Virus verbleibt in einem nicht-replikativen Zustand: der Latenz. Es ist bekannt, dass während der Latenz nur ein geringer Anteil latenter mCMV-Genome in der Lunge die Major Immediate Early (MIE) Gene ie1 und ie2 exprimiert, die Latenz aber dennoch bestehen bleibt, weil das differentielle Splicing des primären IE1/3-Transkripts zum Transaktivator-Transkript IE3 nicht erfolgt. Damit war neben der Initiation der IE-Genexpression am MIE-Promotor-Enhancer das IE1/3-Splicing als zweiter molekularer Latenz-Kontrollpunkt identifiziert. Parallel zur Latenz-assoziierten IE1-Genexpression sind in der Lunge aktivierte CD62L-low CD8 T-Zellen mit Spezifität für das immundominante IE1-Peptid 168-YPHFMPTNL-176 angereichert. Dies legte die Hypothese nahe, dass neben der molekularen Kontrolle der Latenz auch eine immunologische Kontrolle, beispielsweise durch IE1-Epitop-spezifische CD8 T-Zellen besteht. Zur Evaluierung dieser Hypothese wurde in der vorliegenden Arbeit mittels BAC-Mutagenese erstmals ein rekombinantes mCMV generiert, in dem das IE1-Peptid durch Punktmutation der C-terminalen MHC-Ankeraminosäure L176A zerstört ist. Dazu musste zunächst die Technik der BAC-Mutagenese herpesviraler Genome (in Anlehnung an die publizierten Arbeiten von Messerle et al., 1997; Borst et al., 1999, 2004; Wagner et al., 1999) in der Arbeitsgruppe etabliert werden. Neben der Funktionsverlust-Mutante (mCMV-IE1-L176A) wurden zur Kontrolle zwei Revertanten (mCMV-IE1-A176L und mCMV-IE1-A176L*) generiert. In letzterer, als Wobble-Revertante bezeichnet, wird wieder die authentische MHC-Ankeraminosäure L eingesetzt, es verbleibt aber ein singulärer Nukleotidaustausch A->T in der Wobble-Position des Codons als Marker zur Unterscheidung zum WT-mCMV zurück. Der immunologische Phänotyp der Funktionsverlust-Mutante, also die funktionelle Auslöschung des antigenen IE1-Peptids im Priming einer CD8 T-Zell-Antwort, entsprach der Erwartung. Entsprechend konnte nach Infektion mit der Funktionsverlust-Mutante keine Reaktivität gegen das IE1-Peptid nachgewiesen werden. In den Revertanten hingegen war die Erkennung des IE1-Peptids wieder hergestellt. Die Ergebnisse dieser Arbeit zeigen weiter, dass die Funktionsverlust-Mutante sowie die Revertanten ohne signifikante Beeinflussung in vitro in permissiven Fibroblasten und in vivo in verschiedenen Geweben replizieren. Wie aktuelle Daten nach Knochenmarktransplantation und Infektion mit der Funktionsverlust-Mutante im Vergleich zu den Revertanten zeigen, ist die Frequenz Latenz-assoziierter IE1-Transkriptionsereignisse bei der Funktionsverlust-Mutante signifikant erhöht. Damit konnte erstmalig der Beweis für eine Kontrolle der Latenz-assoziierten IE1-Genexpression durch IE1-Epitop-spezifische CD8 T-Zellen und damit für eine Präsentation des IE1-Peptids während der Latenz erbracht…

Subjects/Keywords: Cytomegalovirus, murines Cytomegalovirus, CMV, mCMV, Latenz, CD8 T-Zellen, BAC-Mutagenese, Punktmutationen, MHC Klasse I, Realtime PCR; cytomegalovirus, murine cytomegalovirus, CMV, mCMV, latency, CD8 T cells, BAC mutagenesis, point mutation, MHC class I, realtime PCR; Natural sciences and mathematics

Record Details Similar Records Cite « Share

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Simon, C. O. (2005). Generierung und Charakterisierung von rekombinanten Cytomegaloviren mit Punktmutationen in antigenen Peptiden. (Doctoral Dissertation). Johannes Gutenberg Universität Mainz. Retrieved from http://ubm.opus.hbz-nrw.de/volltexte/2006/937/

Chicago Manual of Style (16^th Edition):

Simon, Christian Oliver. “Generierung und Charakterisierung von rekombinanten Cytomegaloviren mit Punktmutationen in antigenen Peptiden.” 2005. Doctoral Dissertation, Johannes Gutenberg Universität Mainz. Accessed December 11, 2019. http://ubm.opus.hbz-nrw.de/volltexte/2006/937/.

MLA Handbook (7^th Edition):

Simon, Christian Oliver. “Generierung und Charakterisierung von rekombinanten Cytomegaloviren mit Punktmutationen in antigenen Peptiden.” 2005. Web. 11 Dec 2019.

Vancouver:

Simon CO. Generierung und Charakterisierung von rekombinanten Cytomegaloviren mit Punktmutationen in antigenen Peptiden. [Internet] [Doctoral dissertation]. Johannes Gutenberg Universität Mainz; 2005. [cited 2019 Dec 11]. Available from: http://ubm.opus.hbz-nrw.de/volltexte/2006/937/.

Council of Science Editors:

Simon CO. Generierung und Charakterisierung von rekombinanten Cytomegaloviren mit Punktmutationen in antigenen Peptiden. [Doctoral Dissertation]. Johannes Gutenberg Universität Mainz; 2005. Available from: http://ubm.opus.hbz-nrw.de/volltexte/2006/937/

Open Access Theses and Dissertations