| dc.identifier.uri | http://hdl.handle.net/11401/76477 | |
| dc.description.sponsorship | This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. | en_US |
| dc.format | Monograph | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dc.type | Dissertation | |
| dcterms.abstract | Herpesviruses establish life-long infections that represent a détente with the immune system of the host. These large enveloped DNA viruses have two distinct phases of their life cycle. During lytic infection, most viral genes are expressed and infectious virions are produced for dissemination. In contrast, viral gene expression is tightly controlled during the latent stage of infection, and the virus is not easily targeted by the immune system. Gammaherpesviruses evade clearance by the immune response to gain access to B lymphocytes, the primary reservoir of latent infection. In the context of immune suppression, control of the infection is lost, increasing the risk of virus-driven malignancies. Our laboratory seeks to understand the mechanisms by which gammaherpesviruses overcome innate and adaptive immune clearance and hijack immune cells for latency. We use a natural pathogen of murid rodents, murine gammaherpesvirus 68 (MHV68), to probe the interactions between the virus and the host. T cells of the adaptive immune system that recognize both lytic and latent viral antigens control long-term infection. I determined that T cells lacking the negative regulators Suppressor of TCR signaling-1 and -2 (Sts-1 and Sts-2) better respond to gammaherpesvirus-infected cells in vitro. However, hyper-responsiveness in the T cell compartment did not impact pathogenesis in vivo. With regard to innate immunity, the inflammasome is an intracellular surveillance system that can detect pathogen-associated molecules. I found that Caspase1-mediated inflammasome signaling did not contribute to the control of MHV68 pathogenesis; but in vitro investigations uncovered a reduction in the pro-inflammatory molecule IL-1beta upon infection of primary macrophages. Lastly, I sought to examine the role of IKKalpha-dependent non-canonical NF-kappaB signaling pathway during gammaherpesvirus pathogenesis. Although IKKalpha-mediated signaling was dispensable for virus production, IKKalpha signaling was dampened upon extrinsic signaling during lytic infection. In summary, my studies determined that enhancement of T cell responses did not lead to improved clearance of the virus and that MHV68 infection evades activation of pro-inflammatory responses and alternative NF-kappaB signaling. These studies emphasize the complexity of gammaherpesvirus interactions with the innate and adaptive immune arms of the host and uncover novel mechanisms by which a gammaherpesvirus subverts these responses. | |
| dcterms.abstract | Herpesviruses establish life-long infections that represent a détente with the immune system of the host. These large enveloped DNA viruses have two distinct phases of their life cycle. During lytic infection, most viral genes are expressed and infectious virions are produced for dissemination. In contrast, viral gene expression is tightly controlled during the latent stage of infection, and the virus is not easily targeted by the immune system. Gammaherpesviruses evade clearance by the immune response to gain access to B lymphocytes, the primary reservoir of latent infection. In the context of immune suppression, control of the infection is lost, increasing the risk of virus-driven malignancies. Our laboratory seeks to understand the mechanisms by which gammaherpesviruses overcome innate and adaptive immune clearance and hijack immune cells for latency. We use a natural pathogen of murid rodents, murine gammaherpesvirus 68 (MHV68), to probe the interactions between the virus and the host. T cells of the adaptive immune system that recognize both lytic and latent viral antigens control long-term infection. I determined that T cells lacking the negative regulators Suppressor of TCR signaling-1 and -2 (Sts-1 and Sts-2) better respond to gammaherpesvirus-infected cells in vitro. However, hyper-responsiveness in the T cell compartment did not impact pathogenesis in vivo. With regard to innate immunity, the inflammasome is an intracellular surveillance system that can detect pathogen-associated molecules. I found that Caspase1-mediated inflammasome signaling did not contribute to the control of MHV68 pathogenesis; but in vitro investigations uncovered a reduction in the pro-inflammatory molecule IL-1beta upon infection of primary macrophages. Lastly, I sought to examine the role of IKKalpha-dependent non-canonical NF-kappaB signaling pathway during gammaherpesvirus pathogenesis. Although IKKalpha-mediated signaling was dispensable for virus production, IKKalpha signaling was dampened upon extrinsic signaling during lytic infection. In summary, my studies determined that enhancement of T cell responses did not lead to improved clearance of the virus and that MHV68 infection evades activation of pro-inflammatory responses and alternative NF-kappaB signaling. These studies emphasize the complexity of gammaherpesvirus interactions with the innate and adaptive immune arms of the host and uncover novel mechanisms by which a gammaherpesvirus subverts these responses. | |
| dcterms.available | 2017-09-20T16:50:22Z | |
| dcterms.contributor | van der Velden, Adrianus | en_US |
| dcterms.contributor | Krug, Laurie T | en_US |
| dcterms.contributor | Carpino, Nicholas | en_US |
| dcterms.contributor | Bliska, James B | en_US |
| dcterms.contributor | Marcu, Kenneth. | en_US |
| dcterms.creator | Cieniewicz, Brandon | |
| dcterms.dateAccepted | 2017-09-20T16:50:22Z | |
| dcterms.dateSubmitted | 2017-09-20T16:50:22Z | |
| dcterms.description | Department of Molecular and Cellular Biology. | en_US |
| dcterms.extent | 227 pg. | en_US |
| dcterms.format | Monograph | |
| dcterms.format | Application/PDF | en_US |
| dcterms.identifier | http://hdl.handle.net/11401/76477 | |
| dcterms.issued | 2015-05-01 | |
| dcterms.language | en_US | |
| dcterms.provenance | Made available in DSpace on 2017-09-20T16:50:22Z (GMT). No. of bitstreams: 1
Cieniewicz_grad.sunysb_0771E_12685.pdf: 4273751 bytes, checksum: 3a9b402d7773fc3c863b956186c5d443 (MD5)
Previous issue date: 2015 | en |
| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | Virology | |
| dcterms.subject | Gammaherpesvirus, IKK, IKK alpha, Inflammasome, MHV68, T cell | |
| dcterms.title | The interaction of murine gammaherpesvirus 68 with the innate and adaptive immune systems of the host | |
| dcterms.type | Dissertation | |
