The human gammaherpesviruses (GHVs) Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) are DNA tumor viruses that establish lifelong chronic infections of host lymphocytes and other cell types. Through the expression of viral gene products that alter normal cellular signaling pathways and counteract host immune responses, GHVs place the chronically infected host at risk for numerous malignancies. As it relates to the COBRE theme of defining the impact of microbial virulence factors on host inflammatory and immune responses, the overall objective of experiments described in this project is to better define mechanisms by which GHVs counteract innate host defense mechanisms in order to successfully colonize a host. Central to this objective is the utilization of murine gammaherpesvirus-68 (MHV68), a naturally occurring rodent pathogen that is genetically related to EBV and KSHV and recapitulates key aspects of human GHV infection as a tractable small-animal model to define the virus-host interaction in vivo. Extending our published and preliminary data, the current proposal specifically seeks to understand functions of the MHV68 latency-associated nuclear antigen (mLANA), a putative viral transcriptional repressor protein, as a critical modulator of antiviral transcriptional pathways or cellular immune responses activated by interferon alpha/Beta (IFN-I) signaling that would otherwise restrict GHV infection. This work will be accomplished in three integrated but independent specific aims: (1) define IFN-l-mediated control of GHV infection at mucosal barriers, (2) elucidate roles for mLANA-mediated transcriptional control in MHV68 pathogenesis, and (3) define mLANA-interferon regulatory factor 3 (IRF-3) interactions in MHV68 infection. The proposed experiments hold broad significance by addressing two critical gaps in our understanding of GHV pathogenesis: the functions of viral disease determinants in the success of GHV infection and the interactions of GHV with host innate immune response pathways. Moreover, by advancing understanding of the nature of host immune responses, which is fundamentally important to all infectious diseases, the proposed experiments may also hold relevance for diseases caused by diverse and unrelated intracellular pathogens.
Gammaherpesviruses are a group of DNA tumor viruses that include Epstein-Barr- virus (EBV) and Kaposi sarcoma-associated herpesvirus. These viruses cause chronic infection and place an infected person at risk for cancers, including Burkitt and Hodgkin lymphomas. As more than 90% of adults are chronically infected by EBV, an understanding of viral gene functions and how the immune system responds to these infections can have a considerable impact on human health by revealing targets for new antiviral therapies.
|Kothari, Anisha; Hittelman, Walter N; Chambers, Timothy C (2016) Cell Cycle-Dependent Mechanisms Underlie Vincristine-Induced Death of Primary Acute Lymphoblastic Leukemia Cells. Cancer Res 76:3553-61|
|Sengupta, Deepanwita; Tackett, Alan J (2016) Proteomic Findings in Melanoma. J Proteomics Bioinform 9:|
|Byrd, Alicia K; Zybailov, Boris L; Maddukuri, Leena et al. (2016) Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress. J Biol Chem 291:18041-57|
|Fujiwara, T; Zhou, J; Ye, S et al. (2016) RNA-binding protein Musashi2 induced by RANKL is critical for osteoclast survival. Cell Death Dis 7:e2300|
|Jolly, Lee Ann; Novitskiy, Sergey; Owens, Phillip et al. (2016) Fibroblast-Mediated Collagen Remodeling Within the Tumor Microenvironment Facilitates Progression of Thyroid Cancers Driven by BrafV600E and Pten Loss. Cancer Res 76:1804-13|
|Liem, Jason; Liu, Jia (2016) Stress Beyond Translation: Poxviruses and More. Viruses 8:|
|Atanassov, Boyko S; Mohan, Ryan D; Lan, Xianjiang et al. (2016) ATXN7L3 and ENY2 Coordinate Activity of Multiple H2B Deubiquitinases Important for Cellular Proliferation and Tumor Growth. Mol Cell 62:558-71|
|Atwood, Danielle N; Beenken, Karen E; Lantz, Tamara L et al. (2016) Regulatory Mutations Impacting Antibiotic Susceptibility in an Established Staphylococcus aureus Biofilm. Antimicrob Agents Chemother 60:1826-9|
|Sifford, Jeffrey M; Stahl, James A; Salinas, Eduardo et al. (2016) Murine Gammaherpesvirus 68 LANA and SOX Homologs Counteract ATM-Driven p53 Activity during Lytic Viral Replication. J Virol 90:2571-85|
|Byrum, Stephanie D; Burdine, Marie S; Orr, Lisa et al. (2016) A Quantitative Proteomic Analysis of Urine from Gamma-Irradiated Non-Human Primates. J Proteomics Bioinform 9:|
Showing the most recent 10 out of 66 publications