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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Exploratory Grants (P20)
Project #
5P20GM103625-03
Application #
8652484
Study Section
Special Emphasis Panel (ZRR1)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Type
DUNS #
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Kovak, Matthew R; Saraswati, Sarika; Schoen, David J et al. (2014) Investigation of galectin-3 function in the reproductive tract by identification of binding ligands in human seminal plasma. Am J Reprod Immunol 72:403-12
Pawar, Snehalata A; Shao, Lijian; Chang, Jianhui et al. (2014) C/EBP? deficiency sensitizes mice to ionizing radiation-induced hematopoietic and intestinal injury. PLoS One 9:e94967
Winchell, Caylin G; Graham, Joseph G; Kurten, Richard C et al. (2014) Coxiella burnetii type IV secretion-dependent recruitment of macrophage autophagosomes. Infect Immun 82:2229-38
Nakagawa, Mayumi; Coleman, Hannah N; Wang, Xuelian et al. (2014) IL-12 secretion by Langerhans cells stimulated with Candida skin test reagent is mediated by dectin-1 in some healthy individuals. Cytokine 65:202-9
Maddukuri, Leena; Ketkar, Amit; Eddy, Sarah et al. (2014) The Werner syndrome protein limits the error-prone 8-oxo-dG lesion bypass activity of human DNA polymerase kappa. Nucleic Acids Res 42:12027-40
Kennedy, Joshua L; Schroeder, Nikhila; Palacios, Thamiris et al. (2014) Fifty-five-year-old man with chronic yeast infections. Allergy Asthma Proc 35:415-22
Fortune, Danielle E; Lin, Yi-Pin; Deka, Ranjit K et al. (2014) Identification of lysine residues in the Borrelia burgdorferi DbpA adhesin required for murine infection. Infect Immun 82:3186-98
Coleman, Carrie B; McGraw, Jennifer E; Feldman, Emily R et al. (2014) A gammaherpesvirus Bcl-2 ortholog blocks B cell receptor-mediated apoptosis and promotes the survival of developing B cells in vivo. PLoS Pathog 10:e1003916
Groshong, Ashley M; Fortune, Danielle E; Moore, Brendan P et al. (2014) BB0238, a presumed tetratricopeptide repeat-containing protein, is required during Borrelia burgdorferi mammalian infection. Infect Immun 82:4292-306
Beenken, Karen E; Mrak, Lara N; Zielinska, Agnieszka K et al. (2014) Impact of the functional status of saeRS on in vivo phenotypes of Staphylococcus aureus?sarA mutants. Mol Microbiol 92:1299-312

Showing the most recent 10 out of 16 publications