Gamma -herpesviruses such as Kaposi's sarcoma-associated herpesvirus (KSHV;also known as HHV8) and murine gamma herpesvirus 68 (MHV-68) are DNA viruses involving both latent and lytic programs during their interactions with host. KSHV infection leads to an AIDS defining cancer that represents a significant clinical problem. Despite the positive outcome of HAART on Kaposi Sarcoma, little is known about the role of KSHV-specific host immunity in disease progression. The main goal of this project is to understand the role of non-coding RNAs in modulating gamma-herpesvirus life cycle and in regulating host-pathogen interactions. The human host is invaded by a wide range of microbial pathogens and has evolved a number of defensive mechanisms to survive these infections. In addition to adaptive immunity, it is becoming increasingly clear that innate immunity plays an important role in protecting host organisms from infections. To achieve persistent infections, pathogens have co-evolved with host to devise mechanisms to successfully replicate and evade host innate immune system. MicroRNAs (miRNAs) are 18-24 nucleotide single? stranded non-coding RNA, usually generated from noncoding regions of gene transcripts, bind to target mRNAs by base-pairing, and guide posttranscriptional repression of these target mRNAs. A growing number of recent studies support the hypothesis that viruses encode miRNAs that assist viruses to evade immune responses in infected cells and to regulate different phases of viral life cycle. In addition to viral miRNAs, recent studies show that host cells respond to viral infections by changing the expression of cellular miRNAs that could be a part of innate immune response to viral infections. Understanding the RNA-based mechanisms to boost immune system will directly impact the design of new strategies for antiviral and cancer vaccines. Our project will investigate the role of host non-coding RNAs and RNP complexes including RNAi machinery in regulating interactions between a host and MHV-68/KSHV and in evading gammaherpesvirus innate immune mechanisms. We will employ highly innovative, collaborative, multidisciplinary approaches, and support from state of the art cores facilities to address these fundamental questions in an emerging field of biology.

Public Health Relevance

Proposed studies will provide fundamental insights into the host-pathogen biology and into the mechanisms of miRNA-mediated regulation of host-pathogen interactions and gammaherpesvirus innate immune evasion. Results of these studies would offer tremendous potential to not only understand RNA-based immune stimulation at the mechanistic levels, but also for the development of new and effective vaccines for cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA177322-01A1
Application #
8660815
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (O1))
Project Start
2014-09-19
Project End
2019-08-31
Budget Start
2014-09-19
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$443,015
Indirect Cost
$49,837
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Koh, Mei Yee; Gagea, Mihai; Sargis, Timothy et al. (2016) A new HIF-1α/RANTES-driven pathway to hepatocellular carcinoma mediated by germline haploinsufficiency of SART1/HAF in mice. Hepatology 63:1576-91
Xiong, Xiao-Peng; Kurthkoti, Krishna; Chang, Kung-Yen et al. (2016) miR-34 Modulates Innate Immunity and Ecdysone Signaling in Drosophila. PLoS Pathog 12:e1006034
Gong, Danyang; Kim, Yong Hoon; Xiao, Yuchen et al. (2016) A Herpesvirus Protein Selectively Inhibits Cellular mRNA Nuclear Export. Cell Host Microbe 20:642-653
Ward-Kavanagh, Lindsay K; Lin, Wai Wai; Šedý, John R et al. (2016) The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses. Immunity 44:1005-19
Scarzello, Anthony J; Jiang, Qun; Back, Timothy et al. (2016) LTβR signalling preferentially accelerates oncogenic AKT-initiated liver tumours. Gut 65:1765-75
Feng, Jiaying; Gong, Danyang; Fu, Xudong et al. (2015) M1 of Murine Gamma-Herpesvirus 68 Induces Endoplasmic Reticulum Chaperone Production. Sci Rep 5:17228
Shah, Priya S; Wojcechowskyj, Jason A; Eckhardt, Manon et al. (2015) Comparative mapping of host-pathogen protein-protein interactions. Curr Opin Microbiol 27:62-8
York, Autumn G; Williams, Kevin J; Argus, Joseph P et al. (2015) Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling. Cell 163:1716-29
Lau, E; Sedy, J; Sander, C et al. (2015) Transcriptional repression of IFNβ1 by ATF2 confers melanoma resistance to therapy. Oncogene 34:5739-48
Davis, Zoe H; Verschueren, Erik; Jang, Gwendolyn M et al. (2015) Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes. Mol Cell 57:349-60

Showing the most recent 10 out of 13 publications