Herpesviruses are ubiquitous in humans and they have been implicated in diverse malignancies. Human Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus are associated with tumors of lymphoid, epithelial, and endothelial origin in immuno-compromised patients. Due to a paucity of human studies and lack of permissive cell lines and animal models, host immune responses and in vivo infection of KSHV and EBV are largely unknown. Being closely-related KSHV and EBV, murine 3- herpesvirus 68 (3HV68) infects mice, replicates to higher titers in the lung and establishes persistent latent infection in the spleen, providing an excellent tractable animal model to delineate the entire immune responses and viral infection in vivo. Upon viral infection, host innate immune pathways are often activated to induce the production of antiviral inflammatory cytokines and interferons. Using 3HV68 as a model for KSHV and EBV, we have recently discovered that 3HV68 hijacks an innate immune pathway to promote viral lytic replication and to prevent antiviral cytokine production. Thus, we will investigate the molecular mechanisms by which 3HV68 deploys to activate the host innate immune signaling pathway to promote viral transcriptional activation in Aim 1 and to subvert antiviral cytokine production in Aim 2. Furthermore, we will delineate the virus-host interactions that activate the innate immune pathway in Aim 3. Collectively, this study will elucidate a novel mechanism whereby 3HV68 infection activates a host innate immune signaling pathway to enable viral transcription and disable host cytokine production, thereby greatly expanding our current paradigm of immune subversion. Findings gleaned from this study will advance our understanding of host activation and viral exploitation of innate immune responses, and potentially guide our future efforts in vaccine design and antiviral therapeutics to treat malignancies associated with human KSHV and EBV.

Public Health Relevance

The aims of this study are to investigate the molecular mechanisms by which a host innate immune pathway is exploited to facilitate viral infection and to delineate the virus-host interactions that activate the innate immune pathway. Thus, this study will advance our understanding of pathogen immune exploitation, host innate immune responses, and viral pathogenesis. Findings from our study will re-shape our view of antiviral innate immunity, provide an animal model for studies using human tumorigenic herpesviruses, and also potentially guide future efforts to treat herpesvirus-associated malignancies.!

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE021445-03
Application #
8469753
Study Section
Virology - B Study Section (VIRB)
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
2011-09-02
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$393,600
Indirect Cost
$153,600
Name
University of Southern California
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Zhang, Junjie; Feng, Hao; Xu, Simin et al. (2016) Hijacking GPCRs by viral pathogens and tumor. Biochem Pharmacol 114:69-81
Zhao, Jun; Li, Junhua; Xu, Simin et al. (2016) Emerging Roles of Protein Deamidation in Innate Immune Signaling. J Virol 90:4262-8
Zhao, Jun; Zeng, Yi; Xu, Simin et al. (2016) A Viral Deamidase Targets the Helicase Domain of RIG-I to Block RNA-Induced Activation. Cell Host Microbe 20:770-784
Zhang, Junjie; Zhu, Lining; Lu, Xiaolu et al. (2015) Recombinant Murine Gamma Herpesvirus 68 Carrying KSHV G Protein-Coupled Receptor Induces Angiogenic Lesions in Mice. PLoS Pathog 11:e1005001
Zhao, Jun; He, Shanping; Minassian, Arlet et al. (2015) Recent advances on viral manipulation of NF-κB signaling pathway. Curr Opin Virol 15:103-11
He, Shanping; Zhao, Jun; Song, Shanshan et al. (2015) Viral pseudo-enzymes activate RIG-I via deamidation to evade cytokine production. Mol Cell 58:134-46
Zhang, Junjie; He, Shanping; Wang, Yi et al. (2015) Herpesviral G protein-coupled receptors activate NFAT to induce tumor formation via inhibiting the SERCA calcium ATPase. PLoS Pathog 11:e1004768
Brulois, Kevin; Wong, Lai-Yee; Lee, Hye-Ra et al. (2015) Association of Kaposi's Sarcoma-Associated Herpesvirus ORF31 with ORF34 and ORF24 Is Critical for Late Gene Expression. J Virol 89:6148-54
Liang, Qiming; Chang, Brian; Lee, Patrick et al. (2015) Identification of the Essential Role of Viral Bcl-2 for Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication. J Virol 89:5308-17
Minassian, Arlet; Zhang, Junjie; He, Shanping et al. (2015) An Internally Translated MAVS Variant Exposes Its Amino-terminal TRAF-Binding Motifs to Deregulate Interferon Induction. PLoS Pathog 11:e1005060

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