Programmed cell death (PCD) is a major component of host innate immunity against viral infection and tumorigenesis. In addition to a well-characterized apoptosis, autophagy is a new, emerging PCD pathway. Autophagy is an evolutionally conserved and highly regulated homeostasis process by which cytoplasmic components are degraded for removal or turnover via a lysosomal pathway. This process also plays an effective role in anti-microbial and anti-tumor responses by degrading intracellular bacteria and viruses and suppressing cancer cell growth, respectively. Thus, apoptotic and autophagic PCDs are important innate safeguard mechanisms to protect the organism against harmful microbes and unwanted cancerous cells. The goal of this study is to better understand how gamma-2 herpesviruses, including Kaposi's sarcoma herpesvirus (KSHV), herpesvirus saimiri (HVS), and mouse herpesvirus 68 (MHV68), evade host PCD- mediated innate immunity, with a specific focus on the viral Bcl-2, designated as vBcl-2. The loss of vBcl-2 gene from viral genome does not affect the ability of MHV68 and HVS to replicate in culture, nor does it change the acute phase of viral replication in mice and monkeys, respectively. However, MHV68 vBcl-2 mutant exhibits a significant decrease in the latency and reactivation in mice, whereas HVS vBcl-2 mutant no longer induces lymphoma in primates. In addition, gamma-2 herpesvirus vBcl-2 functions not only as an inhibitor of apoptosis by targeting cellular Bax and Bak, but also as an antagonist of autophagy by targeting cellular Beclin1-UVRAG tumor suppressor autophagic complex. Based on these findings, we hypothesize a novel viral immune evasion and pathogenic strategy where vBcl-2 targets both apoptosis and autophagy to escape host PCD-mediated innate immunity and tumor suppression, and that its anti-apoptotic and anti-autophagic activity contribute to the persistence and pathogenesis of gamma-2 herpesvirus in distinctive manners. The proposed research is initially focused on characterizing vBcl-2 mutants to differentiate its anti-apoptotic and anti-autophagic function (Aim 1), followed by investigating how vBcl-2 antagonizes apoptosis (Aim 2) and autophagy (Aim 3). To correlate the effect of vBcl-2 on apoptosis and autophagy with viral persistence and pathogenesis, we will test how the loss of vBcl-2 activity to subvert apoptosis and/or autophagy affects MHV68 persistence and HVS pathogenesis in mice and primates, respectively (Aim 4). With well-established in vitro and in vivo experimental conditions, the proposed study will detail the role of vBcl-2 as an apoptosis and autophagy antagonist in gamma-2 herpesvirus persistence and pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI073099-05
Application #
8134823
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Beisel, Christopher E
Project Start
2007-08-15
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$391,803
Indirect Cost
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
Foo, Suan-Sin; Chen, Weiqiang; Chan, Yen et al. (2017) Asian Zika virus strains target CD14+ blood monocytes and induce M2-skewed immunosuppression during pregnancy. Nat Microbiol 2:1558-1570
Zhu, Ying; Ramos da Silva, Suzane; He, Meilan et al. (2016) An Oncogenic Virus Promotes Cell Survival and Cellular Transformation by Suppressing Glycolysis. PLoS Pathog 12:e1005648
Yang, Yongfei; Quach, Christine; Liang, Chengyu (2016) Autophagy modulator plays a part in UV protection. Autophagy 12:1677-8
Liang, Qiming; Luo, Zhifei; Zeng, Jianxiong et al. (2016) Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy. Cell Stem Cell 19:663-671
Cheng, Fan; He, Meilan; Jung, Jae U et al. (2016) Suppression of Kaposi's Sarcoma-Associated Herpesvirus Infection and Replication by 5'-AMP-Activated Protein Kinase. J Virol 90:6515-25
Lee, Myung-Shin; Yuan, Hongfeng; Jeon, Hyungtaek et al. (2016) Human Mesenchymal Stem Cells of Diverse Origins Support Persistent Infection with Kaposi's Sarcoma-Associated Herpesvirus and Manifest Distinct Angiogenic, Invasive, and Transforming Phenotypes. MBio 7:e02109-15
Suzuki, Yuzo; Maazi, Hadi; Sankaranarayanan, Ishwarya et al. (2016) Lack of autophagy induces steroid-resistant airway inflammation. J Allergy Clin Immunol 137:1382-1389.e9
Lee, Hye-Ra; Mitra, Jaba; Lee, Stacy et al. (2016) Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 (vIRF4) Perturbs the G1-S Cell Cycle Progression via Deregulation of the cyclin D1 Gene. J Virol 90:1139-43
Yang, Yongfei; He, Shanshan; Wang, Qiaoxiu et al. (2016) Autophagic UVRAG Promotes UV-Induced Photolesion Repair by Activation of the CRL4(DDB2) E3 Ligase. Mol Cell 62:507-19
O'Connell, Douglas; Liang, Chengyu (2016) Autophagy interaction with herpes simplex virus type-1 infection. Autophagy 12:451-9

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