Kaposi's sarcoma-associated herpesvirus (KSHV), an important human pathogen accounting for a large percentage of virally caused cancers worldwide, has evolved a variety of stratagems for evading host immune responses to establish a life-long persistent infection. Autophagy pathway consists of four distinct stages of autophagosome biogenesis-induction, vesicle nucleation, vesicle elongation, and vesicle maturation- by forming specific protein complexes. Our study has discovered a novel KSHV-mediated comprehensive inhibition of autophagy pathway where KSHV remarkably confers tight suppression of the autophagy by targeting each step of its signal transduction: by vBcl-2 in vesicle nucleation, by vFLIP in vesicle elongation, and by K7 in vesicle maturation. Specifically, the vBcl-2, vFLIP, and K7 not only possess anti- apoptotic activities but also serve as anti-autophagy molecules via their interactions with the Beclin1, the Atg3 E2 enzyme, and the Rubicon, respectively, which contributes to the establishment of viral persistency. This also indicates how important autophagy is as part of host immune responses against pathogens. Furthermore, we have recently developed an infectious KSHV bacterial artificial chromosome (BAC16) and TALEN- mediated genome editing that allows the efficient genetic manipulation of KSHV genome as well as host genome to study viral persistence and pathogenesis. Thus, the goal of this study is two-fold: firstly, to identify the specific mechanisms of how viral anti-autophagy proteins target and suppress autophagy- mediated host immunity and secondly, to test whether the suppression of autophagy-mediated host immunity is necessary for in vivo KSHV persistent infection. Despite previous extensive cell biology and biochemical studies, the detailed in vivo biological evidences of vBcl-2- and K7-mediated immune evasion for viral persistence are still elusive. In this proposal, we will attempt to define in vivo roles of the vBc-2 and K7 in vial persistence. Specifically, by utilizing in NOD/SCID IL2Rgamma-/- humanized mouse model, we will test whether the loss of vBcl-2 and/or K7 genes from the KSHV genome affects the establishment of viral persistence and how critical autophagy is as a host immune determinant to control the in vivo KSHV latency. This proposal is highly innovative and its successful outcome should significantly impact our understanding of KSHV biology.

Public Health Relevance

Autophagy is a highly regulated homeostatic process where worn-out proteins, malfunctioning organelles, and invading pathogens are swept up and degraded by tiny 'vacuum cleaners.' To avoid host's autophagy-mediated innate immune responses, herpesviruses have evolved elaborate mechanisms to target and modulate differing aspects of autophagy pathway for their persistent infection. Thus, understanding herpesvirus-mediated autophagy evasion tricks is the primary goal of this application.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI073099-08
Application #
8893863
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Beisel, Christopher E
Project Start
2006-12-01
Project End
2016-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
8
Fiscal Year
2015
Total Cost
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
90032
Yang, Yongfei; Jang, Gyu-Beom; Yang, Xuanjun et al. (2018) Central role of autophagic UVRAG in melanogenesis and the suntan response. Proc Natl Acad Sci U S A 115:E7728-E7737
Liang, Qiming; Wei, Dahai; Chung, Brian et al. (2018) Novel Role of vBcl2 in the Virion Assembly of Kaposi's Sarcoma-Associated Herpesvirus. J Virol 92:
Foo, Suan-Sin; Chen, Weiqiang; Chan, Yen et al. (2018) Biomarkers and immunoprofiles associated with fetal abnormalities of ZIKV-positive pregnancies. JCI Insight 3:
Gruffaz, Marion; Zhou, Shenghua; Vasan, Karthik et al. (2018) Repurposing Cytarabine for Treating Primary Effusion Lymphoma by Targeting Kaposi's Sarcoma-Associated Herpesvirus Latent and Lytic Replications. MBio 9:
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
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 90:6515-6525
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
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
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

Showing the most recent 10 out of 69 publications