Despite being a significant human health problem, a majority of KSHV studies have been restricted to the overexpression system of the selected viral genes in the absence of viral complete genome and Infection, leading to limited understanding to in vivo KSHV persistence and pathogenesis that are essential in developing safe and effective anti-viral agents and vaccines against this oncogenic pathogen. Specifically, understanding how KSHV gene products contribute to the establishment of persistent infection and pathogenesis requires a reverse genetics approach for the viral genetic deficiencies, an in vitro and in vivo assay system for the viral oncogenesis, and an animal model for the in vivo viral persistence under active host immune conditions. Fortunately, our Program Project Grant (PPG) leaders have recently established a new "infectious" bacterial artificial clone (BACI6) of KSHV genome that significantly improves the efficiency of the genetic manipulation and virus production (Project 1), a novel system to investigate host's control of the KSHV nucleotide metabolism (Project 2), an efficient KSHV infection and transformation system using primary embryonic metanephric mesenchymal stem cells (MSC cells) (Project 3), and a well-controlled in vivo infection system using a humanized mouse model where KSHV establishes persistent infection and is disseminated into the B and monocyte lineages (Core). Thusly, this multi-disciplinary PPG application is directed toward investigating the host's tricks of Immune recognition and attack as well as the KSHV's tactics of immune evasion and pathogenesis by utilizing recently developed "infectious" KSHV genetic system, in vitro and in vivo transformation assays, and in vivo humanized mouse models. The major goal of this multi-project grant application is to address (1) how hosts have developed effective mechanisms necessary to control KSHV infection and replication, (2) how KSHV has evolved the various mechanisms necessary to thwart and exploit the host defenses, and (3) how KSHV has conferred the infected cells with oncogenic signatures. This application consists of three Projects with multidisciplinary focused schemes. In addition, the Cores provide an efficient genetic manipulation system for KSHV mutagenesis, a state-of-art humanized mouse model for KSHV persistence and a MSC cell/nude mouse system for KSHV oncogenesis and the Administrative Core provides the overall program milestone and data dissemination.
In order to improve our capability of responding to this emerging cancer in immunosuppressed patients more quickly and effectively, we will improve our understanding of how hosts and KSHV combat each other and how KSHV persists in the immune compromised hosts.
|Rodgers, Mary A; Bowman, James W; Fujita, Hiroaki et al. (2014) The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation. J Exp Med 211:1333-47|
|Yan, Qin; Ma, Xinting; Shen, Chenyou et al. (2014) Inhibition of Kaposi's sarcoma-associated herpesvirus lytic replication by HIV-1 Nef and cellular microRNA hsa-miR-1258. J Virol 88:4987-5000|
|Brulois, Kevin; Toth, Zsolt; Wong, Lai-Yee et al. (2014) Kaposi's sarcoma-associated herpesvirus K3 and K5 ubiquitin E3 ligases have stage-specific immune evasion roles during lytic replication. J Virol 88:9335-49|
|Shi, Mude; Cho, Hyelim; Inn, Kyung-Soo et al. (2014) Negative regulation of NF-?B activity by brain-specific TRIpartite Motif protein 9. Nat Commun 5:4820|
|Zhu, Ying; Huang, Yufei; Jung, Jae U et al. (2014) Viral miRNA targeting of bicistronic and polycistronic transcripts. Curr Opin Virol 7:66-72|
|Brulois, Kevin; Jung, Jae U (2014) Interplay between Kaposi's sarcoma-associated herpesvirus and the innate immune system. Cytokine Growth Factor Rev 25:597-609|
|Jones, Tiffany; Ramos da Silva, Suzane; Bedolla, Roble et al. (2014) Viral cyclin promotes KSHV-induced cellular transformation and tumorigenesis by overriding contact inhibition. Cell Cycle 13:845-58|
|Lee, Myung-Shin; Jones, Tiffany; Song, Dae-Yong et al. (2014) Exploitation of the complement system by oncogenic Kaposi's sarcoma-associated herpesvirus for cell survival and persistent infection. PLoS Pathog 10:e1004412|
|Full, Florian; Jungnickl, Doris; Reuter, Nina et al. (2014) Kaposi's sarcoma associated herpesvirus tegument protein ORF75 is essential for viral lytic replication and plays a critical role in the antagonization of ND10-instituted intrinsic immunity. PLoS Pathog 10:e1003863|
|Liang, Qiming; Seo, Gil Ju; Choi, Youn Jung et al. (2014) Crosstalk between the cGAS DNA sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses. Cell Host Microbe 15:228-38|
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