A front line defense against microbial invasion is the receptor-mediated recognition of pathogen-associated molecular patterns (PAMPs), which triggers a signaling cascade that results in the induction of initiate innate immune responses, including the secretion of Type-1 interferons. Pathogen-derived nucleic acids, including DNA, function as potent PAMPs that can trigger this response, and are recognized by TLR9, DAI/RNA polymerase Ill, and likely additional DNA-sensing receptors. Murine Gammaherpesvirus 68 (MHV-68) is closely related to human herpesvirus 8 (HHV8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), which is the causative agent of Kaposi's sarcoma. These viruses contain double stranded DNA genomes, and studies indicate that they likely elicit both TLR9-dependent and TLR9- independent antiviral responses. In this study, we propose to leverage systems-level data to elucidate signaling networks and host-pathogen interactions that form the basis of innate immune responses to gammaherpesviruses. To this end, we have used a variety of methods to systematically generate viral? host protein-protein interaction maps targeting herpesviruses. We hypothesize that a subset of these interactions underlies viral evasion of innate responses. In this proposal, we will characterize host molecular complex that have been experimentally defined to lie at the interface of HHV8 host-pathogen interactions and innate immune responses. Dr. Chanda has over 10 years experience in functional genomics, innate immune signaling, and genetic analysis in mammalian cells, and Dr. Krogan brings over 10 years of experience in the areas of large-scale proteomic and network analysis. These studies are expected to provide global molecular insight into cellular and viral processes that regulate early immune responses to gammaherpesvirus infection, and will be fundamental towards the development of novel vaccines and adjuvants for HHVB

Public Health Relevance

Gamma herpesviruses are a subclass of herpesvirus known for their ability to establish lifelong infections, and include human Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus (KSHV). Insight into the pathogenesis of these viruses will reveal key immune system pathways that are evaded during infection and persistence. This information can ultimately be used to generate novel adjuvants and vaccines.

National Institute of Health (NIH)
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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

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