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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Šedý, John R; Balmert, M Olivia; Ware, Brian C et al. (2017) A herpesvirus entry mediator mutein with selective agonist action for the inhibitory receptor B and T lymphocyte attenuator. J Biol Chem 292:21060-21070
Yau, Edwin H; Kummetha, Indrasena Reddy; Lichinchi, Gianluigi et al. (2017) Genome-Wide CRISPR Screen for Essential Cell Growth Mediators in Mutant KRAS Colorectal Cancers. Cancer Res 77:6330-6339
Gong, Danyang; Dai, Xinghong; Xiao, Yuchen et al. (2017) Virus-Like Vesicles of Kaposi's Sarcoma-Associated Herpesvirus Activate Lytic Replication by Triggering Differentiation Signaling. J Virol 91:
Du, Yushen; Chi, Xiumei; Wang, Chong et al. (2017) Quantifying perinatal transmission of Hepatitis B viral quasispecies by tag linkage deep sequencing. Sci Rep 7:10168
Du, Yushen; Zhang, Tian-Hao; Dai, Lei et al. (2017) Effects of Mutations on Replicative Fitness and Major Histocompatibility Complex Class I Binding Affinity Are Among the Determinants Underlying Cytotoxic-T-Lymphocyte Escape of HIV-1 Gag Epitopes. MBio 8:
Dai, Xinghong; Li, Zhihai; Lai, Mason et al. (2017) In situ structures of the genome and genome-delivery apparatus in a single-stranded RNA virus. Nature 541:112-116
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
Du, Yushen; Wu, Nicholas C; Jiang, Lin et al. (2016) Annotating Protein Functional Residues by Coupling High-Throughput Fitness Profile and Homologous-Structure Analysis. MBio 7:
Scarzello, Anthony J; Jiang, Qun; Back, Timothy et al. (2016) LT?R signalling preferentially accelerates oncogenic AKT-initiated liver tumours. Gut 65:1765-75

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