Interferon (IFN) activity is marshaled early against the initial stages of viral infection, and IFN mediated responses play an essential role in host defense by directly inhibiting viral replication and by indirectly stimulating innate and adaptive immunity. Not surprisingly, IFN mediated signaling is a favored target of viral subterfuge. In this proposal we set out to explore the biophysical and functional attributes of two virally encoded decoy receptors that selectively neutralize the biological effects of type-l and type-Ill IFNs. Ectromelia virus encodes a decoy receptor that promiscuously binds and blocks the antiviral effects of all type-l IFNs in a species independent manner, with the notable exception of murine IFN-beta. The Yaba-like disease virus encodes a related decoy receptor that capably inhibits primate type-l (alpha and beta) as well as type-Ill (lamda) IFNs. Interestingly, neither of these viral proteins shares any significant sequence similarity with the distinct receptor components used for type-l or type-Ill IFN signal transduction. Our proposed studies aim to dissect the mechanism and consequences of selective decoy receptor mediated IFN inhibition using a diverse arsenal of experimental methods.
In Aim 1 of the proposal we will determine the structural basis of IFN inhibition by viral decoy receptors using x-ray crystallography and quantitative protein interaction analysis. Results from these studies will be used in concert with yeast surface display directed evolution to develop variant decoy receptors with unique cytokine binding properties.
In Aim 2 we will examine the cellular mechanisms of IFN decoy receptor function. The secreted poxvirus proteins tightly associate with cell surfaces through an unknown receptor interaction we propose to identify and investigate. We will also examine whether additional viruses encode IFN decoys.
In Aim 3 we will explore the role of IFN sequestration in the mousepox pathogenesis model. Ectromelia recombinants will be generated that encode novel decoy receptors that selectively inhibit the actions of IFN-alpha, IFN-beta, or IFN-lambda at sites of viral infection in order to better understand the specific roles of these cytokines in anti-viral immunity.
The integral role played by IFNs in host anti-viral responses is underscored by the fact that nearly all viruses employ at least one mechanism to disrupt their activity. Our study is focused on obtaining a detailed mechanistic understanding of how distinct viral decoy receptors selectively sabotage different IFNs, and exploiting our results to develop novel reagents that can be used to examine type-specific IFN functions.
|Chen, Linxiao; Valentine, Jenny L; Huang, Chung-Jr et al. (2016) Outer membrane vesicles displaying engineered glycotopes elicit protective antibodies. Proc Natl Acad Sci U S A 113:E3609-18|
|Ulland, Tyler K; Jain, Nidhi; Hornick, Emma E et al. (2016) Nlrp12 mutation causes C57BL/6J strain-specific defect in neutrophil recruitment. Nat Commun 7:13180|
|Miao, Chunhui; Li, Minghua; Zheng, Yi-Min et al. (2016) Cell-cell contact promotes Ebola virus GP-mediated infection. Virology 488:202-15|
|Zhao, Jincun; Vijay, Rahul; Zhao, Jingxian et al. (2016) MAVS Expressed by Hematopoietic Cells Is Critical for Control of West Nile Virus Infection and Pathogenesis. J Virol 90:7098-108|
|Lubman, Olga Y; Fremont, Daved H (2016) Parallel Evolution of Chemokine Binding by Structurally Related Herpesvirus Decoy Receptors. Structure 24:57-69|
|Markosyan, Ruben M; Miao, Chunhui; Zheng, Yi-Min et al. (2016) Induction of Cell-Cell Fusion by Ebola Virus Glycoprotein: Low pH Is Not a Trigger. PLoS Pathog 12:e1005373|
|Grinnage-Pulley, Tara; Mu, Yang; Dai, Lei et al. (2016) Dual Repression of the Multidrug Eï¬„ux Pump CmeABC by CosR and CmeR in Campylobacter jejuni. Front Microbiol 7:1097|
|Teijaro, John R; Studer, Sean; Leaf, Nora et al. (2016) S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-Î± autoamplification. Proc Natl Acad Sci U S A 113:1351-6|
|Grinnage-Pulley, Tara; Zhang, Qijing (2015) Genetic Basis and Functional Consequences of Differential Expression of the CmeABC Efflux Pump in Campylobacter jejuni Isolates. PLoS One 10:e0131534|
|Nukui, Masatoshi; Mori, Yasuko; Murphy, Eain A (2015) A human herpesvirus 6A-encoded microRNA: role in viral lytic replication. J Virol 89:2615-27|
Showing the most recent 10 out of 325 publications