The filoviruses, Ebola and Marburg viruses (EBOV and MARV), are emerging, negative-strand RNA viruses that cause severe viral hemorrhagic fever. The virulence and emerging nature of these zoonotic pathogens makes them a significant threat to human health, potential agents of bioterrorism and NIAID category A priority pathogens. Currently, no approved anti-filovirus therapeutics are available. Filoviral hemorrhagic fever is characterized by uncontrolled, systemic virus replication, excessive inflammation and coagulation, dysregulated dendritic cell (DC) function and lymphocyte apoptosis. We previously identified and structurally characterized filoviral interferon antagonist proteins, including EBOV and MARV VP35, EBOV VP24 and MARV VP40. The VP35s counteract the production of interferon (IFN)-alpha/beta, critical antiviral cytokines. EBOV VP24 and MARV VP40 block the signaling induced by IFN-alpha/beta. We hypothesize that the function of these viral IFN-antagonists will not only counteract the innate antiviral effects of IFN-alpha/beta but, by targeting signaling downstream of pattern recognition, interferon and cytokine receptors, will also be able to disrupt the normal DC maturation process and promote dysregulated DC-T lymphocyte interactions. In this way, the filoviral IFN-antagonists will disrupt both innate and adaptive antiviral immunity. Building on ongoing collaborations between the Basler laboratory at the Icahn School of Medicine at Mt Sinai and the Amarasinghe and Gross laboratories at Washington University, we will characterize the molecular mechanisms of immune disruption by filoviral interferon antagonists. Using in vitro biochemical and structural studies, the Amarasinghe and Gross laboratories at Washington University will define the structural and biochemical basis for how filoviral interferon antagonists interact with host immune system signaling molecules and design loss of function mutants. The Basler laboratory will define the specific signaling pathways affected by each filoviral IFN-antagonist in dendritic cells and macrophages and using the structural and biochemical data provided by Amarasinghe and Gross labs as well as specific knockdown of key signaling molecules will define the impact of filoviral IFN-antagonists on macrophage function and DC cell maturation. The resulting data will generate specific hypotheses regarding the contribution of filoviral IFN-antagonists to EBOV and MARV suppression of DC function (to be tested by Project 2), to promotion of virus replication and induction of IFN and adaptive immune responses in non-human primate models (addressed by Project 3).

Public Health Relevance

Growing concerns of rare but increasing Ebola outbreaks in human populations, coupled with a rising potential of misuse in the form of bioterrorism, underscore the importance of identifying mechanisms of pathogenesis and new therapeutic approaches. Work described in this proposal will characterize how filoviral interferon antagonists modulate host immune mechanisms that control viral replication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI109945-01
Application #
8667709
Study Section
Special Emphasis Panel (ZAI1-ZL-I (J1))
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$730,183
Indirect Cost
$90,662
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Edwards, Megan R; Liu, Hejun; Shabman, Reed S et al. (2018) Conservation of Structure and Immune Antagonist Functions of Filoviral VP35 Homologs Present in Microbat Genomes. Cell Rep 24:861-872.e6
Su, Zhaoming; Wu, Chao; Shi, Liuqing et al. (2018) Electron Cryo-microscopy Structure of Ebola Virus Nucleoprotein Reveals a Mechanism for Nucleocapsid-like Assembly. Cell 172:966-978.e12
Knoverek, Catherine R; Amarasinghe, Gaya K; Bowman, Gregory R (2018) Advanced Methods for Accessing Protein Shape-Shifting Present New Therapeutic Opportunities. Trends Biochem Sci :
Johnson, Britney; VanBlargan, Laura A; Xu, Wei et al. (2018) Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability. Immunity 48:487-499.e5
Younan, Patrick; Iampietro, Mathieu; Bukreyev, Alexander (2018) Disabling of lymphocyte immune response by Ebola virus. PLoS Pathog 14:e1006932
Chanthamontri, C Ken; Jordan, David; Wang, Wenjie et al. (2018) Ebola Viral Protein 35 N-terminus is a Parallel Tetramer. Biochemistry :
Rizk, Maryan G; Basler, Christopher F; Guatelli, John (2017) Cooperation of the Ebola Virus Proteins VP40 and GP1,2 with BST2 To Activate NF-?B Independently of Virus-Like Particle Trapping. J Virol 91:
Xu, Wei; Luthra, Priya; Wu, Chao et al. (2017) Ebola virus VP30 and nucleoprotein interactions modulate viral RNA synthesis. Nat Commun 8:15576
Liu, Gai; Nash, Peter J; Johnson, Britney et al. (2017) A Sensitive in Vitro High-Throughput Screen To Identify Pan-filoviral Replication Inhibitors Targeting the VP35-NP Interface. ACS Infect Dis 3:190-198
Younan, Patrick; Ramanathan, Palaniappan; Graber, Jessica et al. (2017) The Toll-Like Receptor 4 Antagonist Eritoran Protects Mice from Lethal Filovirus Challenge. MBio 8:

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