Infections with filoviruses Ebola (EBOV) and Marburg (MARV), lead to the """"""""immune paralysis"""""""" characterized by a deficient T cell response and lymphopenia, despite the lack of infection of T cells, and a severe hemorrhagic fever with up to 80% mortality. Over the past decade, researchers identified multiple mechanisms of type I interferon (IFN-I) antagonism mediated by filovirus proteins. However, the mechanisms of the rapid and deleterious disabling of the adaptive immune response by filoviruses remain unknown. Dendritic cells (DC), which are the professional antigen-presenting cells, are believed to be readily infected, but do not undergo normal maturation. Our preliminary data have demonstrated the strong connection between IFN-I antagonism caused by EBOV and the lack of DC maturation. The central hypothesis of the proposal is that the unusually strong and redundant antagonism of the IFN-I response mediated by filovirus proteins and by multiple mechanisms, blocks maturation of DC, resulting in the deficient and/or aberrant stimulation of T cells. The hypothesis will be tested by pursuing three specific aims: 1) Determine the role of IFN-antagonizing domains and IFN-I signaling in the maturation of DC and in the activation, proliferation and apoptosis of T cells;2) Determine the role of soluble factors secreted by the infected DC and specific inhibitory and pro-apoptotic molecules in the activation, proliferation and apoptosis of T cells;3) Determine whether the suppression of T cell activation and proliferation or T cell apoptosis during filovirus infection can be reversed by induction of DC maturation. The project will involve the infection of DC derived from donor blood with a recombinant EBOV, its mutants with the IFN-I antagonizing domains disabled, or MARV;stimulation of primary human CD4+ and CD8+ T cells;characterization of the effects of filovirus infection and IFN-antagonizing domains on transcriptomes of infected DC and stimulated T cells by deep sequencing;blockade of IFN-I signaling and immuno-suppressive and pro-apoptotic pathways;and attempts to rescue maturation of infected DC with cytokine cocktails. Together, these experiments represent a broad, integrated approach to investigate the mechanisms of disabling the adaptive immune response by filoviruses.

Public Health Relevance

Filoviruses cause outbreaks of severe hemorrhagic fever in humans with no approved vaccines or methods of treatment. The proposed research is relevant for public health and NIH's mission because it is aimed at the investigation of fundamental mechanisms of the unusually rapid disabling of the adaptive immune system by the virus in order to reduce the burdens of human disease caused by the virus.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-ZL-I (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
New York
United States
Zip Code
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:

Showing the most recent 10 out of 46 publications