The members of the filovirus family, Ebola (EBOV) and Marburg (MARV) viruses, cause a severe hemorrhagic disease in infected humans and non-human primates with high fatality rates. Infected individuals who go on to succumb to EBOV exhibit disregulated immune responses which appears to result from several factors, including viral mediated impairment and disregulation of innate immune responses and subsequent failure to develop protective adaptive immunity. Studies of both human survivors and in animal models of EBOV disease suggest that a well-regulated cytokine response early in the course of the infection may be crucial to the outcome of the disease. Understanding the earliest events that occur in the interaction of the virus with cells of the host immune systems should shed light on the important determinants that influence the ability of a host to control the infection. The important early events are likely to center around monocytes, macrophages, and dendritic cells (DCs). These cells not only orchestrate innate and adaptive immune responses but are also the initial targets of viral infection. However, the available data on how these cells respond to EBOV infection is fragmentary and often contradictory. Therefore, developing a conceptual framework to understand how EBOV affects early innate responses remains challenging. This U01 application brings together the expertise to carefully dissect the early events of EBOV infection and pathogenesis in vitro and in vivo. The main objectives of this application are to: identify key events that lead to disregulated immunity in fatal Ebola disease, identify correlates of protection in survivors of EBOV infection and identify potential targets for therapeutic intervention both early in the host innate immune response, and later when uncontrolled inflammatory responses ensue.
The aims are to 1) characterize the profiles of early cytokine and chemokine expression in EBOV infection, and compare how they differ to highly pathogenic less pathogenic EBOV;2) determine if Toll-like receptors (TLRs) are activated by EBOV, and/or if EBOV infection individually or globally inhibits TLR activation in innate cells;3) characterize the early cytokine responses in vivo, determine the role of TLRs and TLR signaling pathways on the pathogenesis of EBOV in vivo, and the role of alarmins in the """"""""cytokine storm"""""""" that is a hall-mark of the late stages of EBOV infection;and 4) dissect the differences in early innate immune responses in a non-human primate model of EBOV disease upon infection by different EBOV species. The ultimate goal of this work is to identify new targets for therapeutic intervention into EBOV hemorrhagic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI082954-03
Application #
8099009
Study Section
Special Emphasis Panel (ZAI1-BDP-I (J4))
Program Officer
Miller, Lara R
Project Start
2009-06-15
Project End
2014-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
3
Fiscal Year
2011
Total Cost
$647,213
Indirect Cost
Name
Boston University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
McElroy, Anita K; Mühlberger, Elke; Muñoz-Fontela, César (2018) Immune barriers of Ebola virus infection. Curr Opin Virol 28:152-160
Nelson, Emily V; Schmidt, Kristina M (2017) Analysis of the Cellular Stress Response During Ebola Virus Infection by Immunofluorescence. Methods Mol Biol 1628:211-225
Olejnik, Judith; Nelson, Emily V (2017) Analyzing Apoptosis Induction and Evasion in Ebola Virus-Infected Cells. Methods Mol Biol 1628:227-241
Brauburger, Kristina; Cressey, Tessa; Mühlberger, Elke (2017) Nonradioactive Northern Blot Analysis to Detect Ebola Virus Minigenomic mRNA. Methods Mol Biol 1628:143-159
Cressey, Tessa; Brauburger, Kristina; Mühlberger, Elke (2017) Modeling Ebola Virus Genome Replication and Transcription with Minigenome Systems. Methods Mol Biol 1628:79-92
Nelson, Emily V; Schmidt, Kristina M; Deflubé, Laure R et al. (2016) Ebola Virus Does Not Induce Stress Granule Formation during Infection and Sequesters Stress Granule Proteins within Viral Inclusions. J Virol 90:7268-7284
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Brauburger, Kristina; Boehmann, Yannik; Tsuda, Yoshimi et al. (2014) Analysis of the highly diverse gene borders in Ebola virus reveals a distinct mechanism of transcriptional regulation. J Virol 88:12558-71
Gantke, Thorsten; Boussouf, Sabrina; Janzen, Julia et al. (2013) Ebola virus VP35 induces high-level production of recombinant TPL-2-ABIN-2-NF-?B1 p105 complex in co-transfected HEK-293 cells. Biochem J 452:359-65

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