Among viruses that cause disease in humans members of the family Filoviridae, Ebola virus (EBOV) and Marburg virus (MARV), stand out for their impressive lethality. These viruses are among the most deadly human pathogens known to man with reported case fatality rates of up to 90%. This high level of virulence is primarily mediated by the ability of these viruses to subvert the host immune response. Recent studies have shown that filoviruses can interfere with the development of successful innate immune responses thereby preventing the priming of the adaptive arm of the immune system. Our understanding of the subversion of innate immune pathways upon filovirus infection in vivo and the significance of these evasion strategies on the ability of the primate host in mounting successful antiviral responses remains incomplete. Here, we will leverage the robust cynomolgus macaque infection model and carry out immunological assays and high throughput genomic analyses to characterize evasion of the innate immune responses by filoviruses and the consequences of these strategies on development of protective adaptive immunity. We will then extend these observations by monitoring the immune response following infection with EBOV VP35 and VP24 mutants. Finally, we will compare development of innate and adaptive immunity in animals infected with Bundibugyo EBOV (BEBOV). Since BEBOV infection results in ~ 67% mortality in macaques, we will be able to delineate specific immune failures that result in a lethal outcome. A better understanding of the immune processes that regulate the outcome of EBOV infection may inform novel approaches for therapeutic intervention. We propose three aims: 1) Modulation of innate immunity by filoviruses in vivo. Innate immune responses provide the first line of defense against infections. In vitro studies have shown that wild type filoviruses can antagonize the IFN response. We will characterize the subversion of the innate immune response in macaques using immunological and gene expression approaches;2) Role of VP24 and VP35 on the evasion of innate immune responses in vivo. Macaques will be infected with EBOVs with mutations in VP24 and/or VP35 proteins that affect IFN antagonist activity. We will confirm the role of these proteins in the subversion of the host response by characterizing the development of adaptive immunity in the absence of these evasion strategies;3: Validation of innate immune evasion's role in pathogenesis in vivo. Macaques will be infected with BEBOV. The lower mortality rate of BEBOV versus other filoviruses will allow us to identify specific pathways of virus-induced immune dysfunction associated with virulence.

Public Health Relevance

The filoviruses, Ebola and Marburg, are among the most lethal pathogens that affect man. Currently, there are no licensed vaccines or treatments approved for humans. For these reasons, filoviruses are classified as Tier 1 Category A select agents. The ability of filoviruses to counteract the host immune response promotes uncontrolled viral replication and thereby severe disease and death. A better understanding of these subversion strategies is critical to the development of more effective countermeasures.

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 #
8667712
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
$799,758
Indirect Cost
$99,300
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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