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| Status |
Public on Dec 31, 2016 |
| Title |
Ebolavirus species associated with differential pathogenicity induce distinct host responses in human macrophages |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Highly pathogenic Zaire ebolavirus (EBOV) infection is associated with a dysregulated immune response and high levels of cytokines and chemokines are observed in fatal human cases. . In stark contrast Reston ebolavirus (RESTV) might be non-pathogenic for humans yet the underlying mechanisms determining pathogenicity for different Ebola viruses are not understood. In this study we investigate antiviral immune responses in EBOV- and RESTV- infected primary human monocyte-derived macrophages (MDM). We provide evidence that increased pathogenicity of the highly pathogenic EBOV is associated with a strong activation of host responses from infected MDM. The observed cytokine response after EBOV infection is strikingly similar to LPS-mediated immune signatures however EBOV caused significant induction of the interferon response in addition. In contrast we show that the low pathogenic RESTV fails to elicit significant immune responses in infected MDM. These results demonstrate a correlation of pathogenicity and excessive MDM activation for different Ebola virus species. Interaction of the viral glycoprotein (GP) with Toll-like receptor 4 (TLR4) leading to activation of NF_B signaling is responsible for this effect rather than differences in replication or blocking of immune signaling. We demonstrate that inhibition of TLR4 is able to abolish EBOV-GP mediated NF_B activation which might offer the possibility to develop targeted treatments for EBOV limiting the extreme immune response that seems to be detrimental to the host.
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| Overall design |
RNA was isolated from primary cultured human macrophages (n=3 donors) that were either mock-infected, infected with Ebola virus (Kikwit-95) or Reston virus (Pennsylvania), or treated with lipopolysaccharide (LPS).
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| Contributor(s) |
Olejnik J, Forero A, Rasmussen AL, Mühlberger E |
| Citation(s) |
28331091 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| U01 AI082954 |
Early Host Immune Response in Protection Against Filovirus Infection |
BOSTON UNIVERSITY |
MUEHLBERGER |
| U19 AI109761 |
Systems Biology Approaches to Molecular Diagnostics and Antiviral Drug Targeting |
UNIVERSITY OF WASHINGTON |
KATZE |
| R03 AI114293 |
Filovirus replication: initiation mechanism and role of RNA secondary structures |
BOSTON UNIVERSITY |
MUEHLBERGER |
| UC6 AI058618 |
National Center/Emerging Infectous Diseases & Biodefense |
BOSTON UNIVERSITY |
MURPHY |
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| |
| Submission date |
Jul 08, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Angela Rasmussen |
| E-mail(s) |
alr2105@cumc.columbia.edu
|
| Organization name |
Columbia University
|
| Department |
Center for Infection and Immunity
|
| Street address |
722 W. 168th St
|
| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10032 |
| Country |
USA |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (42)
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| Relations |
| BioProject |
PRJNA328248 |
| SRA |
SRP078152 |
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