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Title: Differential Regulation of Interferon Responses by Ebola and Marburg Virus VP35 Proteins

Abstract

Suppression of innate immune responses during filoviral infection contributes to disease severity. Ebola (EBOV) and Marburg (MARV) viruses each encode a VP35 protein that suppresses RIG-I-like receptor signaling and interferon-α/β (IFN-α/β) production by several mechanisms, including direct binding to double stranded RNA (dsRNA). Here, we demonstrate that in cell culture, MARV infection results in a greater upregulation of IFN responses as compared to EBOV infection. This correlates with differences in the efficiencies by which EBOV and MARV VP35s antagonize RIG-I signaling. Furthermore, structural and biochemical studies suggest that differential recognition of RNA elements by the respective VP35 C-terminal IFN inhibitory domain (IID) rather than affinity for RNA by the respective VP35s is critical for this observation. Our studies reveal functional differences in EBOV versus MARV VP35 RNA binding that result in unexpected differences in the host response to deadly viral pathogens.

Authors:
 [1];  [2];  [3];  [4];  [5];  [5];  [6];  [2];  [4];  [3];  [2];  [5]
  1. Icahn School of Medicine at Mount Sinai, New York, NY (United States); Washington Univ. School of Medicine, St. Louis, MO (United States)
  2. Washington Univ. School of Medicine, St. Louis, MO (United States)
  3. Univ. of Texas Medical Branch at Galveston, TX (United States)
  4. Univ. of California, Riverside, CA (United States)
  5. Icahn School of Medicine at Mount Sinai, New York, NY (United States)
  6. Icahn School of Medicine at Mount Sinai, New York, NY (United States); J. Craig Venter Inst., Rockville, MD (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Institutes of Health (NIH); Dept. of the Defense, Defense Threat Reduction Agency
OSTI Identifier:
1351395
Grant/Contract Number:  
R01AI107056; U191099565; R01AI059536; U19AI109945; U19AI109664; HDTRA1-12-1-0051
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Cell Reports
Additional Journal Information:
Journal Volume: 14; Journal Issue: 7; Journal ID: ISSN 2211-1247
Publisher:
Elsevier
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; filovirus; immune evasion; pattern associated molecular pattern (PAMP); RIG-I like receptor; type I interferon; VP35

Citation Formats

Edwards, Megan R., Liu, Gai, Mire, Chad E., Sureshchandra, Suhas, Luthra, Priya, Yen, Benjamin, Shabman, Reed S., Leung, Daisy W., Messaoudi, Ilhem, Geisbert, Thomas W., Amarasinghe, Gaya K., and Basler, Christopher F. Differential Regulation of Interferon Responses by Ebola and Marburg Virus VP35 Proteins. United States: N. p., 2016. Web. doi:10.1016/j.celrep.2016.01.049.
Edwards, Megan R., Liu, Gai, Mire, Chad E., Sureshchandra, Suhas, Luthra, Priya, Yen, Benjamin, Shabman, Reed S., Leung, Daisy W., Messaoudi, Ilhem, Geisbert, Thomas W., Amarasinghe, Gaya K., & Basler, Christopher F. Differential Regulation of Interferon Responses by Ebola and Marburg Virus VP35 Proteins. United States. doi:10.1016/j.celrep.2016.01.049.
Edwards, Megan R., Liu, Gai, Mire, Chad E., Sureshchandra, Suhas, Luthra, Priya, Yen, Benjamin, Shabman, Reed S., Leung, Daisy W., Messaoudi, Ilhem, Geisbert, Thomas W., Amarasinghe, Gaya K., and Basler, Christopher F. Thu . "Differential Regulation of Interferon Responses by Ebola and Marburg Virus VP35 Proteins". United States. doi:10.1016/j.celrep.2016.01.049. https://www.osti.gov/servlets/purl/1351395.
@article{osti_1351395,
title = {Differential Regulation of Interferon Responses by Ebola and Marburg Virus VP35 Proteins},
author = {Edwards, Megan R. and Liu, Gai and Mire, Chad E. and Sureshchandra, Suhas and Luthra, Priya and Yen, Benjamin and Shabman, Reed S. and Leung, Daisy W. and Messaoudi, Ilhem and Geisbert, Thomas W. and Amarasinghe, Gaya K. and Basler, Christopher F.},
abstractNote = {Suppression of innate immune responses during filoviral infection contributes to disease severity. Ebola (EBOV) and Marburg (MARV) viruses each encode a VP35 protein that suppresses RIG-I-like receptor signaling and interferon-α/β (IFN-α/β) production by several mechanisms, including direct binding to double stranded RNA (dsRNA). Here, we demonstrate that in cell culture, MARV infection results in a greater upregulation of IFN responses as compared to EBOV infection. This correlates with differences in the efficiencies by which EBOV and MARV VP35s antagonize RIG-I signaling. Furthermore, structural and biochemical studies suggest that differential recognition of RNA elements by the respective VP35 C-terminal IFN inhibitory domain (IID) rather than affinity for RNA by the respective VP35s is critical for this observation. Our studies reveal functional differences in EBOV versus MARV VP35 RNA binding that result in unexpected differences in the host response to deadly viral pathogens.},
doi = {10.1016/j.celrep.2016.01.049},
journal = {Cell Reports},
issn = {2211-1247},
number = 7,
volume = 14,
place = {United States},
year = {2016},
month = {2}
}

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