Ebolaviruses associated with differential pathogenicity induce distinct host responses in human macrophages

Judith Olejnik, Adriana Forero, Laure R. Deflubé, Adam J. Hume, Whitney A. Manhart, Andrew Nishida, Andrea Marzi, Michael G. Katze, Hideki Ebihara, Angela L. Rasmussen, Elke Mühlberger

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Ebola virus (EBOV) and Reston virus (RESTV) are members of the Ebolavirus genus which greatly differ in their pathogenicity. While EBOV causes a severe disease in humans characterized by a dysregulated inflammatory response and elevated cytokine and chemokine production, there are no reported disease-associated human cases of RESTV infection, suggesting that RESTV is nonpathogenic for humans. The underlying mechanisms determining the pathogenicity of different ebolavirus species are not yet known. In this study, we dissected the host response to EBOV and RESTV infection in primary human monocyte-derived macrophages (MDMs). As expected, EBOV infection led to a profound proinflammatory response, including strong induction of type I and type III interferons (IFNs). In contrast, RESTV-infected macrophages remained surprisingly silent. Early activation of IFN regulatory factor 3 (IRF3) and NF-κB was observed in EBOV-infected, but not in RESTV-infected, MDMs. In concordance with previous results, MDMs treated with inactivated EBOV and Ebola virus-like particles (VLPs) induced NF-κB activation mediated by Toll-like receptor 4 (TLR4) in a glycoprotein (GP)-dependent manner. This was not the case in cells exposed to live RESTV, inactivated RESTV, or VLPs containing RESTV GP, indicating that RESTV GP does not trigger TLR4 signaling. Our results suggest that the lack of immune activation in RESTV-infected MDMs contributes to lower pathogenicity by preventing the cytokine storm observed in EBOV infection. We further demonstrate that inhibition of TLR4 signaling abolishes EBOV GP-mediated NF-κB activation. This finding indicates that limiting the excessive TLR4-mediated proinflammatory response in EBOV infection should be considered as a potential supportive treatment option for EBOV disease.

Original languageEnglish (US)
Article numbere00179-17
JournalJournal of Virology
Volume91
Issue number11
DOIs
StatePublished - Jun 1 2017

Fingerprint

Ebolavirus
Virulence
macrophages
pathogenicity
Macrophages
Ebola Hemorrhagic Fever
Viruses
Toll-Like Receptor 4
viruses
Glycoproteins
monocytes
glycoproteins
Virus Diseases
Virion
virus-like particles
infection
Interferon Regulatory Factor-3
Cytokines
Reston
Interferon Type I

Keywords

  • Chemokines
  • Cytokines
  • Ebola virus
  • Filovirus
  • Host response
  • Interferons
  • Macrophages
  • Reston virus
  • Toll-like receptor 4
  • Toll-like receptors

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Olejnik, J., Forero, A., Deflubé, L. R., Hume, A. J., Manhart, W. A., Nishida, A., ... Mühlberger, E. (2017). Ebolaviruses associated with differential pathogenicity induce distinct host responses in human macrophages. Journal of Virology, 91(11), [e00179-17]. https://doi.org/10.1128/JVI.00179-17

Ebolaviruses associated with differential pathogenicity induce distinct host responses in human macrophages. / Olejnik, Judith; Forero, Adriana; Deflubé, Laure R.; Hume, Adam J.; Manhart, Whitney A.; Nishida, Andrew; Marzi, Andrea; Katze, Michael G.; Ebihara, Hideki; Rasmussen, Angela L.; Mühlberger, Elke.

In: Journal of Virology, Vol. 91, No. 11, e00179-17, 01.06.2017.

Research output: Contribution to journalArticle

Olejnik, J, Forero, A, Deflubé, LR, Hume, AJ, Manhart, WA, Nishida, A, Marzi, A, Katze, MG, Ebihara, H, Rasmussen, AL & Mühlberger, E 2017, 'Ebolaviruses associated with differential pathogenicity induce distinct host responses in human macrophages', Journal of Virology, vol. 91, no. 11, e00179-17. https://doi.org/10.1128/JVI.00179-17
Olejnik, Judith ; Forero, Adriana ; Deflubé, Laure R. ; Hume, Adam J. ; Manhart, Whitney A. ; Nishida, Andrew ; Marzi, Andrea ; Katze, Michael G. ; Ebihara, Hideki ; Rasmussen, Angela L. ; Mühlberger, Elke. / Ebolaviruses associated with differential pathogenicity induce distinct host responses in human macrophages. In: Journal of Virology. 2017 ; Vol. 91, No. 11.
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abstract = "Ebola virus (EBOV) and Reston virus (RESTV) are members of the Ebolavirus genus which greatly differ in their pathogenicity. While EBOV causes a severe disease in humans characterized by a dysregulated inflammatory response and elevated cytokine and chemokine production, there are no reported disease-associated human cases of RESTV infection, suggesting that RESTV is nonpathogenic for humans. The underlying mechanisms determining the pathogenicity of different ebolavirus species are not yet known. In this study, we dissected the host response to EBOV and RESTV infection in primary human monocyte-derived macrophages (MDMs). As expected, EBOV infection led to a profound proinflammatory response, including strong induction of type I and type III interferons (IFNs). In contrast, RESTV-infected macrophages remained surprisingly silent. Early activation of IFN regulatory factor 3 (IRF3) and NF-κB was observed in EBOV-infected, but not in RESTV-infected, MDMs. In concordance with previous results, MDMs treated with inactivated EBOV and Ebola virus-like particles (VLPs) induced NF-κB activation mediated by Toll-like receptor 4 (TLR4) in a glycoprotein (GP)-dependent manner. This was not the case in cells exposed to live RESTV, inactivated RESTV, or VLPs containing RESTV GP, indicating that RESTV GP does not trigger TLR4 signaling. Our results suggest that the lack of immune activation in RESTV-infected MDMs contributes to lower pathogenicity by preventing the cytokine storm observed in EBOV infection. We further demonstrate that inhibition of TLR4 signaling abolishes EBOV GP-mediated NF-κB activation. This finding indicates that limiting the excessive TLR4-mediated proinflammatory response in EBOV infection should be considered as a potential supportive treatment option for EBOV disease.",
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