Ebolaviruses Associated with Differential Pathogenicity Induce Distinct Host Responses in Human Macrophages.
Ebola virus (EBOV) and Reston virus (RESTV) are members of theEbolavirusgenus 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.IMPORTANCEEmerging infectious diseases are a major public health concern, as exemplified by the recent devastating Ebola virus (EBOV) outbreak. Different ebolavirus species are associated with widely varying pathogenicity in humans, ranging from asymptomatic infections for Reston virus (RESTV) to severe disease with fatal outcomes for EBOV. In this comparative study of EBOV- and RESTV-infected human macrophages, we identified key differences in host cell responses. Consistent with previous data, EBOV infection is associated with a proinflammatory signature triggered by the surface glycoprotein (GP), which can be inhibited by blocking TLR4 signaling. In contrast, infection with RESTV failed to stimulate a strong host response in infected macrophages due to the inability of RESTV GP to stimulate TLR4. We propose that disparate proinflammatory host signatures contribute to the differences in pathogenicity reported for ebolavirus species and suggest that proinflammatory pathways represent an intriguing target for the development of novel therapeutics.
Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA.|National Emerging Infectious Diseases Laboratories, Boston University, Boston, Massachusetts, USA.
Judith
J
Olejnik
Department of Microbiology, University of Washington, Seattle, Washington, USA.
Adriana
A
Forero
Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA.|National Emerging Infectious Diseases Laboratories, Boston University, Boston, Massachusetts, USA.
Laure R
LR
Deflubé
Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA.|National Emerging Infectious Diseases Laboratories, Boston University, Boston, Massachusetts, USA.
Adam J
AJ
Hume
Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA.|National Emerging Infectious Diseases Laboratories, Boston University, Boston, Massachusetts, USA.
Whitney A
WA
Manhart
Department of Microbiology, University of Washington, Seattle, Washington, USA.
Andrew
A
Nishida
Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, USA.
Andrea
A
Marzi
Department of Microbiology, University of Washington, Seattle, Washington, USA.
Michael G
MG
Katze
Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, USA.
Hideki
H
Ebihara
Department of Microbiology, University of Washington, Seattle, Washington, USA.
Angela L
AL
Rasmussen
Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA muehlber@bu.edu.|National Emerging Infectious Diseases Laboratories, Boston University, Boston, Massachusetts, USA.
Elke
E
Mühlberger
D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology; D029043:Ebolavirus / Q000276:immunology* / Q000472:pathogenicity* / Q000502:physiology; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology; D007372:Interferons / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014709:Vero Cells; D014774:Virulence
D018925:Chemokines; D016207:Cytokines; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D007372:Interferons
Ebola virus; Reston virus; Toll-like receptor 4; Toll-like receptors; chemokines; cytokines; filovirus; host response; interferons; macrophages