Ebola Virus-Like Particles Stimulate Type I Interferons and Proinflammatory Cytokine Expression Through the Toll-Like Receptor and Interferon Signaling Pathways

Natarajan Ayithan; Steven B Bradfute; Scott M Anthony; Kelly S Stuthman; John M Dye; Sina Bavari; Mike Bray; Keiko Ozato

doi:10.1089/jir.2013.0035

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Ebola Virus-Like Particles Stimulate Type I Interferons and Proinflammatory Cytokine Expression Through the Toll-Like Receptor and Interferon Signaling Pathways

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Ebola Virus-Like Particles Stimulate Type I Interferons and Proinflammatory Cytokine Expression Through the Toll-Like Receptor and Interferon Signaling Pathways

Natarajan Ayithan, Steven B Bradfute, Scott M Anthony, Kelly S Stuthman, John M Dye, Sina Bavari, Mike Bray and Keiko Ozato

Journal of interferon & cytokine research, Vol.34(2), pp.79-89

02/01/2014

DOI: 10.1089/jir.2013.0035

PMCID: PMC3924795

PMID: 24102579

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Abstract

Ebola viruses (EBOV) can cause severe hemorrhagic disease with high case fatality rates. Currently, no vaccines or therapeutics are approved for use in humans. Ebola virus-like particles (eVLP) comprising of virus protein (VP40), glycoprotein, and nucleoprotein protect rodents and nonhuman primates from lethal EBOV infection, representing as a candidate vaccine for EBOV infection. Previous reports have shown that eVLP stimulate the expression of proinflammatory cytokines in dendritic cells (DCs) and macrophages (MΦs) in vitro . However, the molecular mechanisms and signaling pathways through which eVLP induce innate immune responses remain obscure. In this study, we show that eVLP stimulate not only the expression of proinflammatory cytokines but also the expression of type I interferons (IFNs) and IFN-stimulated genes (ISGs) in murine bone marrow-derived DCs (BMDCs) and MΦs. Our data indicate that eVLP trigger host responses through toll-like receptor (TLR) pathway utilizing 2 distinct adaptors, MyD88 and TRIF. More interestingly, eVLP activated the IFN signaling pathway by inducing a set of potent antiviral ISGs. Last, eVLP and synthetic adjuvants, Poly I:C and CpG DNA, cooperatively increased the expression of cytokines and ISGs. Further supporting this synergy, eVLP when administered together with Poly I:C conferred mice enhanced protection against EBOV infection. These results indicate that eVLP stimulate early innate immune responses through TLR and type I IFN signaling pathways to protect the host from EBOV infection.

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Title: Subtitle: Ebola Virus-Like Particles Stimulate Type I Interferons and Proinflammatory Cytokine Expression Through the Toll-Like Receptor and Interferon Signaling Pathways
Creators: Natarajan Ayithan - National Institutes of Health
Steven B Bradfute - Medical Research Institute
Scott M Anthony - Medical Research Institute
Kelly S Stuthman - Medical Research Institute
John M Dye - Medical Research Institute
Sina Bavari - Medical Research Institute
Mike Bray - National Institutes of Health
Keiko Ozato - Eunice Kennedy Shriver National Institute of Child Health and Human Development
Resource Type: Journal article
Publication Details: Journal of interferon & cytokine research, Vol.34(2), pp.79-89
DOI: 10.1089/jir.2013.0035
PMID: 24102579
PMCID: PMC3924795
NLM abbreviation: J Interferon Cytokine Res
ISSN: 1079-9907
eISSN: 1557-7465
Publisher: Mary Ann Liebert, Inc
Language: English
Date published: 02/01/2014
Academic Unit: Pathology
Record Identifier: 9984185177502771

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