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      Comparative Transcriptomics in Ebola Makona-Infected Ferrets, Nonhuman Primates, and Humans

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          Abstract

          The domestic ferret is a uniformly lethal model of infection for 3 species of Ebolavirus known to be pathogenic in humans. Reagents to systematically analyze the ferret host response to infection are lacking; however, the recent publication of a draft ferret genome has opened the potential for transcriptional analysis of ferret models of disease. In this work, we present comparative analysis of longitudinally sampled blood taken from ferrets and nonhuman primates infected with lethal doses of the Makona variant of Zaire ebolavirus. Strong induction of proinflammatory and prothrombotic signaling programs were present in both ferrets and nonhuman primates, and both transcriptomes were similar to previously published datasets of fatal cases of human Ebola virus infection.

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          DDX60, a DEXD/H box helicase, is a novel antiviral factor promoting RIG-I-like receptor-mediated signaling.

          Hiroyuki Oshiumi, Tsukasa Seya, Moeko Miyashita … (2011)
          The cytoplasmic viral RNA sensors RIG-I and MDA5 are important for the production of type I interferon and other inflammatory cytokines. DDX60 is an uncharacterized DEXD/H box RNA helicase similar to Saccharomyces cerevisiae Ski2, a cofactor of RNA exosome, which is a protein complex required for the integrity of cytoplasmic RNA. Expression of DDX60 increases after viral infection, and the protein localizes at the cytoplasmic region. After viral infection, the DDX60 protein binds to endogenous RIG-I protein. The protein also binds to MDA5 and LGP2 but not to the downstream factors IPS-1 and IκB kinase ε (IKK-ε). Knockdown analysis shows that DDX60 is required for RIG-I- or MDA5-dependent type I interferon and interferon-inducible gene expression in response to viral infection. However, DDX60 is dispensable for TLR3-mediated signaling. Purified DDX60 helicase domains possess the activity to bind to viral RNA and DNA. Expression of DDX60 promotes the binding of RIG-I to double-stranded RNA. Taken together, our analyses indicate that DDX60 is a novel antiviral helicase promoting RIG-I-like receptor-mediated signaling.
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            DDX60 Is Involved in RIG-I-Dependent and Independent Antiviral Responses, and Its Function Is Attenuated by Virus-Induced EGFR Activation.

            Hiroyuki Oshiumi, Moeko Miyashita, Masaaki Okamoto … (2015)
            RIG-I-mediated type I interferon (IFN) production and nuclease-mediated viral RNA degradation are essential for antiviral innate immune responses. DDX60 is an IFN-inducible cytoplasmic helicase. Here, we report that DDX60 is a sentinel for both RIG-I activation and viral RNA degradation. We show that DDX60 is an upstream factor of RIG-I that activates RIG-I signaling in a ligand-specific manner. DDX60 knockout attenuates RIG-I signaling and significantly reduces virus-induced type I IFN production in vivo. In addition, we show that DDX60 is involved in RIG-I-independent viral RNA degradation. DDX60 and RIG-I adaptor MAVS double-knockout mice reveal a role for DDX60-dependent RNA degradation in antiviral responses. Several viruses induced DDX60 phosphorylation via epidermal growth factor receptor (EGFR), leading to attenuation of the DDX60 antiviral activities. Our results define DDX60 as a sentinel for cytoplasmic antiviral response, which is counteracted by virus-mediated EGF receptor activation.
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              Transcriptomic signatures differentiate survival from fatal outcomes in humans infected with Ebola virus

              Xuan Liu, Emily Speranza, César Muñoz-Fontela … (2017)
              Background In 2014, Western Africa experienced an unanticipated explosion of Ebola virus infections. What distinguishes fatal from non-fatal outcomes remains largely unknown, yet is key to optimising personalised treatment strategies. We used transcriptome data for peripheral blood taken from infected and convalescent recovering patients to identify early stage host factors that are associated with acute illness and those that differentiate patient survival from fatality. Results The data demonstrate that individuals who succumbed to the disease show stronger upregulation of interferon signalling and acute phase responses compared to survivors during the acute phase of infection. Particularly notable is the strong upregulation of albumin and fibrinogen genes, which suggest significant liver pathology. Cell subtype prediction using messenger RNA expression patterns indicated that NK-cell populations increase in patients who survive infection. By selecting genes whose expression properties discriminated between fatal cases and survivors, we identify a small panel of responding genes that act as strong predictors of patient outcome, independent of viral load. Conclusions Transcriptomic analysis of the host response to pathogen infection using blood samples taken during an outbreak situation can provide multiple levels of information on both disease state and mechanisms of pathogenesis. Host biomarkers were identified that provide high predictive value under conditions where other predictors, such as viral load, are poor prognostic indicators. The data suggested that rapid analysis of the host response to infection in an outbreak situation can provide valuable information to guide an understanding of disease outcome and mechanisms of disease. Electronic supplementary material The online version of this article (doi:10.1186/s13059-016-1137-3) contains supplementary material, which is available to authorized users.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Infect Dis
                Journal ID (iso-abbrev): J. Infect. Dis
                Journal ID (publisher-id): jid
                Title: The Journal of Infectious Diseases
                Publisher: Oxford University Press (US )
                ISSN (Print): 0022-1899
                ISSN (Electronic): 1537-6613
                Publication date (Print): 15 December 2018
                Publication date (Electronic): 23 August 2018
                Publication date PMC-release: 23 August 2018
                Volume: 218
                Issue: Suppl 5 , Marburg and Ebola Viruses: Marking 50 Years Since Discovery
                Pages: S486-S495
                Affiliations
                [1 ]Galveston National Laboratory, University of Texas Medical Branch, Galveston
                [2 ]Departments of Microbiology and Immunology, University of Texas Medical Branch, Galveston
                [3 ]Departments of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston
                [4 ]Department of Microbiology, Bioinformatics Program, National Emerging Infectious Disease Laboratories, Boston University, Massachusetts
                [5 ]Integrated Research Facility at Fort Detrick, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland
                Author notes

                R. W. C. and E. S. contributed equally to this work.

                Correspondence: T. W. Geisbert, PhD, University of Texas Medical Branch, Galveston National Laboratory, 301 University Blvd., Galveston, TX 77550-0610 ( twgeisbe@ 123456utmb.edu ).
                Article
                Publisher ID: jiy455
                DOI: 10.1093/infdis/jiy455
                PMC ID: 6249602
                SO-VID: ade27845-7cc0-48de-b794-3c4bdf7e2497
                Copyright © © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                Page count
                Pages: 10
                Funding
                Funded by: National Science Foundation 10.13039/100000001
                Award ID: DGE-1247312
                Award ID: RO1AI1096159
                Funded by: National Institute of Allergy and Infectious Diseases 10.13039/100000060
                Award ID: HHSN272200700016I
                Categories
                Subject: Supplement Articles
                Subject: Immunology/Host Response

                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: animal model,ebola virus,ferret,transcriptomics,vaccines
                Data availability:
                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: animal model, ebola virus, ferret, transcriptomics, vaccines

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