92
views
0
recommends
+1 Recommend
2 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Effective Post-Exposure Treatment of Ebola Infection

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Ebola viruses are highly lethal human pathogens that have received considerable attention in recent years due to an increasing re-emergence in Central Africa and a potential for use as a biological weapon. There is no vaccine or treatment licensed for human use. In the past, however, important advances have been made in developing preventive vaccines that are protective in animal models. In this regard, we showed that a single injection of a live-attenuated recombinant vesicular stomatitis virus vector expressing the Ebola virus glycoprotein completely protected rodents and nonhuman primates from lethal Ebola challenge. In contrast, progress in developing therapeutic interventions against Ebola virus infections has been much slower and there is clearly an urgent need to develop effective post-exposure strategies to respond to future outbreaks and acts of bioterrorism, as well as to treat laboratory exposures. Here we tested the efficacy of the vesicular stomatitis virus-based Ebola vaccine vector in post-exposure treatment in three relevant animal models. In the guinea pig and mouse models it was possible to protect 50% and 100% of the animals, respectively, following treatment as late as 24 h after lethal challenge. More important, four out of eight rhesus macaques were protected if treated 20 to 30 min following an otherwise uniformly lethal infection. Currently, this approach provides the most effective post-exposure treatment strategy for Ebola infections and is particularly suited for use in accidentally exposed individuals and in the control of secondary transmission during naturally occurring outbreaks or deliberate release.

          Author Summary

          Being highly pathogenic for humans and monkeys and the subject of former weapons programs makes Ebola virus one of the most feared pathogens worldwide today. Due to a lack of licensed pre- and post-exposure intervention, our current response depends on rapid diagnostics, proper isolation procedures, and supportive care of case patients. Consequently, the development of more specific countermeasures is of high priority for the preparedness of many nations. In this study, we investigated an attenuated vesicular stomatitis virus expressing the Ebola virus surface glycoprotein, which had previously demonstrated convincing efficacy as a vaccine against Ebola infections in rodents and monkeys, for its potential use in the treatment of an Ebola virus infection. Surprisingly, treatment of guinea pigs and mice as late as 24 h after lethal Ebola virus infection resulted in 50% and 100% survival, respectively. More important, 50% of rhesus macaques (4/8) were protected if treated 20 to 30 min after Ebola virus infection. Currently, this approach provides the most effective treatment strategy for Ebola infections and seems particularly suited for the use in accidental exposures and the control of human-to-human transmission during outbreaks.

          Related collections

          Most cited references38

          • Record: found
          • Abstract: found
          • Article: not found

          Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection.

          Ebola virus (EBOV) infection causes a severe and fatal hemorrhagic disease that in many ways appears to be similar in humans and nonhuman primates; however, little is known about the development of EBOV hemorrhagic fever. In the present study, 21 cynomolgus monkeys were experimentally infected with EBOV and examined sequentially over a 6-day period to investigate the pathological events of EBOV infection that lead to death. Importantly, dendritic cells in lymphoid tissues were identified as early and sustained targets of EBOV, implicating their important role in the immunosuppression characteristic of EBOV infections. Bystander lymphocyte apoptosis, previously described in end-stage tissues, occurred early in the disease-course in intravascular and extravascular locations. Of note, apoptosis and loss of NK cells was a prominent finding, suggesting the importance of innate immunity in determining the fate of the host. Analysis of peripheral blood mononuclear cell gene expression showed temporal increases in tumor necrosis factor-related apoptosis-inducing ligand and Fas transcripts, revealing a possible mechanism for the observed bystander apoptosis, while up-regulation of NAIP and cIAP2 mRNA suggest that EBOV has evolved additional mechanisms to resist host defenses by inducing protective transcripts in cells that it infects. The sequence of pathogenetic events identified in this study should provide new targets for rational prophylactic and chemotherapeutic interventions.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Development of a preventive vaccine for Ebola virus infection in primates.

            Outbreaks of haemorrhagic fever caused by the Ebola virus are associated with high mortality rates that are a distinguishing feature of this human pathogen. The highest lethality is associated with the Zaire subtype, one of four strains identified to date. Its rapid progression allows little opportunity to develop natural immunity, and there is currently no effective anti-viral therapy. Therefore, vaccination offers a promising intervention to prevent infection and limit spread. Here we describe a highly effective vaccine strategy for Ebola virus infection in non-human primates. A combination of DNA immunization and boosting with adenoviral vectors that encode viral proteins generated cellular and humoral immunity in cynomolgus macaques. Challenge with a lethal dose of the highly pathogenic, wild-type, 1976 Mayinga strain of Ebola Zaire virus resulted in uniform infection in controls, who progressed to a moribund state and death in less than one week. In contrast, all vaccinated animals were asymptomatic for more than six months, with no detectable virus after the initial challenge. These findings demonstrate that it is possible to develop a preventive vaccine against Ebola virus infection in primates.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Ebola virus VP24 binds karyopherin alpha1 and blocks STAT1 nuclear accumulation.

              Ebola virus (EBOV) infection blocks cellular production of alpha/beta interferon (IFN-alpha/beta) and the ability of cells to respond to IFN-alpha/beta or IFN-gamma. The EBOV VP35 protein has previously been identified as an EBOV-encoded inhibitor of IFN-alpha/beta production. However, the mechanism by which EBOV infection inhibits responses to IFNs has not previously been defined. Here we demonstrate that the EBOV VP24 protein functions as an inhibitor of IFN-alpha/beta and IFN-gamma signaling. Expression of VP24 results in an inhibition of IFN-induced gene expression and an inability of IFNs to induce an antiviral state. The VP24-mediated inhibition of cellular responses to IFNs correlates with the impaired nuclear accumulation of tyrosine-phosphorylated STAT1 (PY-STAT1), a key step in both IFN-alpha/beta and IFN-gamma signaling. Consistent with this proposed function for VP24, infection of cells with EBOV also confers a block to the IFN-induced nuclear accumulation of PY-STAT1. Further, VP24 is found to specifically interact with karyopherin alpha1, the nuclear localization signal receptor for PY-STAT1, but not with karyopherin alpha2, alpha3, or alpha4. Overexpression of VP24 results in a loss of karyopherin alpha1-PY-STAT1 interaction, indicating that the VP24-karyopherin alpha1 interaction contributes to the block to IFN signaling. These data suggest that VP24 is likely to be an important virulence determinant that allows EBOV to evade the antiviral effects of IFNs.
                Bookmark

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                ppat
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                January 2007
                19 January 2007
                : 3
                : 1
                : e2
                Affiliations
                [1 ] Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
                [2 ] Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada
                [3 ] Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
                [4 ] Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, United States of America
                [5 ] Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America
                [6 ] Biodefense Clinical Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
                Washington University School of Medicine, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: Heinz_Feldmann@ 123456phac-aspc.gc.ca (HF); Steven_Jones@ 123456phac-aspc.gc.ca (SMJ)
                Article
                06-PLPA-RA-0358R2 plpa-03-01-05
                10.1371/journal.ppat.0030002
                1779298
                17238284
                08e708f8-638d-4ce3-bcec-720ffdef1432
                This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
                History
                : 7 September 2006
                : 13 November 2006
                Page count
                Pages: 8
                Categories
                Research Article
                Infectious Diseases
                Virology
                Viruses
                Animals
                Custom metadata
                Feldmann H, Jones SM, Daddario-DiCaprio KM, Geisbert JB, Ströher U, et al. (2007) Effective post-exposure treatment of Ebola infection. PLoS Pathog 3(1): e2. doi: 10.1371/journal.ppat.0030002

                Infectious disease & Microbiology
                Infectious disease & Microbiology

                Comments

                Comment on this article