scholarly journals Less Is More: Ebola Virus Surface Glycoprotein Expression Levels Regulate Virus Production and Infectivity

2014 ◽  
Vol 89 (2) ◽  
pp. 1205-1217 ◽  
Author(s):  
Gopi S. Mohan ◽  
Ling Ye ◽  
Wenfang Li ◽  
Ana Monteiro ◽  
Xiaoqian Lin ◽  
...  
Keyword(s):  
Rna Editing ◽  
Ebola Virus ◽  
Virus Production ◽  
Surface Glycoprotein ◽  
Cell Physiology ◽  
Virus Infectivity ◽  
Virus Surface ◽  
Expression Levels ◽  
Less Is More ◽  
Ebov Infection

ABSTRACTThe Ebola virus (EBOV) surface glycoprotein (GP1,2) mediates host cell attachment and fusion and is the primary target for host neutralizing antibodies. Expression of GP1,2at high levels disrupts normal cell physiology, and EBOV uses an RNA-editing mechanism to regulate expression of the GP gene. In this study, we demonstrate that high levels of GP1,2expression impair production and release of EBOV virus-like particles (VLPs) as well as infectivity of GP1,2-pseudotyped viruses. We further show that this effect is mediated through two mechanisms. First, high levels of GP1,2expression reduce synthesis of other proteins needed for virus assembly. Second, viruses containing high levels of GP1,2are intrinsically less infectious, possibly due to impaired receptor binding or endosomal processing. Importantly, proteolysis can rescue the infectivity of high-GP1,2-containing viruses. Taken together, our findings indicate that GP1,2expression levels have a profound effect on factors that contribute to virus fitness and that RNA editing may be an important mechanism employed by EBOV to regulate GP1,2expression in order to optimize virus production and infectivity.IMPORTANCEThe Ebola virus (EBOV), as well as other members of theFiloviridaefamily, causes severe hemorrhagic fever that is highly lethal, with up to 90% mortality. The EBOV surface glycoprotein (GP1,2) plays important roles in virus infection and pathogenesis, and its expression is tightly regulated by an RNA-editing mechanism during virus replication. Our study demonstrates that the level of GP1,2expression profoundly affects virus particle production and release and uncovers a new mechanism by which Ebola virus infectivity is regulated by the level of GP1,2expression. These findings extend our understanding of EBOV infection and replication in adaptation of host environments, which will aid the development of countermeasures against EBOV infection.

scholarly journals Shedding of Ebola Virus Surface Glycoprotein Is a Mechanism of Self-regulation of Cellular Cytotoxicity and Has a Direct Effect on Virus Infectivity

2015 ◽  
Vol 212 (suppl 2) ◽  
pp. S322-S328 ◽  
Author(s):  
Olga Dolnik ◽  
Valentina A. Volchkova ◽  
Beatriz Escudero-Perez ◽  
Philip Lawrence ◽  
Hans-Dieter Klenk ◽  
...  
Keyword(s):  
Direct Effect ◽  
Ebola Virus ◽  
Self Regulation ◽  
Surface Glycoprotein ◽  
Virus Infectivity ◽  
Cellular Cytotoxicity ◽  
Virus Surface

scholarly journals Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Punya Shrivastava-Ranjan ◽  
Mike Flint ◽  
Éric Bergeron ◽  
Anita K. McElroy ◽  
Payel Chatterjee ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Virus Disease ◽  
Statin Treatment ◽  
Ebola Virus Disease ◽  
Health Concern ◽  
Virus Infectivity ◽  
Viral Glycoprotein ◽  
Antiviral Effects ◽  
Ebov Infection ◽  
Glycoprotein Processing

ABSTRACTEbola virus (EBOV) infection is a major public health concern due to high fatality rates and limited effective treatments. Statins, widely used cholesterol-lowering drugs, have pleiotropic mechanisms of action and were suggested as potential adjunct therapy for Ebola virus disease (EVD) during the 2013–2016 outbreak in West Africa. Here, we evaluated the antiviral effects of statin (lovastatin) on EBOV infectionin vitro. Statin treatment decreased infectious EBOV production in primary human monocyte-derived macrophages and in the hepatic cell line Huh7. Statin treatment did not interfere with viral entry, but the viral particles released from treated cells showed reduced infectivity due to inhibition of viral glycoprotein processing, as evidenced by decreased ratios of the mature glycoprotein form to precursor form. Statin-induced inhibition of infectious virus production and glycoprotein processing was reversed by exogenous mevalonate, the rate-limiting product of the cholesterol biosynthesis pathway, but not by low-density lipoprotein. Finally, statin-treated cells produced EBOV particles devoid of the surface glycoproteins required for virus infectivity. Our findings demonstrate that statin treatment inhibits EBOV infection and suggest that the efficacy of statin treatment should be evaluated in appropriate animal models of EVD.IMPORTANCETreatments targeting Ebola virus disease (EVD) are experimental, expensive, and scarce. Statins are inexpensive generic drugs that have been used for many years for the treatment of hypercholesterolemia and have a favorable safety profile. Here, we show the antiviral effects of statins on infectious Ebola virus (EBOV) production. Our study reveals a novel molecular mechanism in which statin regulates EBOV particle infectivity by preventing glycoprotein processing and incorporation into virus particles. Additionally, statins have anti-inflammatory and immunomodulatory effects. Since inflammation and dysregulation of the immune system are characteristic features of EVD, statins could be explored as part of EVD therapeutics.

Characterization of an Anti-Ebola virus Hyperimmune Globulin Derived from Convalescent Plasma

2021 ◽  
Author(s):  
Jonathan M Ciencewicki ◽  
Andrew S Herbert ◽  
Nadia Storm ◽  
Nicole M Josleyn ◽  
Kathleen Huie ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Virus Disease ◽  
Fold Increase ◽  
Surface Glycoprotein ◽  
Post Exposure Prophylaxis ◽  
Emerging Viruses ◽  
Live Virus ◽  
Glycoprotein Antigen ◽  
Ebov Infection ◽  
Exposure Prophylaxis

Abstract Backrgound Convalescent plasma has been used to treat many viral diseases including Ebola. The manufacture of a purified anti-Ebola virus (EBOV) intravenous immunoglobulin (IVIG) from pooled convalescent plasma is described in this paper. Methods An ELISA targeting an EBOV surface glycoprotein antigen was used to determine the immunoglobulin titer of pooled plasma and purified anti-EBOV IVIG. Anti-EBOV IVIG was also tested in neutralization assays using a vesicular stomatitis virus pseudovirion expressing EBOV glycoprotein on its surface and with live EBOV. Finally, the efficacy of the anti-EBOV IVIG was assessed in a mouse model of EBOV infection. Results In the ELISA, the anti-EBOV IVIG was shown to have a seven-fold increase in IgG titer over pooled convalescent plasma. In both the pseudovirion and live virus assays, the anti-EBOV IVIG showed approximately five- to six-fold increased potency over pooled plasma. Anti-EBOV IVIG also significantly improved survivability in mice infected with the virus when administered concurrently or two days after infection. Conclusions These data support this purified anti-EBOV IVIG merits additional investigation and clinical trials for treatment and post-exposure prophylaxis of Ebola virus disease. The experience gained can be applied to manufacture hyperimmune globulins against other emerging viruses.

scholarly journals Antagonism of STAT3 signalling by Ebola virus

2020 ◽  
Author(s):  
Angela R. Harrison ◽  
Megan Dearnley ◽  
Shawn Todd ◽  
Diane Green ◽  
Glenn A. Marsh ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ebola Virus ◽  
Significant Risk ◽  
Disease Outbreaks ◽  
Case Fatality ◽  
Cell Physiology ◽  
Haemorrhagic Fever ◽  
Nuclear Trafficking ◽  
Ebov Infection ◽  
Stat3 Signalling

AbstractMany viruses target signal transducers and activators of transcription (STAT) 1 and 2 to antagonise antiviral interferon (IFN) signalling, but targeting of signalling by other STATs/cytokines, including STAT3/interleukin (IL-) 6 that regulate processes important to Ebola virus (EBOV) haemorrhagic fever, is poorly defined. We report that EBOV potently inhibits STAT3 responses to IL-6 family cytokines, and that this is mediated by the IFN-antagonist VP24. Mechanistic analysis indicates that VP24 effects a unique strategy combining distinct karyopherin-dependent and karyopherin-independent mechanisms to antagonise STAT3-STAT1 heterodimers and STAT3 homodimers, respectively. This appears to reflect distinct mechanisms of nuclear trafficking of the STAT3 complexes, revealed for the first time by our analysis of VP24 function. These findings are consistent with major roles for global inhibition of STAT3 signalling in EBOV infection, and provide new insights into the molecular mechanisms of STAT3 nuclear trafficking, significant to pathogen-host interactions, cell physiology and pathologies such as cancer.Author summaryEbola virus (EBOV) continues to pose a significant risk to human health globally, causing ongoing disease outbreaks with case-fatality rates between 40 and 60%. Suppression of immune responses is a critical component of EBOV haemorrhagic fever, but understanding of EBOV impact on signalling by cytokines other than interferon is limited. We find that infectious EBOV inhibits interleukin-6 cytokine signalling via antagonism of STAT3. The antagonistic strategy uniquely combines two distinct mechanisms, which appear to reflect differing nuclear trafficking mechanisms of critical STAT3 complexes. This provides fundamental insights into the mechanisms of pathogenesis of a lethal virus, and biology of STAT3, a critical player in immunity, development, growth and cancer.

scholarly journals BoHV-4-based vector delivering Ebola virus surface glycoprotein

2016 ◽  
Vol 14 (1) ◽  
Author(s):  
Alfonso Rosamilia ◽  
Sarah Jacca ◽  
Giulia Tebaldi ◽  
Silvia Tiberti ◽  
Valentina Franceschi ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Surface Glycoprotein ◽  
Virus Surface

scholarly journals Proteolytic Processing of the Ebola Virus Glycoprotein Is Not Critical for Ebola Virus Replication in Nonhuman Primates

2007 ◽  
Vol 81 (6) ◽  
pp. 2995-2998 ◽  
Author(s):  
Gabriele Neumann ◽  
Thomas W. Geisbert ◽  
Hideki Ebihara ◽  
Joan B. Geisbert ◽  
Kathleen M. Daddario-DiCaprio ◽  
...  
Keyword(s):  
Virus Replication ◽  
Nonhuman Primates ◽  
Ebola Virus ◽  
Proteolytic Processing ◽  
Surface Glycoprotein ◽  
Wild Type Virus ◽  
Virus Infectivity ◽  
Recognition Sequence ◽  
Furin Cleavage ◽  
Virus Glycoprotein

ABSTRACT Enveloped viruses often require cleavage of a surface glycoprotein by a cellular endoprotease such as furin for infectivity and virulence. Previously, we showed that Ebola virus glycoprotein does not require the furin cleavage motif for virus replication in cell culture. Here, we show that there are no appreciable differences in disease progression, hematology, serum biochemistry, virus titers, or lethality in nonhuman primates infected with an Ebola virus lacking the furin recognition sequence compared to those infected with wild-type virus. We conclude that glycoprotein cleavage by subtilisin-like endoproteases is not critical for Ebola virus infectivity and virulence in nonhuman primates.

scholarly journals A Novel Mechanism for LSECtin Binding to Ebola Virus Surface Glycoprotein through Truncated Glycans

2007 ◽  
Vol 283 (1) ◽  
pp. 593-602 ◽  
Author(s):  
Alex S. Powlesland ◽  
Tanja Fisch ◽  
Maureen E. Taylor ◽  
David F. Smith ◽  
Bérangère Tissot ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Surface Glycoprotein ◽  
Virus Surface

scholarly journals Partnership for Research on Ebola VACcination (PREVAC): protocol of a randomized, double-blind, placebo-controlled phase 2 clinical trial evaluating three vaccine strategies against Ebola in healthy volunteers in four West African countries

2020 ◽  
Author(s):  
Moses Badio ◽  
Edouard Lhomme ◽  
Mark Kieh ◽  
Abdoul Habib Beavogui ◽  
Stephen B Kennedy ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Healthy Volunteers ◽  
Antibody Titer ◽  
Ebola Virus ◽  
Surface Glycoprotein ◽  
Phase 2 ◽  
Double Blind ◽  
Virus Surface ◽  
Double Blind Placebo ◽  
Phase 2 Clinical Trial

Abstract IntroductionThe Ebola virus disease (EVD) outbreak in 2014–2016 in West Africa was the largest on record and provided an opportunity for large clinical trials and accelerated efforts to develop an effective and safe preventative vaccine. Multiple questions regarding the safety, immunogenicity, and efficacy of EVD vaccines remain unanswered. To address these gaps in the evidence base, the Partnership for Research on Ebola Vaccines (PREVAC) trial was designed. This paper describes the design, methods, and baseline results of the PREVAC trial and discusses challenges that led to different protocol amendments.MethodsThis is a randomized, double-blind, placebo-controlled phase 2 clinical trial of three vaccine strategies against the Ebola virus in healthy volunteers 1 year of age and above. The three vaccine strategies being studied are the rVSVΔG-ZEBOV-GP vaccine, with and without a booster dose at 56 days, and the Ad26.ZEBOV,MVA-FN-Filo vaccine regimen with Ad26.ZEBOV given as the first dose and the MVA-FN-Filo vaccination given 56 days later. There have been 4 versions of the protocol with those enrolled in Version 4.0 comprising the primary analysis cohort. The primary endpoint is based on the antibody titer against the Ebola virus surface glycoprotein measured 12 months following the final injection.ResultsFrom April 2017 to December 2018, a total of 5,002 volunteers were screened and 4,789 enrolled. Participants were enrolled at 6 sites in four countries (Guinea, Liberia, Sierra Leone, and Mali). Of the 4,789 participants, 2,560 (53%) were adults and 2,229 (47%) were children. Those < 18 years of age included 549 (12%) aged 1 to 4 years; 750 (16%) 5 to 11 years; and 930 (19%) aged 12–17 years. At baseline, the median (25th, 75th percentile) antibody titer to Ebola virus glycoprotein for 1,090 participants was 72 (50, 116) EU/mL.DiscussionThe PREVAC trial is evaluating - placebo-controlled - two promising Ebola candidate vaccines in advanced stages of development. The results will address unanswered questions related to short- and long-term safety and immunogenicity for three vaccine strategies in adults and children.Trial registrationClinicaltrials.gov, NCT02876328. Registred 23 August 2016, https://clinicaltrials.gov/ct2/show/NCT02876328

scholarly journals Antagonism of STAT3 signalling by Ebola virus

2021 ◽  
Vol 17 (6) ◽  
pp. e1009636
Author(s):  
Angela R. Harrison ◽  
Shawn Todd ◽  
Megan Dearnley ◽  
Cassandra T. David ◽  
Diane Green ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Molecular Mechanisms ◽  
Ebola Virus ◽  
Cell Physiology ◽  
Nuclear Trafficking ◽  
Signal Transducers ◽  
Host Interactions ◽  
Ebov Infection ◽  
Interferon Signalling ◽  
Stat3 Signalling

Many viruses target signal transducers and activators of transcription (STAT) 1 and 2 to antagonise antiviral interferon signalling, but targeting of signalling by other STATs/cytokines, including STAT3/interleukin 6 that regulate processes important to Ebola virus (EBOV) haemorrhagic fever, is poorly defined. We report that EBOV potently inhibits STAT3 responses to interleukin-6 family cytokines, and that this is mediated by the interferon-antagonist VP24. Mechanistic analysis indicates that VP24 effects a unique strategy combining distinct karyopherin-dependent and karyopherin-independent mechanisms to antagonise STAT3-STAT1 heterodimers and STAT3 homodimers, respectively. This appears to reflect distinct mechanisms of nuclear trafficking of the STAT3 complexes, revealed for the first time by our analysis of VP24 function. These findings are consistent with major roles for global inhibition of STAT3 signalling in EBOV infection, and provide new insights into the molecular mechanisms of STAT3 nuclear trafficking, significant to pathogen-host interactions, cell physiology and pathologies such as cancer.

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