West African Ebola Epidemic after One Year — Slowing but Not Yet under Control

Agua-Agum, Junerlyn; Ariyarajah, Archchun; Aylward, Bruce; Blake, Isobel M.; Brennan, Richard; Cori, Anne; Donnelly, Christl A.; Dorigatti, Ilaria; Dye, Christopher; Eckmanns, Tim; Ferguson, Neil; Formenty, Pierre; Fraser, Christophe; Garcia, Erika; Garske, Tini; Hinsley, Wes; Holmes, David; Hugonnet, Stéphane; Iyengar, Swathi; Jombart, Thibaut; Ravindran, Krishnan; Meijers, Sascha; Mills, Harriet L.; Mohamed, Yasmine; Nedjati-Gilani, Gemma; Newton, Emily; Nouvellet, Pierre; Pelletier, Louise; Perkins, Devin; Riley, Steven; Sagrado, María José; Schnitzler, J; Schumacher, Dirk; Shah, Anita; Kerkhove, Maria D. Van; Varsaneux, Olivia; Kannangarage, Niluka

doi:10.1056/nejmc1414992

Cited by 172 publications

(150 citation statements)

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“…Ebola virus causes severe hemorrhagic fever and is responsible for a significant and sustained outbreak in Western Africa 2013–2015 (Agua-Agum et al, 2015; Burke et al, 1978). Ebola virus belongs to the family filoviridae, which also contains four other members of the ebolavirus genus, the pathogenic Marburg virus (MARV) and the recently discovered Lloviu virus (LLOV) (Negredo et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Assembly of the Ebola Virus Nucleoprotein from a Chaperoned VP35 Complex

et al. 2015

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Summary Ebolavirus NP oligomerizes into helical filaments found at the core of the virion, encapsidates the viral RNA genome, and serves as a scaffold for additional viral proteins within the viral nucleocapsid. We identified a portion of the phosphoprotein homologue VP35 that binds with high affinity to nascent NP and regulates NP assembly and viral genome binding. Removal of the VP35 peptide leads to NP self-assembly via its N-terminal oligomerization arm. NP oligomerization likely causes a conformational change between the NP N- and C-terminal domains, facilitating RNA binding. These functional data are complemented by a crystal structure of the NP°-VP35 complex at 2.4 Å resolution. The interactions between NP and VP35 illuminated by these structures are conserved among filoviruses and provide key targets for therapeutic intervention.

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Section: Introductionmentioning

confidence: 99%

Assembly of the Ebola Virus Nucleoprotein from a Chaperoned VP35 Complex

et al. 2015

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“…Ebola virus is a non-segmented negative-sense RNA virus (NNSV), which can cause severe hemorrhagic fever with high case fatality rates during outbreaks as highlighted by the 2013–2016 West African outbreak (Messaoudi et al, 2015; Team et al, 2015). The enveloped Ebola virions contain a single-stranded RNA (ssRNA) genome encoding seven structural proteins known as Ebola nucleoprotein (eNP), viral protein (VP) 35 (eVP35), eVP40, glycoprotein (eGP), eVP30, eVP24 and the large protein (eL) (Messaoudi et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Electron Cryo-microscopy Structure of Ebola Virus Nucleoprotein Reveals a Mechanism for Nucleocapsid-like Assembly

Shi

et al. 2018

Cell

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Summary Ebola virus nucleoprotein (eNP) assembles into higher-ordered structures that form the viral nucleocapsid (NC) and serve as the scaffold for viral RNA synthesis. However, molecular insights into the NC assembly process are lacking. Using a hybrid approach, we characterized the NC-like assembly of eNP, identified novel regulatory elements, and described how these elements impact function. We generated a three-dimensional structure of the eNP NC-like assembly at 5.8 Å using electron cryo-microscopy and identified a new regulatory role for eNP helices α22–α23. Biochemical, biophysical, and mutational analysis revealed inter-eNP contacts within α22–α23 are critical for viral NC-assembly and regulate viral RNA synthesis. These observations suggest that the N-terminus and α22–α23 of eNP function as context dependent regulatory modules (CDRMs). Our current study provides a framework for a structural mechanism for NC-like assembly and a new therapeutic target.

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“…Filoviruses cause severe hemorrhagic fever in humans and nonhuman primates with fatality rates of up to 90% in humans (2). The recent EBOV outbreak in West Africa underlines the emerging potential of filoviruses and the consequences that those outbreaks can have for public health and the stability of a whole region (3). Filoviruses are classified as biosafety level 4 (BSL4) pathogens that need to be handled under the highest biosafety conditions (4).…”

Section: T He Nonsegmented Negative-sense Rna Viruses Ebola Virus (Ementioning

confidence: 99%

RNA Binding of Ebola Virus VP30 Is Essential for Activating Viral Transcription

Biedenkopf

Schlereth

Grünweller

et al. 2016

J Virol

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The template for Ebola virus (EBOV) transcription and replication is the helical viral nucleocapsid composed of the viral negative-sense (؊) RNA genome, which is complexed by the nucleoprotein (NP), VP35, polymerase L, VP24, and VP30. While viral replication is exerted by polymerase L and its cofactor VP35, EBOV mRNA synthesis is regulated by the viral nucleocapsid protein VP30, an essential EBOV-specific transcription factor. VP30 is a homohexameric phosphoprotein containing a nonconventional zinc finger. The transcriptional support activity of VP30 is strongly influenced by its phosphorylation state. We studied here how RNA binding contributed to VP30's function in transcriptional activation. Using a novel mobility shift assay and the 3=-terminal 154 nucleotides of the EBOV genome as a standard RNA substrate, we detected that RNA binding of VP30 was severely impaired by VP30 mutations that (i) destroy the protein's capability to form homohexamers, (ii) disrupt the integrity of its zinc finger domain, (iii) mimic its fully phosphorylated state, or (iv) alter the putative RNA binding region. RNA binding of the mutant VP30 proteins correlated strongly with their transcriptional support activity. Furthermore, we showed that the interaction between VP30 and the polymerase cofactor VP35 is RNA dependent, while formation of VP30 homohexamers and VP35 homotetramers is not. Our data indicate that RNA binding of VP30 is essential for its transcriptional support activity and stabilizes complexes of VP35/L polymerase with the (؊) RNA template to favor productive transcriptional initiation in the presence of termination-active RNA secondary structures. IMPORTANCEEbola virus causes severe fevers with unusually high case fatality rates. The recent outbreak of Ebola virus in West Africa claimed more than 11,000 lives and threatened to destabilize a whole region because of its dramatic effects on the public health systems. It is currently not completely understood how Ebola virus manages to balance viral transcription and replication in the infected cells. This study shows that transcriptional support activity of the Ebola virus transcription factor VP30 is highly correlated with its ability to bind viral RNA. The interaction between VP30 and VP35, the Ebola virus polymerase cofactor, is dependent on the presence of RNA as well. Our data contribute to the understanding of the dynamic interplay between nucleocapsid proteins and the viral RNA template in order to promote viral RNA synthesis.

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West African Ebola Epidemic after One Year — Slowing but Not Yet under Control

Cited by 172 publications

References 1 publication

Assembly of the Ebola Virus Nucleoprotein from a Chaperoned VP35 Complex

Assembly of the Ebola Virus Nucleoprotein from a Chaperoned VP35 Complex

Electron Cryo-microscopy Structure of Ebola Virus Nucleoprotein Reveals a Mechanism for Nucleocapsid-like Assembly

RNA Binding of Ebola Virus VP30 Is Essential for Activating Viral Transcription

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