Soluble Glycoprotein Is Not Required for Ebola Virus Virulence in Guinea Pigs

Hoenen, Thomas; Marzi, Andrea; Scott, Dana; Feldmann, Friederike; Callison, Julie; Safronetz, David; Ebihara, Hideki; Feldmann, Heinz

doi:10.1093/infdis/jiv111

Cited by 15 publications

(10 citation statements)

References 17 publications

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“…However, the fast emergence of revertants both in vivo and in vitro (in certain cell lines) when sGP production is reduced by introducing an 8A genotype (i.e. 8 uridine residues in the virus genome, leading to production of predominantly 8A mRNAs) in the editing site suggests an important role of sGP in the biology of ebolaviruses (Volchkova et al, 2011;Kugelman et al, 2012;Hoenen et al, 2015;Tsuda et al, 2015). In vitro, sGP exerts vascular effects, notably the restoration of the barrier function suggesting an anti-inflammatory role (Wahl-Jensen et al, 2005); however, the relevance of this finding is currently not clear.…”

Section: Gp: One Gene Many Proteinsmentioning

confidence: 99%

“…Interestingly, when EBOV is serially passaged in certain cell lines like Vero cells, the GP gene gets modified to predominantly generate GP 1,2 by addition of an 8th U in the editing site (n.b., in contrast to transcriptional editing this occurs on the genome level) (Volchkova et al, 2011). However, when this EBOV is further passaged in animals or in other cell lines like Huh7 cells, the genotype reverts back so that sGP is again produced as the main product of transcription (Volchkova et al, 2011;Hoenen et al, 2015;Tsuda et al, 2015). This observation suggests that either the importance of the function of sGP or the importance of GP gene modulation is dependent on the host cell environment.…”

Section: Modulation Of Cytotoxicity and Inflammationmentioning

confidence: 99%

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Filovirus proteins for antiviral drug discovery: A structure/function analysis of surface glycoproteins and virus entry

et al. 2016

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This review focuses on the recent progress in our understanding of filovirus protein structure/function and its impact on antiviral research. Here we focus on the surface glycoprotein GP and its different roles in filovirus entry. We first describe the latest advances on the characterization of GP gene-overlapping proteins sGP, ssGP and Δ-peptide. Then, we compare filovirus surface GP proteins in terms of structure, synthesis and function. As they bear potential in drug-design, the discovery of small organic compounds inhibiting filovirus entry is a currently very active field. Although it is at an early stage, the development of antiviral drugs against Ebola and Marburg virus entry might prove essential to reduce outbreak-associated fatality rates through post-exposure treatment of both suspected and confirmed cases.

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Section: Gp: One Gene Many Proteinsmentioning

confidence: 99%

Section: Modulation Of Cytotoxicity and Inflammationmentioning

confidence: 99%

Filovirus proteins for antiviral drug discovery: A structure/function analysis of surface glycoproteins and virus entry

et al. 2016

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“…GP, the only transmembrane surface protein, is responsible for host cell binding and virus internalization 1 6 . Little is known about the functional roles of the secreted proteins sGP and ssGP 1 3 4 7 .…”

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confidence: 99%

Conserved differences in protein sequence determine the human pathogenicity of Ebolaviruses

Pappalardo

Juliá

Howard

et al. 2016

Sci Rep

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Reston viruses are the only Ebolaviruses that are not pathogenic in humans. We analyzed 196 Ebolavirus genomes and identified specificity determining positions (SDPs) in all nine Ebolavirus proteins that distinguish Reston viruses from the four human pathogenic Ebolaviruses. A subset of these SDPs will explain the differences in human pathogenicity between Reston and the other four ebolavirus species. Structural analysis was performed to identify those SDPs that are likely to have a functional effect. This analysis revealed novel functional insights in particular for Ebolavirus proteins VP40 and VP24. The VP40 SDP P85T interferes with VP40 function by altering octamer formation. The VP40 SDP Q245P affects the structure and hydrophobic core of the protein and consequently protein function. Three VP24 SDPs (T131S, M136L, Q139R) are likely to impair VP24 binding to human karyopherin alpha5 (KPNA5) and therefore inhibition of interferon signaling. Since VP24 is critical for Ebolavirus adaptation to novel hosts, and only a few SDPs distinguish Reston virus VP24 from VP24 of other Ebolaviruses, human pathogenic Reston viruses may emerge. This is of concern since Reston viruses circulate in domestic pigs and can infect humans, possibly via airborne transmission.

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“…Gross pathology and histology also revealed no departure from typical EVD historically reported in the literature [ 53 ]. Guinea pig studies with clones engineered to express either 7U or 8U have confirmed that either challenge results in fatal EVD with the 8U rapidly reverting to 7U [ 51 , 54 ]. Given the lack of differences between the end stage disease and the rapid return back to a predominantly 7U genotype, the data presented herein support the conclusion that an 8U challenge is attenuated compared to a 7U challenge, but only in the disease course and not in terms of lethality, especially considering that all animals had reverted back to the 7U majority population by the time of euthanasia.…”

Section: Discussionmentioning

confidence: 99%

Ebola Virus Infections in Nonhuman Primates Are Temporally Influenced by Glycoprotein Poly-U Editing Site Populations in the Exposure Material

Trefry

Wollen

Nasar

et al. 2015

Viruses

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Recent experimentation with the variants of the Ebola virus that differ in the glycoprotein’s poly-uridine site, which dictates the form of glycoprotein produced through a transcriptional stutter, has resulted in questions regarding the pathogenicity and lethality of the stocks used to develop products currently undergoing human clinical trials to combat the disease. In order to address these concerns and prevent the delay of these critical research programs, we designed an experiment that permitted us to intramuscularly challenge statistically significant numbers of naïve and vaccinated cynomolgus macaques with either a 7U or 8U variant of the Ebola virus, Kikwit isolate. In naïve animals, no difference in survivorship was observed; however, there was a significant delay in the disease course between the two groups. Significant differences were also observed in time-of-fever, serum chemistry, and hematology. In vaccinated animals, there was no statistical difference in survivorship between either challenge groups, with two succumbing in the 7U group compared to 1 in the 8U challenge group. In summary, survivorship was not affected, but the Ebola virus disease course in nonhuman primates is temporally influenced by glycoprotein poly-U editing site populations.

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Soluble Glycoprotein Is Not Required for Ebola Virus Virulence in Guinea Pigs

Cited by 15 publications

References 17 publications

Filovirus proteins for antiviral drug discovery: A structure/function analysis of surface glycoproteins and virus entry

Filovirus proteins for antiviral drug discovery: A structure/function analysis of surface glycoproteins and virus entry

Conserved differences in protein sequence determine the human pathogenicity of Ebolaviruses

Ebola Virus Infections in Nonhuman Primates Are Temporally Influenced by Glycoprotein Poly-U Editing Site Populations in the Exposure Material

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