Recently Identified Mutations in the Ebola Virus-Makona Genome Do Not Alter Pathogenicity in Animal Models

Marzi, Andrea; Chadinah, Spencer; Haddock, Elaine; Feldmann, Friederike; Arndt, Nicolette; Martellaro, Cynthia; Scott, Dana; Hanley, Patrick W.; Nyenswah, Tolbert; Sow, Samba O.; Massaquoi, Moses; Feldmann, Heinz

doi:10.1016/j.celrep.2018.04.027

Cited by 58 publications

(86 citation statements)

References 41 publications

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“…However, in vivo experiments have yet to unambiguously ascribe a pheno type to A82V and similar mutations in the context of pathogenesis. For instance, initial studies with Ifnar −/− immunodeficient laboratory mice and rhesus monkeys did not demonstrate an effect of A82V on disease severity or virus shedding 80 . This lack of an effect may be due to the true lack of effect of these mutations on pathogenesis, limitations of the in vivo studies (such as compensatory mutations for the A82V phenotype observed in vitro), or intrinsic differences among laboratory mice, NHPs and humans, such as infection cofactors or immune responses.…”

Section: Box 1 | Anthropology In Filovirus Disease Outbreak Controlmentioning

confidence: 99%

Ebola virus disease

Jacob

Crozier

Fischer

et al. 2020

Nat Rev Dis Primers

456

345

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To date, 12 distinct filoviruses have been described 1. The seven filoviruses that have been found in humans belong either to the genus Ebolavirus (Bundibugyo virus (BDBV), Ebola virus (EBOV), Reston virus (RESTV), Sudan virus (SUDV) and Taï Forest virus (TAFV); Fig. 1) or to the genus Marburgvirus (Marburg virus (MARV) and Ravn virus (RAVV)) 2. The WHO International Classification of Diseases Revision 11 (ICD-11) of 2018 recognizes two major subcategories of filovirus disease (FVD): Ebola disease caused by BDBV, EBOV, SUDV or TAFV, and Marburg disease caused by MARV or RAVV. Ebola virus disease (EVD) is defined as a disease only caused by EBOV. This subcategorization of FVD is largely based on the increasing evidence of molecular differences between ebolaviruses and marburgviruses, differences that may influence virus-host reservoir tropism, pathogenesis and disease phenotype in accidental primate hosts 2. Since the discovery of filoviruses in 1967 (reF. 3), 43 FVD outbreaks (excluding at least five laboratoryacquired infections) have been recorded in or exported from Africa 4. The epidemiological definition of outbreak is one or more cases above the known endemic prevalence. For example, the single case of TAFV infection recorded in a setting in which FVD had never been reported before (Côte d'Ivoire) 5 is still considered an outbreak. All FVD outbreaks, with the exception of that caused by TAFV, were characterized by extremely high case-fatality rates (CFRs, also known as lethality). Until 2013, the most extensive outbreak, caused by SUDV, involved 425 cases and 224 deaths (CFR 52.7%) 6. The overall limited numbers of FVD cases (1967-2013: 2,886 cases including 1,982 deaths 4), the typical remote and rural locations of outbreaks and the often delayed announcement of new outbreaks to the international community 7 have prevented the systematic study of clinical FVD in humans. Thus, the commonly used description of FVD was derived either from observation of small groups of patients in care settings that were not well-equipped for diagnosis, treatment and disease characterization, or from observations of even smaller samples, such as individuals who were transferred from Equatorial Africa to Europe and the USA or who fell sick in Europe or the USA after contracting the virus elsewhere. Pathological characterization of FVD via autopsies has been rare 7,8. In the absence of extensive human clinical data, FVD could only be defined further via the use of experimental animal infections 9,10 .

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Section: Box 1 | Anthropology In Filovirus Disease Outbreak Controlmentioning

confidence: 99%

Ebola virus disease

Jacob

Crozier

Fischer

et al. 2020

Nat Rev Dis Primers

456

345

View full text Add to dashboard Cite

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“…If there was indeed an increase in both EBOV transmissibility and virulence, then higher virulence is likely to have directly increased viral fitness, and in the absence of an evolutionary trade-off as only a single substitution was identified. However, these apparent changes in phenotype also coincided with the movement of the virus from Guinea to Sierra Leone, such that any change in case numbers and mortality could in fact be due to a change in epidemiological factors (such as access to health care or differing human demographics and/or transmission networks), and recent studies using animal models suggest that A82V has no direct impact on virulence 118 .…”

Section: Heritabilitymentioning

confidence: 99%

The phylogenomics of evolving virus virulence

2018

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| How virulence evolves after a virus jumps to a new host species is central to disease emergence. Our current understanding of virulence evolution is based on insights drawn from two perspectives that have developed largely independently: long-standing evolutionary theory based on limited real data examples that often lack a genomic basis, and experimental studies of virulence-determining mutations using cell culture or animal models. A more comprehensive understanding of virulence mutations and their evolution can be achieved by bridging the gap between these two research pathways through the phylogenomic analysis of virus genome sequence data as a guide to experimental study.

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“…The magnitude of the West African EVD epidemic in 2013-2016 has stimulated speculation about possible changes in EBOV or its infectious process, which could have caused its rapid spread [32]. The documented case-fatality rate of the epidemic was not superior to that observed in other historical outbreaks [33], and a greater pathogenicity of EBOV Makona has also been reasonably ruled out in animal models [34,35].…”

Section: Discussionmentioning

confidence: 99%

Glycosylation-dependent enhanced cell-binding and infectivity through DC-SIGN in the West African Ebola virus Makona

Lasala

Luczkowiak

Kremer

et al. 2019

Preprint

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Since its discovery in Zaire in 1976, most ebolavirus outbreaks described occurred mainly in remote and poorly communicated areas of Central Africa and affected a limited number of individuals. Nonetheless, the Ebola epidemic that began in West Africa at the end of 2013 spread rapidly and reached an unprecedented scale. This epidemic was caused by the Makona variant of Zaire ebolavirus (EBOV). Monitoring of the EBOV Makona evolution throughout the epidemic identified the A82V substitution in the EBOV glycoprotein (GP) at the beginning of the epidemic, which correlated with its rapid spread. The Makona GP-V82 variant exhibits slightly higher human and primate cell infectivity. Host factors responsible for the enhanced transmission of EBOV Makona have yet to be identified. Here we show that the GP A82V substitution increases EBOV avidity for its DC-SIGN lectin receptor, which enhances cell-binding and infectivity of dendritic cells and macrophages, the primary cell subsets infected during the initial stages of the disease. Using a pseudotype lentivirus system, we identified two GP N-linked glycosylation responsible of the augmented Makona GP-V82 cell infection. Crystal structures indicated how the GP A82V substitution drives exposure of a key glycan and facilitates lectin recognition. Thus, DC-SIGN might be an important host determinant for the unique dissemination of EBOV during the 2013-2016 epidemic, which likely promoted host-to-host transmission by enhancing viral infection of dendritic cells in the skin and mucosa. This study also reveals that variations in virus envelope glycosylations can be a common pathway for virus adaptation to human transmission. Synopsis The Zaire ebolavirus (EBOV) Makona, responsible of the largest outbreak of Ebola virus disease (EVD) in West Africa from 2013-2016, displayed a glycosylation-dependent enhancement of binding and subsequent infectivity in cells expressing the DC-SIGN surface lectin.

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Recently Identified Mutations in the Ebola Virus-Makona Genome Do Not Alter Pathogenicity in Animal Models

Cited by 58 publications

References 41 publications

Ebola virus disease

Ebola virus disease

The phylogenomics of evolving virus virulence

Glycosylation-dependent enhanced cell-binding and infectivity through DC-SIGN in the West African Ebola virus Makona

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