scholarly journals Both Epistasis and Diversifying Selection Drive the Structural Evolution of the Ebola Virus Glycoprotein Mucin-Like Domain

2016 ◽  
Vol 90 (11) ◽  
pp. 5475-5484 ◽  
Author(s):  
Neke Ibeh ◽  
Jean Claude Nshogozabahizi ◽  
Stéphane Aris-Brosou
Keyword(s):  
Ebola Virus ◽  
Mechanistic Model ◽  
Central Africa ◽  
Structural Evolution ◽  
Dimensional Structure ◽  
Structural Constraints ◽  
Weak Selection ◽  
Complex Interplay ◽  
Correlated Evolution ◽  
Diversifying Selection

ABSTRACTThroughout the last 3 decades, Ebola virus (EBOV) outbreaks have been confined to isolated areas within Central Africa; however, the 2014 variant reached unprecedented transmission and mortality rates. While the outbreak was still under way, it was reported that the variant leading up to this outbreak evolved faster than previous EBOV variants, but evidence for diversifying selection was undetermined. Here, we test this selection hypothesis and show that while previous EBOV outbreaks were preceded by bursts of diversification, evidence for site-specific diversifying selection during the emergence of the 2014 EBOV clade is weak. However, we show strong evidence supporting an interplay between selection and correlated evolution (epistasis), particularly in the mucin-like domain (MLD) of the EBOV glycoprotein. By reconstructing ancestral structures of the MLD, we further propose a structural mechanism explaining how the substitutions that accumulated between 1918 and 1969 distorted the MLD, while more recent epistatic substitutions restored part of the structure, with the most recent substitution being adaptive. We suggest that it is this complex interplay between weak selection, epistasis, and structural constraints that has shaped the evolution of the 2014 EBOV variant.IMPORTANCEThe role that selection plays in the emergence of viral epidemics remains debated, particularly in the context of the 2014 EBOV outbreak. Most critically, should such evidence exist, it is generally unclear how this relates to function and increased virulence. Here, we show that the viral lineage leading up to the 2014 outbreak underwent a complex interplay between selection and correlated evolution (epistasis) in a protein region that is critical for immune evasion. We then reconstructed the three-dimensional structure of this domain and showed that the initial mutations in this lineage deformed the structure, while subsequent mutations restored part of the structure. Along this mutational path, the first and last mutations were adaptive, while the intervening ones were epistatic. Altogether, we provide a mechanistic model that explains how selection and epistasis acted on the structural constraints that materialized during the 2014 EBOV outbreak.

scholarly journals Impacts of environmental and socio-economic factors on emergence and epidemic potential of Ebola in Africa

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
David W. Redding ◽  
Peter M. Atkinson ◽  
Andrew A. Cunningham ◽  
Gianni Lo Iacono ◽  
Lina M. Moses ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Virus Disease ◽  
Emerging Infectious Diseases ◽  
Central Africa ◽  
Fold Increase ◽  
Healthcare Intervention ◽  
Economic Factors ◽  
Modelling Framework ◽  
Global Change Scenarios ◽  
Socio Economic Factors

Abstract Recent outbreaks of animal-borne emerging infectious diseases have likely been precipitated by a complex interplay of changing ecological, epidemiological and socio-economic factors. Here, we develop modelling methods that capture elements of each of these factors, to predict the risk of Ebola virus disease (EVD) across time and space. Our modelling results match previously-observed outbreak patterns with high accuracy, and suggest further outbreaks could occur across most of West and Central Africa. Trends in the underlying drivers of EVD risk suggest a 1.75 to 3.2-fold increase in the endemic rate of animal-human viral spill-overs in Africa by 2070, given current modes of healthcare intervention. Future global change scenarios with higher human population growth and lower rates of socio-economic development yield a 1.63-fold higher likelihood of epidemics occurring as a result of spill-over events. Our modelling framework can be used to target interventions designed to reduce epidemic risk for many zoonotic diseases.

scholarly journals Tensor clustering with algebraic constraints gives interpretable groups of crosstalk mechanisms in breast cancer

2019 ◽  
Vol 16 (151) ◽  
pp. 20180661 ◽  
Author(s):  
Anna Seigal ◽  
Mariano Beguerisse-Díaz ◽  
Birgit Schoeberl ◽  
Mario Niepel ◽  
Heather A. Harrington
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Time Course ◽  
Dimensional Structure ◽  
Breast Cancer Cell Lines ◽  
Structural Constraints ◽  
Clustering Method ◽  
Algebraic Constraints

We introduce a tensor-based clustering method to extract sparse, low-dimensional structure from high-dimensional, multi-indexed datasets. This framework is designed to enable detection of clusters of data in the presence of structural requirements which we encode as algebraic constraints in a linear program. Our clustering method is general and can be tailored to a variety of applications in science and industry. We illustrate our method on a collection of experiments measuring the response of genetically diverse breast cancer cell lines to an array of ligands. Each experiment consists of a cell line–ligand combination, and contains time-course measurements of the early signalling kinases MAPK and AKT at two different ligand dose levels. By imposing appropriate structural constraints and respecting the multi-indexed structure of the data, the analysis of clusters can be optimized for biological interpretation and therapeutic understanding. We then perform a systematic, large-scale exploration of mechanistic models of MAPK–AKT crosstalk for each cluster. This analysis allows us to quantify the heterogeneity of breast cancer cell subtypes, and leads to hypotheses about the signalling mechanisms that mediate the response of the cell lines to ligands.

STRUCTURE SIMULATIONS OF LIQUID S AND LIQUID Te BY UNCONSTRAINED REVERSE MONTE CARLO METHOD

1996 ◽  
Vol 10 (25) ◽  
pp. 1267-1276 ◽  
Author(s):  
M. ANDRECUT
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Method ◽  
Three Dimensional ◽  
Distribution Model ◽  
Dimensional Structure ◽  
Angle Distribution ◽  
Structural Constraints ◽  
Reverse Monte Carlo ◽  
Three Body ◽  
Reverse Monte Carlo Method

A spatial atomic distribution model of liquid S (L-S) and liquid Te (L-Te) was generated by using the experimental diffraction data and reverse Monte Carlo method without applying structural constraints. The obtained models have been analysed in terms of near-atomic-neighbour, bond-angle distribution, three-body correlations and chain statistics. The analysis of the generated models has shown that the three-dimensional structure of the investigated liquids can be well described as a network of short chains.

scholarly journals Episodic diversifying selection and intragenomic interactions shape the evolution of DNA and RNA viruses

2019 ◽  
Author(s):  
Stéphane Aris-Brosou ◽  
Louis Parent ◽  
Neke Ibeh
Keyword(s):  
Rna Viruses ◽  
Viral Evolution ◽  
Amino Acid Level ◽  
Mutation Rates ◽  
Correlated Evolution ◽  
Dna Viruses ◽  
Diversifying Selection ◽  
Dna And Rna ◽  
Show Evidence ◽  
Key Aspects

AbstractViruses are known to have some of the highest and most diverse mutation rates found in any biological replicator, topped by single-stranded (ss) RNA viruses, while double-stranded (ds) DNA viruses have rates approaching those of bacteria. As mutation rates are tightly and negatively correlated with genome size, selection is a clear driver of viral evolution. However, the role of intragenomic interactions as drivers of viral evolution is less well documented. To understand how these two processes affect viral evolution, we systematically surveyed ssRNA, ssDNA, dsRNA, and dsDNA viruses, to find which virus type and which functions show evidence for episodic diversifying selection and correlated evolution. We show that while evidence for selection is mostly found in single stranded viruses, and correlated evolution is more prevalent in DNA viruses, the genes that are affected by both processes are involved in key aspects of their life cycle, favoring viral stability over proliferation. We further show that both evolutionary processes are intimately linked at the amino acid level, which suggests that selection alone does not explain the whole evolutionary —and epidemiological— potential of viruses.

scholarly journals Prediction of Ebola Virus Disease (EVD) infestation trends across fruit bats migratory seasons

2019 ◽  
Author(s):  
Jean Pierre NAMAHORO ◽  
Xiao Haijun
Keyword(s):  
Ebola Virus ◽  
Democratic Republic Of Congo ◽  
Virus Disease ◽  
Transmission Rate ◽  
Central Africa ◽  
Secondary Data ◽  
Ebola Virus Disease ◽  
Commodity Chain ◽  
Fruit Bats ◽  
Bivariate Correlation

Abstract Background : The majority of the rural populace of West and Central Africa participate actively in bushmeat commodity trade. The peak of this trade usually occurs during the migration of massive flocks of fruit bats. Unfortunately, this commercial period happens to coincides with the most conducive time for the spread of Ebola Virus Disease (EVD) which is transmitted by these fruit bats. We, therefore, conducted this study to predict EVD infestation trend among individuals who might be vulnerable and/or infected (hunters, vendors, and consumers of bushmeat) as a result of this seasonal bats migration. Methods: A secondary data collected in Ghana and semi-structured questionnaires were administered to international students from 7 countries (Democratic Republic of Congo (DRC), Ghana, Liberia, Zambia, Gabon, Guinea, and Ivory-Coast) and responses collated were used in this study. Bivariate correlation, probabilistic transmission rate of EVD, and probabilistic model (P-SIR) were employed to predict susceptible and infected individuals. Results : In all affected countries, it was observed that; there was a yearly bats’ migration pattern. 80 % of all interviewees confirmed that hunting, trading and consuming of bats influenced the rapid spread of EVD. The bivariate correlation between fruit bats and people involved in the bushmeat commodity chain was significant (p < 0.05) and the probability of infected bats were equally significant across the sampled countries. The estimated probabilistic rate was between 0.0099 and 0.01120, while individuals susceptible to EVD were predicted to be approximately between 5 and 45 (hunters), 0-18 f(vendors), and 25-90 (consumers). Conclusion : The migratory season of fruit bats contributes to EVD transmission in the most affected countries. People should avoid bushmeat consumption or eradicate all activities leading to the interaction with fruit bats to reduce the spread of EVD (Ebola) especially during the migratory seasons. Policy-makers and government agencies should also put in mechanisms that will protect their citizens during the fruit bats season. Keywords : bushmeat commodity chain, Ebola, migration season, EVD, fruit bats

scholarly journals Ebola virus requires phosphatidylserine scrambling activity for efficient budding and optimal infectivity

2021 ◽  
Author(s):  
Marissa D. Acciani ◽  
Maria F. Lay Mendoza ◽  
Katherine E. Havranek ◽  
Avery M. Duncan ◽  
Hersha Iyer ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Apoptotic Cell ◽  
Transmembrane Protein ◽  
Central Africa ◽  
Viral Envelope ◽  
Cell Entry ◽  
Host Cells ◽  
Target Cells ◽  
Caspase Cleavage ◽  
Envelope Surface

Ebola virus (EBOV) attaches to target cells using two categories of cell surface receptors, C-type lectins and phosphatidylserine (PS) receptors. PS receptors typically bind to apoptotic cell membrane PS and orchestrate the uptake and clearance of apoptotic debris. Many enveloped viruses also contain exposed PS and can therefore exploit these receptors for cell entry. Viral infection can induce PS externalization in host cells, resulting in increased outer PS levels on budding virions. Scramblase enzymes carry out cellular PS externalization, thus, we targeted these proteins in order to manipulate viral envelope PS levels. We investigated two scramblases previously identified to be involved in EBOV PS levels, transmembrane protein 16F and Xk-related protein 8 (XKR8), as possible mediators of cellular and viral envelope surface PS levels during the replication of recombinant vesicular stomatitis virus containing its native glycoprotein (rVSV/G) or the EBOV glycoprotein (rVSV/EBOV-GP). We found that rVSV/G and rVSV/EBOV-GP virions produced in XKR8 knockout cells contain decreased levels of PS on their surfaces, and the PS-deficient rVSV/EBOV-GP virions are 70% less efficient at infecting cells through PS receptors. We also observed reduced rVSV and EBOV virus-like particle (VLP) budding in ΔXKR8 cells. Deleting XKR8 in HAP1 cells reduced rVSV/G and rVSV/EBOV-GP budding by 60% and 65% respectively, and reduced Ebola VLP budding more than 60%. We further demonstrated that caspase cleavage of XKR8 is required to promote budding. This suggests that XKR8, in addition to mediating virion PS levels, may also be critical for enveloped virus budding at the plasma membrane. Importance Within the last decade, countries in western and central Africa have experienced the most widespread and deadly Ebola outbreaks since the virus was identified in 1976. While outbreaks are primarily attributed to zoonotic transfer events, new evidence is emerging that outbreaks may be caused by a combination of spillover events and viral latency or persistence in survivors. The possibility that Ebola can remain dormant then re-emerge in survivors highlights the critical need to prevent the virus from entering and establishing infection in human cells. Thus far, host-cell scramblases TMEM16F and XKR8 have been implicated in Ebola envelope surface phosphatidylserine (PS) and cell entry using PS receptors. We assessed the contributions of these proteins using CRISPR knockout cells and two EBOV models: rVSV/EBOV-GP and EBOV VLPs. We observed that XKR8 is required for optimal EBOV envelope PS levels and infectivity, and particle budding across all viral models.

scholarly journals Differential requirements for FcγR engagement by protective antibodies against Ebola virus

2019 ◽  
Vol 116 (40) ◽  
pp. 20054-20062 ◽  
Author(s):  
Stylianos Bournazos ◽  
David J. DiLillo ◽  
Arthur J. Goff ◽  
Pamela J. Glass ◽  
Jeffrey V. Ravetch
Keyword(s):  
Ebola Virus ◽  
Structural Constraints ◽  
Global Public Health ◽  
Protective Activity ◽  
Protective Function ◽  
Multiple Strategies ◽  
Animal Disease Models ◽  
Protective Antibodies ◽  
Effector Activity

Ebola virus (EBOV) continues to pose significant threats to global public health, requiring ongoing development of multiple strategies for disease control. To date, numerous monoclonal antibodies (mAbs) that target the EBOV glycoprotein (GP) have demonstrated potent protective activity in animal disease models and are thus promising candidates for the control of EBOV. However, recent work in a variety of virus diseases has highlighted the importance of coupling Fab neutralization with Fc effector activity for effective antibody-mediated protection. To determine the contribution of Fc effector activity to the protective function of mAbs to EBOV GP, we selected anti-GP mAbs targeting representative, protective epitopes and characterized their Fc receptor (FcγR) dependence in vivo in FcγR humanized mouse challenge models of EBOV disease. In contrast to previous studies, we find that anti-GP mAbs exhibited differential requirements for FcγR engagement in mediating their protective activity independent of their distance from the viral membrane. Anti-GP mAbs targeting membrane proximal epitopes or the GP mucin domain do not rely on Fc–FcγR interactions to confer activity, whereas antibodies against the GP chalice bowl and the fusion loop require FcγR engagement for optimal in vivo antiviral activity. This complexity of antibody-mediated protection from EBOV disease highlights the structural constraints of FcγR binding for specific viral epitopes and has important implications for the development of mAb-based immunotherapeutics with optimal potency and efficacy.

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