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Functional Characterization of Adaptive Mutations during the West African Ebola Virus Outbreak.

ABSTRACT: The Ebola virus (EBOV) outbreak in West Africa started in December 2013, claimed more than 11,000 lives, threatened to destabilize a whole region, and showed how easily health crises can turn into humanitarian disasters. EBOV genomic sequences of the West African outbreak revealed nonsynonymous mutations, which induced considerable public attention, but their role in virus spread and disease remains obscure. In this study, we investigated the functional significance of three nonsynonymous mutations that emerged early during the West African EBOV outbreak. Almost 90% of more than 1,000 EBOV genomes sequenced during the outbreak carried the signature of three mutations: a D759G substitution in the active center of the L polymerase, an A82V substitution in the receptor binding domain of surface glycoprotein GP, and an R111C substitution in the self-assembly domain of RNA-encapsidating nucleoprotein NP. Using a newly developed virus-like particle system and reverse genetics, we found that the mutations have an impact on the functions of the respective viral proteins and on the growth of recombinant EBOVs. The mutation in L increased viral transcription and replication, whereas the mutation in NP decreased viral transcription and replication. The mutation in the receptor binding domain of the glycoprotein GP improved the efficiency of GP-mediated viral entry into target cells. Recombinant EBOVs with combinations of the three mutations showed a growth advantage over the prototype isolate Makona C7 lacking the mutations. This study showed that virus variants with improved fitness emerged early during the West African EBOV outbreak.

Importance

The dimension of the Ebola virus outbreak in West Africa was unprecedented. Amino acid substitutions in the viral L polymerase, surface glycoprotein GP, and nucleocapsid protein NP emerged, were fixed early in the outbreak, and were found in almost 90% of the sequences. Here we showed that these mutations affected the functional activity of viral proteins and improved viral growth in cell culture. Our results demonstrate emergence of adaptive changes in the Ebola virus genome during virus circulation in humans and prompt further studies on the potential role of these changes in virus transmissibility and pathogenicity.

SUBMITTER: Dietzel E

PROVIDER: S-EPMC5215343 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Micronutrient supplementation is recommended in Ebola virus disease (EVD); however, there are limited data on therapeutic impacts of specific micronutrients. OBJECTIVE:To evaluate the association between vitamin A supplementation and mortality in EVD. METHODS:This retrospective cohort included patients with EVD admitted to 5 International Medical Corps Ebola Treatment Units (ETUs) in 2 countries during 2014-2015. Protocolized treatments with micronutrients were used at all ETUs: however, because of resource constraints, only a subset of patients received vitamin A. Standardized data on demographics, clinical characteristics, malaria status, and Ebola viral loads (cycle threshold values) were collected. The outcome of interest was mortality between cases treated with 200,000 IU of vitamin A on care days 1 and/or 2, and those not. Propensity scores based on the first 48 h of care were derived using covariates of age, ETU duration, malaria status, cycle threshold values, and clinical symptoms. Patients were matched 1:1 using nearest neighbors with replacement. Mortality between cases treated and not treated with vitamin A was compared using generalized estimating equations to calculate RR with associated 95% CI. RESULTS:There were 424 cases analyzed, of which 330 (77.8%) were treated with vitamin A. The mean age was 30.5 y and 40.3% were men. The most common symptoms were diarrhea (85.6%), anorexia (80.7%), and abdominal pain (76.9%). Mortality proportions among cases treated and not treated with vitamin A were 55.0% and 71.9%, respectively. In the propensity-matched analysis, mortality was significantly lower among cases receiving vitamin A (RR = 0.77, 95% CI: 0.59, 0.99; P = 0.041). In a subgroup analysis of patients treated with multivitamins already containing vitamin A, additional vitamin A supplementation did not impact mortality. CONCLUSION:Early vitamin A supplementation was associated with reduced mortality in patients with EVD, and should be further studied and considered for use in future epidemics.

Project description:BackgroundThe WHO declared the 2014 west African Ebola epidemic a public health emergency of international concern in view of its potential for further international spread. Decision makers worldwide are in need of empirical data to inform and implement emergency response measures. Our aim was to assess the potential for Ebola virus to spread across international borders via commercial air travel and assess the relative efficiency of exit versus entry screening of travellers at commercial airports.MethodsWe analysed International Air Transport Association data for worldwide flight schedules between Sept 1, 2014, and Dec 31, 2014, and historic traveller flight itinerary data from 2013 to describe expected global population movements via commercial air travel out of Guinea, Liberia, and Sierra Leone. Coupled with Ebola virus surveillance data, we modelled the expected number of internationally exported Ebola virus infections, the potential effect of air travel restrictions, and the efficiency of airport-based traveller screening at international ports of entry and exit. We deemed individuals initiating travel from any domestic or international airport within these three countries to have possible exposure to Ebola virus. We deemed all other travellers to have no significant risk of exposure to Ebola virus.FindingsBased on epidemic conditions and international flight restrictions to and from Guinea, Liberia, and Sierra Leone as of Sept 1, 2014 (reductions in passenger seats by 51% for Liberia, 66% for Guinea, and 85% for Sierra Leone), our model projects 2.8 travellers infected with Ebola virus departing the above three countries via commercial flights, on average, every month. 91,547 (64%) of all air travellers departing Guinea, Liberia, and Sierra Leone had expected destinations in low-income and lower-middle-income countries. Screening international travellers departing three airports would enable health assessments of all travellers at highest risk of exposure to Ebola virus infection.InterpretationDecision makers must carefully balance the potential harms from travel restrictions imposed on countries that have Ebola virus activity against any potential reductions in risk from Ebola virus importations. Exit screening of travellers at airports in Guinea, Liberia, and Sierra Leone would be the most efficient frontier at which to assess the health status of travellers at risk of Ebola virus exposure, however, this intervention might require international support to implement effectively.FundingCanadian Institutes of Health Research.

Project description:INTRODUCTION:The Ebola virus disease (EVD) outbreak in West Africa, affecting Guinea, Liberia and Sierra Leone from 2014 to 2016, was a substantial public health crisis with health impacts extending past EVD itself. Access to maternal health services (MHS) was disrupted during the epidemic, with reductions in antenatal care, facility-based deliveries and postnatal care. We aimed to identify and describe barriers related to the uptake and provision of MHS during the 2014-2016 EVD outbreak in West Africa. METHODS:In June 2020, we conducted a scoping review of peer-reviewed publications and grey literature from relevant stakeholder organisations. Search terms were generated to identify literature that explained underlying access barriers to MHS. Published literature in scientific journals was first searched and extracted from PubMed and Web of Science databases for the period between 1 January 2014 and 27 June 2020. We hand-searched relevant stakeholder websites. A 'snowball' approach was used to identify relevant sources uncaptured in the systematic search. The identified literature was examined to synthesise themes using an existing framework. RESULTS:Nineteen papers were included, with 26 barriers to MHS uptake and provision identified. Three themes emerged: (1) fear and mistrust, (2) health system and service constraints, and (3) poor communication. Our analysis of the literature indicates that fear, experienced by both service users and providers, was the most recurring barrier to MHS. Constrained health systems negatively impacted MHS on the supply side. Poor communication and inadequately coordinated training efforts disallowed competent provision of MHS. CONCLUSIONS:Barriers to accessing MHS during the EVD outbreak in West Africa were influenced by complex but inter-related factors at the individual, interpersonal, health system and international level. Future responses to EVD outbreaks need to address underlying reasons for fear and mistrust between patients and providers, and ensure MHS are adequately equipped both routinely and during crises.

Project description:BackgroundIn an attempt to assess the effects of the Ebola viral disease (EVD) on hospital functions in Sierra Leone, the aim of this study was to evaluate changes in provisions of surgery and non-Ebola admissions during the first year of the EVD outbreak.MethodsAll hospitals in Sierra Leone known to perform inpatient surgery were assessed for non-Ebola admissions, volume of surgery, caesarean deliveries and inguinal hernia repairs between January 2014 and May 2015, which was a total of 72 weeks. Accumulated weekly data were gathered from readily available hospital records at bi-weekly visits during the peak of the outbreak from September 2014 to May 2015. The Mann-Whitney U test was used to compare weekly median admissions during the first year of the EVD outbreak, with the 20 weeks before the outbreak, and weekly median volume of surgeries performed during the first year of the EVD outbreak with identical weeks of 2012. The manuscript is prepared according to the STROBE checklist for cross-sectional studies.ResultsOf the 42 hospitals identified, 40 had available data for 94% (2719/2880) of the weeks. There was a 51% decrease in weekly median non-Ebola admissions and 41% fewer weekly median surgeries performed compared with the 20 weeks before the outbreak (admission) and 2012 (volume of surgery). Governmental hospitals experienced a smaller reduction in non-Ebola admissions (45% versus 60%) and surgeries (31% versus 53%) compared to private non-profit hospitals. Governmental hospitals realized an increased volume of cesarean deliveries by 45% during the EVD outbreak, thereby absorbing the 43% reduction observed in the private non-profit hospitals.ConclusionsBoth non-Ebola admissions and surgeries were severely reduced during the EVD outbreak. In addition to responding to the EVD outbreak, governmental hospitals were able to maintain certain core health systems functions. Volume of surgery is a promising indicator of hospital functions that should be further explored.

Project description:BackgroundTo date, epidemiological studies at the index site of the 2013-16 west African Ebola outbreak in Meliandou, Guinea, have been restricted in their scope. We aimed to determine the occurrence of previously undocumented Ebola virus disease (EVD) cases and infections, and to reconstruct transmission events.MethodsThis cross-sectional seroprevalence survey of the adult population of Meliandou used a highly specific oral fluid test and detailed interviews of all households in the village and key informants. Each household was interviewed, with all members prompted to describe the events of the outbreak, any illness within the household, and possible contact with suspected cases. Information for deceased individuals was provided by relatives living in the same household. Symptoms were based on Ebola virus Makona variant EVD case definitions (focusing on fever, vomiting, and diarrhoea). For antibody testing, we used an Ebola virus glycoprotein IgG capture enzyme immunoassay developed from a previously validated assay. A maximum exposure level was assigned to every participant using a predetermined scale. We used a generalised linear model (logit function) to estimate odds ratios for the association of sociodemographic variables and exposure level with Ebola virus infection. We adjusted estimates for age and maximum exposure, as appropriate.FindingsBetween June 22, and July 9, 2017, we enrolled 237 participants from 27 households in Meliandou. Two households refused to participate and one was absent. All adults in participating households who were present for the interview provided an oral fluid swab for testing, of which 224 were suitable for analysis. In addition to the 11 EVD deaths described previously, on the basis of clinical description and oral fluid testing, we found two probable EVD deaths and eight previously unrecognised anti-Ebola virus IgG-positive survivors, including one who had mild symptoms and one who was asymptomatic, resulting in a case fatality of 55·6% (95% CI 30·8-78·5) for adults. Health-care work (adjusted odds ratio 6·64, 1·54-28·56; p=0·001) and level of exposure (odds ratio adjusted for linear trend across five levels 2·79, 1·59-4·883; p<0·0001) were independent risk factors for infection.InterpretationEbola virus infection was more widespread in this spillover population than previously recognised (21 vs 11 cases). We show the first serological evidence of survivors in this population (eight anti-Ebola virus IgG seropositive) and report a case fatality lower than previously reported (55·6% vs 100% in adults). These data show the high community coverage achievable by using a non-invasive test and, by accurately documenting the beginnings of the west African Ebola virus outbreak, reveal important insight into transmission dynamics and risk factors that underpin Ebola virus spillover events.FundingUS Food and Drug Administration, Wellcome Trust, and German Research Council.

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Functional Characterization of Adaptive Mutations during the West African Ebola Virus Outbreak.

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