The Ebola virus (EBOV) emerged in 1976 in the Democratic Republic of the Congo and had 318 reported cases (Burd, 2014). Particular strains and mutations of the Ebola virus are prominent in each of the outbreaks and are the reason for the continuing outbreaks. Three major mutations in the virus were prevalent in the population during the outbreak in West Africa in 2014 to 2016. The Ebola virus and the mutations present during the outbreak in West Africa from 2014 to 2016 created the largest and most complex Ebola outbreak in history caused by Ebola virus species.
The Ebola virus disease (EVD) is a deadly disease that affects humans and nonhuman primates. It was discovered in 1976 near the Ebola River in what is now the Democratic Republic of Congo and believed to be animal-borne. There are six known species of the genus Ebolavirus and their nucleotide sequences differ from 35 to 40%. They are named by the region in which they were discovered. The species that cause disease in humans are the Bundibugyo ebolavirus (BDBV), Sudan ebolavirus (SUDV), Ta?? Forest ebolavirus (TAFV), and Ebola virus (originally Zaire ebolavirus) (EBOV). EBOV is the type species and has the highest mortality rate with the greatest number of outbreaks. In the 2014-2016 epidemic in Sierra Leone, Guinea and Liberia, 28,616 people were infected and 11,310 killed. The EBOV gained access into other countries in Africa, Europe and North America, mainly due to travel of individuals. EBOV is still an epidemic threat as shown by the current outbreak starting in May 2018 in the Democratic Republic of the Congo (Burd, 2014).
The initial case of Ebola virus disease in western Africa was reported in Guinea in December 2013. The first case of the outbreak was an 18-month-old boy in Guinea who most likely attained the disease after being in contact with a bat and died on December 6, 2013. This was most likely the source of the spread of the disease from person-to-person (Burd, 2014). Several fatal cases of diarrhea led to an official medical alert that was issued on January 24, 2104. The disease spread to the capital of Guinea and the Ministry of Health issued an alert for an unidentified illness on March 13, 2014. The Pasteur Institute in France confirmed the illness as Ebola virus disease (EBD) caused by Zaire ebolavirus. On March 23, 2014 the WHO declared an outbreak of EBD following 49 confirmed cases of the disease and 29 deaths. Due to poor containment and preventative methods, the disease spread to Guinea’s neighboring countries (CDC, 2017). The outbreak keeps gaining momentum by poor sanitation and inadequate medical facilities. Also the traditions of West Africa involve close handling of the dead but still-contagious bodies posing a hazard during burial practices (Burd, 2014).
Wong, G., et al. (2018) investigated three of the prevalent mutations that impacted viral fitness in the 2014-2016 outbreak. The mutations were found in the glycoprotein (GP), nucleoprotein (NP) and RNA-dependent RNA polymerase (L) in the virus in cell cultures from clinical samples from EBOV patients during the 2014-2016 epidemic. Over 97% of known EBOV strains between 2014 and 2016 contained the GP, NP and/or L mutations; A82V in the glycoprotein, R111C in the nucleoprotein, and D759G in the RNA-dependent RNA-polymerase. These mutations were generated based on the sequence of EBOV/C07 (WT), a Guinean isolate from the EBOV epidemic and is commonly used as a preliminary model for West African EBOV studies.
The NP and L mutations appear to decrease virulence, whereas GP slightly increases virulence but mainly impacts the specificity of a virus for a certain host. Single nucleotide polymorphisms (SNPs) in the genome arose and became dominant in the human population, with high frequency. SNPs were found in non-synonymous mutations and possibly contribute to virulence. For instance, the mutant A82V in the glycoprotein (GP) in studies using EBOV GP-pseudotyped viruses have shown this mutation results in increased tropism for human-origin cell lines but decreased tropism for bat-origin cell lines and an increase in infectivity. This mutation, located at the NPC1-binding site on EBOV GP had increased frequency. Diehl et al. (2018) found that GP-A82V had an ability to infect primate cells, including human dendritic cells. The increased infectivity was restricted to cells that have primate-specific NPC1 sequences at the EBOV interface, that showed that the mutation was an adaptation to the human host. GP-A82V was associated with increased mortality, consistent with the hypothesis that the heightened intrinsic infectivity of GP-A82V contributed to disease severity during the EVD epidemic. The mutant R111C in the nucleoprotein impacts viral transcription and replication. Lastly the mutant D759G in the RNA-dependent RNA polymerase impacts viral replication.
Host-origin cell lines such as monkey (VeroE6), human (Huh7 and A549) and insectivorous bat (Tb1.Lu) were used for in vitro studies because of their susceptibility to in vitro infection with EBOV. The models used were ferrets and Type I interferon receptor-deficient mice (Ifnar1-/-). The results showed that these single mutations had new characteristics of replication and virulence implying better viral evolution for better replication and adaption to the host.
The in vitro data suggests that L and NP are better equipped for replication in VeroE6 and A549 cells compared to WT and GP, while L has a disadvantage in replication in Huh7 cells compared to WT, GP and NP. The results are consistent with previous in vitro data and results, where infection of VeroE6 and Huh7 cell lines by a live EBOV mutant while carrying the GP, NP and L mutations would be expected to result in enhanced replication.
For in vivo studies, Ifnar1-/- mice were aptly used because this phenotype has shown to be susceptible to infection by wild-type filoviruses including a disease evolvement similar to humans and nonhuman primates (NHPs), even after a low dose of the virus. They are low in cost and do not have demanding requirements. Low doses are more helpful for detecting small variations in phenotype. The results of this study indicate that the L mutation decreases the virulence of EBOV in vivo as shown by mice and ferrets. The increased length of virus shedding, that is the release of virus progeny following reproduction throughout infection, in the ferrets may contribute to increased transmission. This can serve as evidence for the large number of cases during the 2014-2016 epidemic. In conclusion, NP decreases the in vivo virulence and GP increases in vivo virulence.
An interesting point from the study was the different results from the in vitro and in vivo studies. It was noted that the differences arose as neither cell culture, Ifnar1-/- mice or domestic ferrets can accurately outline human EBOV disease, leading to conflicting outcomes. The immune system was also only moderately modeled in these studies due to its complexity in humans. This study provides a stable outline for testing virulence changes associated with mutants and identifying compromised areas of the virus, which could lead to further tests for antivirals as well as surveillance studies.
Furthermore, Marzi et al. (2018) demonstrated that identified mutations in the EBOV-Makona genome, which was prominent during the West African epidemic, do not significantly alter pathogenicity. This was tested in Ifnar-/- mice and rhesus macaque monkeys. They infected mice and rhesus macaques with EBOV-Makona isolates containing or missing those mutations. All of the isolates behaved very similarly independent of the genotype, causing severe or lethal disease in mice and macaques. So they were not able to detect any evidence for differences in virus shedding. No specific biological phenotype could be associated with these EBOV-Makona mutations in those two animal models. It was proposed that EBOV-Makona has certain properties that bring about higher pathogenicity and transmissibility in humans. They as well as others have studied certain biological aspects of EBOV-Makona in comparison with previous EBOV isolates (Mayinga 1976 and Kikwit 1995), including Wong, et al. Even with controversial outcomes, no convincing findings has been published that EBOV-Makona bears unusual biological features explaining higher pathogenicity or increased transmissibility. They were unable to find any significant differences between these EBOV-Makona isolates in mice and rhesus macaques, suggesting that these mutations lead at most to modestly decreased pathogenicity in animal models.
The 2014-2016 EBOV disease became a large epidemic due to poor sanitation and medical care, high population mobility and traditional practices. The prolonged nature of the EBOV disease epidemic in West Africa meant that the virus had undergone mutations and adapted to its human hosts over time. Several non-synonymous mutations have become fixed in the population during the emergence of the virus in 2014-2016. Studies with pseudotyped viruses carrying the GP mutation only, as well as in vitro with live virus carrying all three of the GP, NP and L mutations appeared to exhibit enhanced virulence. The mutations discussed had no impact on pathogenicity in animal models, as they always caused disease. The mutations did have a profound impact on infectivity as the Ebola virus is very infectious, pathogenic, and virulent as it causing a severe, often fatal disease.
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