Evolution of Virulence in the Ebola Virus
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The Ebola virus is a member of the Filoviridae family of virus and is the pathogen responsible for Ebola Hemorrhagic Fever, an emerging disease that appears in infrequent epidemic outbreaks mainly in sub-Saharan Africa. The Ebola Virus is composed of several distinct subspecies, ranging from the extremely virulent Ebola Sudan and Ebola Zaire Viruses to the asymptomatic (in humans) Ebola Reston. Many outbreaks of Ebola Hemorrhagic Fever display mortality rates approaching 90%. Application of evolutionary concepts of disease and virulence evolution can be used to help explain this high level of virulence. Another important factor is the possible presence of less virulent outbreaks of Ebola Hemorrhagic Fever that go unreported due to small scale and lack of "characteristic" virulence A further understanding of the selective mechanisms behind virulence may suggest strategies to impose selection for less virulent strains of the virus and to develop possible vaccines, thus helping to curb the deadly effect of Ebola outbreaks.
The Filovirus family contains the Ebola Virus genus and the closely related Marburg Virus. Both of these genera are known to cause extremely dangerous hemorrhagic fever type illnesses. These Viruses are contain a single strand of negative RNA and typically measure 1400 nm in length with a diameter of approximately 80 nm. The various species of Ebola virus sporadically infect both human and non-human primates, causing Ebola Hemorrhagic Fever. Recent evidence suggests that the virus may have a natural reservoir in various bat populations. The virus sporadically jumps from this natural host species (in which it is avirulent) to host species such as chimpanzees, macaques, gorillas and humans where it typically exhibits high virulence. The mechanisms of this transition and the role of reservoir hosts is poorly understood at present (Leroy et al 2005)
The Virus is transferred through direct contact with infected bodily fluids, most frequently by means of direct contact with an infected individual. Contaminated medical implements can also spread the infection in medical settings, especially during early stages when an epidemic has not yet been fully realized. In many of the early outbreaks this was a major means of transmission, due to the presence of the virus and nature of its transmission being poorly understood. Local funerary customs also contributed to the spread of the disease. Isolation of infectious patients, proper disposal of contaminated remains and excreta and use of efficient sanitation and barrier nursing techniques can effectively prevent transmission during an outbreak. It is important that these measures be implemented immediately upon suspicion of Ebola Hemorrhagic Fever in order to minimize spread of the virus within the community (Ebola virus disease in southern Sudan 1983).
Initial during initial stages of infection the Ebola virus selectively targets dendritic cells, monocytes and macrophages, which spread through the circulatory and lymphatic systems to the liver spleen and lymph nodes. From here the virus can efficiently spread throughout the body. The infected monocytes and macrophages also release massive amounts of cytokines, helping to trigger virus-induced shock by causing damage to the endothelial structures. Infected dendritic cells are prevented from releasing costimulatory cytokines necessary for the production of T-cells, preventing sufficient immune response to the infection (Aleksandrowicz et al 2008). Symptoms of Ebola Hemorrhagic Fever usually manifest 2-21 days after infection. Initial symptoms include fever, weakness, aches in the muscles and joints, sore throat. These progress to rash, impaired liver and kidney function and in some cases both external and internal bleeding due to deterioration of the vascular lining (World Health Organization). The massive release of cytokines and virus particles from monocytes and macrophages impairs the function of endothelial tissue, allowing it to become permeable to water and macromolecules (Aleksandrowicz et al 2008). Gastro-intestinal bleeding is a common symptom, and is frequently associated with lethal cases. (Ebola Haemorrhagic Fever in Zaire 1978)
The First known outbreaks of the Ebola virus occurred nearly simultaneously in Zaire (modern Democratic Republic of the Congo) and Sudan in 1976. These outbreaks, although close both geographically and chronologically were caused by two distinct subspecies of the virus (Ebola Zaire and Ebola Sudan respectively). The Zaire outbreak was centered in the village of Yambuku and its environs. 318 cases were reported in this epidemic, of which 280 were fatal (mortality 88%). All cases in this epidemic were tied to either close contact with a confirmed case or receiving a parenteral injection at the local hospital (Ebola Haemorrhagic Fever in Zaire 1978). Early cases in the Sudan outbreak were textile workers from the town of Nzara. 151 of the 284 reported cases were fatal (mortality 53%) (Known Cases and Outbreaks of Ebola Hemorrhagic Fever). Three years later, in August of 1979 another, smaller scale outbreak occurred in Nzara and the nearby town of Yambio, resulting in 34 cases, with 22 fatalities (65% mortality) (Center for Disease Control, 2006). Communities affected by these outbreaks share several characteristics. One of the most significant of these is the nature of available medical care. All were served by small, undersupplied and understaffed hospitals. Unsanitary conditions within these hospitals and the prevalence of family members carrying out day to day care for afflicted individuals being allowed the virus to spread quickly through the local population. The Yambuku hospital utilized five needles and syringes for prenatal, inpatient and outpatient wards, with little sterilization between uses. This fact alone almost ensured transition of the virus between patients in the hospital. Lack of barrier nursing practices also allowed high transmission to the staff (11 of the 17 medical staff died as a result of Ebola Hemorrhagic Fever) and caregivers as well A high prevalence of infection was found amongst individuals present at funerals of deceased patients in all outbreaks.
The reproductive success of a pathogen is dependent upon its ability to replicate itself and to infect new hosts by transfer of its propagules. Rapid replication can increase a pathogens chance of transference, but this requires a greater toll on the hosts system and is likely to lead to an increased chance of host mortality. Due to this, there is believed to be a natural correspondence between a pathogens growth rate and virulence. The relationship between these two factors is explained by the trade-off hypothesis of virulence evolution. This theory largely replaced the commonly accepted idea that a parasite or pathogen should evolve towards avirulence, but it not fully accepted. The avirulence theory assumed that a parasite low virulence would maximize a pathogen's overall lifetime reproductive success by increasing the time of infection to nearly infinite limits. The reasoning behind this theory has been explained thusly:
The parasite makes a profession out of living at its neighbours' expenses and all its industry consists of exploiting it with economy, without putting its life in danger. It is like a poor person who needs help to survive, but who nevertheless does not kill its chicken in order to have the eggs (Van Beneden 1875).
The frequent down trend in virulence from the time a pathogen is introduced to a novel population was offered as evidence for this theory. The trade-off theory developed when evolutionary ecologists began to question the avirulence theory. It proposes that there is a link between ease of transmission and virulence. According to this theory, virulence is an outgrowth of a rapid replication rate in the pathogen, which strains host resources and reduces host fitness (resulting in host mortality). The Trade-off theory links the variables of virulence, transmission and host recovery in a relationship summarized by the following mathematical model:
(Alizon, Hurford, Mideo & Van Baalen 2009)
In the above equation R0 represents the pathogens baseline reproduction ratio, in this case a measure of relative fitness. The S value is the number of susceptible hosts within a population. Î² represents rate of transmission, Î± is the death rate in the host due to infection (virulence), Î¼ stands for the natural death rate in the host population, and Î³ is a factor representing the recovery rate from the infection. According to this model, any change in virulence, transmission rate or recovery rate will have an effect on the other two variables. A high transmission rate will typically go along with a high virulence and low recovery rate. The reproductive success of a pathogen comes from successfully balancing these variables to maximize R0 (Alizon et al). High Virulence will allow for high reproduction and transmission, but only up to a point. Natural selection should favor strains that are able to maximize this trade-off. Eventually, virulence can reach a level where the increased transmission is no longer balanced out by the risk of dying along with a host before being able to jump to a new one. This is especially true in isolated host populations or other conditions that limit horizontal transmission, which could possibly explain the low virulence and chronic nature of some infections.
Virulence is typically defined as morbidity and mortality of the host organism as a result of parasite or pathogen activity. Measurements of a pathogen's virulence are traditionally given in terms of parasite induced death rate (PIHD). This definition is suitable for a general discussion of a disease as it includes all deleterious effects on the host. A more specific and narrow definition is required in order to examine selective pressures on the evolution of virulence in a disease, however. The generalized definition, according to Ebert and Bull in their work on virulence evolution, fails to differentiate between virulence's effects on host and pathogen fitness, and therefore fail to give an accurate assessment of selective pressure on the pathogen's evolution. For this reason it is important to consider specific aspects of the host/pathogen system (such as means of transference, rate of pathogen growth, etc) before drawing conclusions about the selective pressures for increased or reduced virulence in the pathogen (Ebert & Bull 2008). In the case of the Ebola virus and Ebola Hemorrhagic Fever virulence can be discussed in terms of host death. Unlike with some pathogens, death of the host does not immediately end transmission of the virus. Some studies indicate that the corpse can remain infectious for several days after death. Several epidemics have been traced to contact between the index case and the contaminated remains of a chimpanzee (Ivory Coast 1994, Gabon 1996, Gabon 1996-97) (Chart) and contaminated monkey meat may have played a role in the index case of the initial 1976 Zaire outbreak (Ebola Haemorrhagic Fever in Zaire 1978).
Ebert and Bull define three general stages of evolution in a pathogen transferring to a novel host and the selective pressures involved in each. The first phase includes the initial interactions between a pathogen and the novel host. In some cases this infection is not capable of horizontal transfer between hosts in the novel population. Other situations involve short chains of secondary infection from the index infection. Infections in this phase are likely exposed to great selective pressures, as they are in an entirely new environment, one for which their genes may or may not be particularly suitable. Genes that may not have had a measureable fitness effect in the pathogens normal host environment can suddenly exert great selective pressure. Because of this there is frequently a great range of virulence expressed by different pathogens during this phase. The second phase occurs during the period when a pathogen has established a foothold within the novel population. It follows the epidemic infection model and increases rapidly within the population, because of this rapid growth it is possible for a pathogen to evolve rapidly in this phase. Selective pressure on the host can also be extreme in this phase. The second phase also applies when a mutation in a parasite that has already obtained equilibrium within a host population is significant enough that it gains a selective advantage over other strains and spreads rapidly. Ebert and Bull's third phase is reached when a pathogen has become firmly established within a host population. Pathogens in this phase are well adapted to the host, but will still experiences selective pressures due to host demographic and environmental changes. The Ebola virus, in human hosts, remains largely within the first phase, although it could be argued that it briefly enters the second phase on a local level during some outbreaks. It causes short lived epidemics when it does infect a human population, but fails to survive long term and become an endemic pathogen. During this initial stage the virus can be exposed to great selective pressure as it is in an unusual host. Evolutionary dynamics within an epidemic scenario, as proposed by Bolker et al, favor pathogens with a high growth and transference rates, and the high virulence that is associated with them, due to the large number of susceptible hosts in the novel population. This differs from a pathogen in later stages, which has reached dynamic equilibrium with the host. These situations tend to select for moderate virulence and longer duration of infection. (Bolker et al).
A possible explanation for the extreme virulence in Ebola outbreaks may simply be reporting bias. Many of the early and milder symptoms of Ebola Hemorrhagic Fever are quite similar to those of other diseases endemic to the region, such as malaria, and measles. Some outbreaks are actually mistaken for cases of other diseases until post-infection laboratory tests detect particles of an Ebola strain. A 1994 outbreak in gold mining camps in Gabon (52 cases, 60% mortality) was believed to be a yellow fever epidemic until almost a year after the last case. It is possible that less virulent strains of the virus are simply mistaken for other common infections, treated as such, and never reported (CHART). Ebola virus antibodies were detected in sera from 18% of adults in the 1979 Nzara outbreak who were not infected. This is evidence that "It is likely that sporadic infection is more common than can be appreciated from these dramatic outbreaks, which probably represent the extreme of the interaction between man and the virus." (Baron et al). This fits in with the inherent virulence variance in phase one pathogens suggested by Ebert and Bull above. Other factors that can affect the evolution of virulence in a pathogen are host population density and ease of transmission. These factors are frequently interrelated, as both directly influence the number of susceptible hosts a pathogen is able to infect during its lifespan. A high density of susceptible hosts (such as when a pathogen is emerging in a novel host population) is likely to greatly increase greatly increase a pathogens reproductive success, and select for pathogens that can replicate quickly and take advantage of the abundant hosts. Likewise, easy transition from one host to the next also selects for pathogens that are able to rapidly replicate and "seize the day", as it were. Both of these conditions, which favor pathogens with high growth rates, also favor high virulence in accordance with the Trade-off hypothesis (Ebert & Bull 2008).
The abovementioned concepts and principles fit in with epidemiological data from outbreaks of Ebola Hemorrhagic Fever. Initial outbreaks of Ebola Hemorrhagic Fever took place within areas with a relatively high concentration of susceptible hosts. The 1976 outbreak centered on the Yambuku Mission Hospital is a good example. This hospital served as the primary medical facility for a local population of around 60,000 as well as travelers. This facility was relatively small, having 17 staff members and holding 120 beds in its crowded wards. It also processed some 6000-12000 outpatients on a monthly basis. Combine this with the five improperly sterilized syringes used to administer injections (the primary dosage method at this facility) and a severe lack of barrier nursing procedures. This would appear to be an optimal situation for the transmission of pathogens that spread through contaminated body fluids. According to the Trade-off Hypothesis and the selective conditions outlined above, pathogen strains that have high reproduction rates (and hence high virulence) would be at a distinct selective advantage. Cases cared for out of the hospital setting would also tend to favor quickly reproducing and more virulent pathogens. Horizontal transfer by physical contact is directly affected by the concentration of virus particles in a contaminated fluid; hence a virus with a higher reproduction rate would be able to successfully exploit a given number of transfer opportunities. This setting lacks the direct viral inoculation by contaminated needle present in the hospital setting, which would perhaps result in less effective transmission. This would also favor more strongly virulent pathogens, which reproduce quickly and successfully exploit transmission opportunities (Ebola Haemorrhagic Fever in Zaire 1978). The conditions present during the 1976 Sudan outbreak were largely similar. Transmission occurred mainly to family members providing nursing care (without barrier nursing techniques) and through contaminated medical equipment and direct contact in a hospital setting. These conditions would also seem to favor more virulent pathogens.
Other examples of particularly high virulence outbreaks (in terms of host mortality) also occur under conditions with large amounts of close contact between potential hosts, likely resulting in high transmission. Examples of these situations are found in the 1994 and 1996-97 Gabon outbreaks, which took place at a mining camp and (initially) a remote forest camp respectively. Both of these outbreaks featured transmission of numerous secondary infections through close contact with infected individuals.
According to the Trade-off hypothesis, high transmission rates are linked to high levels of virulence. By reducing rate of transmission it may be possible to artificially select for less virulent strains. In the hospital and home care setting, hosts suffering from highly virulent strains with high symptom manifestation (high virulence) are likely to transmit the virus to other hosts, favoring virulent strains. Application of sanitation and barrier nursing practices can reduce transmission of the virulent strains present under these conditions. This could potential favor any less virulent strains, i.e. ones that do not manifest severe symptoms that require hospitalization and are unlikely to be fatal, present in the environment. This could gradually reduce overall virulence over the course of the outbreak. Even if less virulent strains are not present, prevention of transmission is likely to slow and eventually stop the outbreak as the number of remaining susceptible hosts is reduced through various means (Ewald 2004).
The Ebola Virus and Ebola Hemorrhagic Fever present an interesting case for evolution of virulence in a pathogen. The periodic outbreaks of the disease offer examples of how selective pressures imposed on a pathogen follow the predictions of the Trade-off hypothesis linking virulence (and attendant host mortality) with rate of transmission. This hypothesis and the conclusions it suggests fit with data observed in outbreaks of virulent Ebola Hemorrhagic Fever. Conditions of dense susceptible host population and rapid and effective transmission seem to demonstrate high incidences of virulence indicating that there may be selective pressure for virulent strains under these conditions. Evidence of strains showing low virulence is suggested by the Ebola virus' presence in a natural reservoir species and by the formation of antibodies by healthy individuals not linked to current epidemics. Due to this (presumed) variation amongst strains and the relationship between transmission and virulence proposed by the Trade-off hypothesis, reduction of transmission of the virus in hospital and homecare settings may lead to a reduction in strain virulence in prolonged outbreaks.
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