Myxomatosis was introduced into the rabbit population of Australia in order to control the spread of rabbits on the continent. Explain why this failed and what the implications are for how viruses and their hosts co-evolve.
Background
Myxoma virus (MYXV) causes myxomatosis ' a high mortality rate disease (90%-99% fatal) ' in European rabbits (Oryctolagus cuniculus) whilst only causes benign local fibroma in its natural South American rabbit host (Sylvilagus brasiliensis). Originally introduced into Australia in 1859 for hunting, the European rabbit population grew uncontrollably due to the lack of natural predators, causing massive crop and vegetation damage. Suggested as early as 1919, MYXV was finally introduced to control the wild rabbits in 1950.
MYXV is a zoonotic infection spread by the bite of mosquitoes, predominantly by Culex annulirostris but also Anopheles annulipes.. The virus does not replicate within the vector, but adheres to the mouthparts, ready to be injected, or obtained, when the vector takes a blood meal.
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The infection spread rapidly during spring and summer, when mosquitoes are abundant, but slowly in winter. Given the large numbers of rabbits and virus particles, and the almost 100% lethal nature of the infection, advantageous mutations were quickly selected. Within 3 years, less-virulent viruses appeared, as did rabbits that survived the infection. The coevolution observed implies a host-virus interaction coming to an equilibrium; some infected rabbits die, but they die more slowly, and many rabbits survive. Hopes for control were gone since mortality rate reduced to below the reproductive rate of the rabbits. Two fundamental changes occurred which resulted in this failure to control the spread of rabbits: (1) New, less lethal strains of virus appeared and replaced the original strain, and (2) The rabbit population became more resistant.
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Pathogenesis.
The impact on virulence of proteins that modulate the host response to infection. Poxviruses replicate exclusively in the cytoplasm of infected cells. Immediately following cell entry, the virion core is transported to the perinuclear region where partial uncoating occurs and, transcription takes place using enzymes and TF packaged in the virion. Viral assembly occurs in virus factories termed virosomes. Two forms of infectious virus are produced;
1.Intracellular mature virions, which are released upon cell lysis
2.Extracellular enveloped virions, which has acquired a double membrane from the ER.
MYXV possesses genes encoding proteins with roles in pathogenesis in various levels, some are described in Table 4. The MSW strain of the Californian MYXV is the most virulent in European rabbits, and this could be due to an expansion of the terminal inverted repeats (TIRs) of the genome, with duplication of the 153R, 152R alongside few other virulence genes.
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Attenuation of MYXV. definition.
Virulence factors. MYXV encodes proteins which bind host antiviral and proinflammatory factors such as IFN-y, IL-1, TNF, and chemokines. These proteins significantly modulate the host immune and inflammatory responses. Inhibition of apoptosis by M11L, T1 and T2 are critical for virus replication in lymphocytes and thus in dissemination of the virus within the host. Serp2 converting enzyme, which inhibits IL-1, is also likely to be important in inhibiting apoptosis. Disruption of any of the virulence factors and/or virulence genes encoding these proteins would dramatically attenuate the virus Table 4.
Virulence and transmission. Virulence and transmission is most likely to occur when virus titres are over 107 infectious unit per gram of skin. Highly lethal viruses reached this infectivity threshold for only a few days before the rabbit died, whereas moderately attenuated viruses, such as grade III or grade IV strains, allowed infected rabbits to survive longer and, therefore, increase the period for which they were infectious for mosquitoes. In contrast, very attenuated viruses, such as grade V strains, were only infectious for a short period before viral replication was controlled by the host. Thus, the moderately attenuated viruses were more likely to be transmitted and these rapidly became the predominant strains in the field of Australia. (How coevolution limits itself to moderate level).
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Natural Selection. Unlike in South America, where S. brasiliensis plays a role as a reservoir host, there was no reservoir host in Australia. This is critical in the evolution of attenuated MYXV. Having a perfect equilibrium between MYXV and S. brasiliensis allows a stable genetic pool in the population. In Australia, highly lethal viruses which left no survivors were likely to reduce the density of rabbit populations to the extent of local virus extinction. Thus, there is a great selective pressure imposed on MYXV causing attenuation in the genetic pool within the population.
Resistance in Rabbits. definition. Conceptually, resistance can be viewed as the control of virus replication and spread within the host.
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Fig 1. The relation between mortality rates of European rabbits after MYXV infection at Lake Urana, Australia. Rabbits of at least 4 months of age, and in good physical condition, were challenged with five rabbit-infectious dose KM13 strain of MYXV, intradermally. Innate resistance.
Genetic resistance. Fig 3 development of innate resistance. A large proportion of kittens would have been born to the 78% of parents which were seronegative. Interestingly, antibodies are detectable for at least two to three years following infection, so these animals must have avoided infection with MYXV during the first epidemic. In the following years there was a predominance of attenuated strains of MYXV which allowed survival of more infected rabbits. Development of resistance could be attributed in the existence of polymorphisms in the population at one or more critical genetic loci as resistance is unlikely to have depended on novel mutations occurring over such short period of time. INNATE RESISTANCE?
Mechanisms of resistance. The virus replicates to high titres in the skin at the inoculation site, but is unable to replicate in rabbit lymphocytes in vitro. Infected lymphocyte undergo apoptosis, thus controlling the dissemination of virus as well as development of systemic disease.
Resistance could be mediated at the level of replication in the initial inoculation site or replication in distal tissues. Replication could be controlled at the level of cell permittivity, as occurs in flavivirus-resistant mice, i.e. the ability of the virus to attach to, enter, replicate in and spread from a cell. Alternatively, effectors of the innate or acquired immune systems could intervene to destroy infected cells by using, for example NK cells and CD8 T cells or to make cells nonpermissive for replication by the action of IFN. MYXV actively suppresses apoptosis in infected lymphocytes and the early inflammatory response to infection. In particular, critical antiviral cytokines, such as TNF and IFN-y, are targeted by specific viral proteins. Resistant rabbits may produce higher levels of antiviral effector cells and molecules, perhaps through an NK cell response such as that controlled by the rmp1 gene.
Sire Effect. This nongenetic, acquired resistance enhanced survival of kittens to MYXV challenge if the kittens were born to does which had mated with males that survived myxomatosis. Even more complicated was the fact that the kittens from subsequent mating of that female with males which had not been exposed to MYXV were also protected. This enhanced survival of kittens was termed the 'sire effect'. Often overlooked in evolutionary studies, this observation brings the question of the significance of nongenetic factors in coevolution of two antagonists.
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Temperature. Under laboratory settings, temperature was shown to have an effect in the resistance of rabbits against MYXV infection. Rabbits housed in hot (26-39 oC) environment have significantly lower mortality rate at 10-30%, compared to 92% in cold (-3-27 oC) and 63% in temperate (20-22 oC) environments. This temperature effect may play a significant role in aiding the development of resistance in the evolution of rabbits by aiding selection of resistant rabbits in warmer regions in Australia. One possible mechanism is by limiting the dissemination from the skin to the lymph node.
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Host-virus coevolution
Coevolution refers to the reciprocal adaptive change in phenotype of two antagonists, through reciprocal selective pressures, or, in other words, evolutionary change in one species is driven by evolutionary change in another. The host-virus interaction in MYXV and European rabbits is fantastic example that genetic variations and reciprocal phenotypic effects drive coevolution. As important as virulence is towards pathogenicity, host resistance is fundamentally inseparable from it. Emphasis: the two events occur concurrently. However, does this imply that host-virus coevolution renders any biological control futile? Host-virus coevolution always result in the attenuation of virus, and resistance in host(?)
Implies that persistence and/or when transmission is not positively linked to virulence is the stable equilibrium state of host-virus coevolution. A successful host-parasite equilibrium occurs. On the other hand, implies that there are various pathways of evolution which will be discussed in relation to the trajectory of rabbit-MYXV coevolution.
MYXV is a DNA virus that replicates its genome without the high error rate of RNA viruses so it unlikely that there was significant genetic variation in the initial virus populations. Low transmission rate?
Further important questions include whether there is ongoing selection pressure on the virus driven by increasing resistance in the rabbit population, what capacity the rabbit has for further evolution, and what the cost of resistance is to the rabbit?
Evolutionary trajectories. Further implications on the coevolution of virus-host. 'the conclusion that can be drawn from something although it is not explicitly stated.'
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1.Rabbits evolve the ultimate resistance that very readily prevents dissemination and controls replication. This leads to clearance and eradication of MYXV within the population. This scenario is very unlikely and is rather fictional. Only valid under the assumption that grade V MYXV becomes selected for in the population and that MYXV will not evolve to overcome the resistance.
2.Rabbits evolve very strong resistance that prevents dissemination and generalized disease, limiting virus replication to the inoculation site. Virus would be required to maintain sufficient immunosuppression capacity to prevent clearance at the inoculation site but not overwhelm the rabbit. Grade 5 viruses would not be selected as they would be too readily controlled by the rabbit immune system. Viruses selected in these conditions of high resistance could be of very high lethality for non-resistant rabbits. Viruses mutates to lose the ability to disseminate within the host while retaining its resistance to immune clearance from the inoculation site. However, it is questionable how well such a virus would compete with field strains that cause generalized disease, because multiple virus-rich tissues would provide more opportunities for insect transmission than a single fibroma unless it had very prolonged persistence. balance –
3.Genetic resistance in the rabbit population reaches a plateau because further selection for virus virulence is not possible. Virus strains with sufficient virulence to cause the generalized lethal disease optimal for transmission continue to predominate in the field, causing appreciable mortality in the population, but not driving further selection. Rabbit resistance may also plateau because the costs of resistance are too high or there is insufficient genetic polymorphism for further selection in absence of mutation in the rabbit genome. In such scenario, with viruses
4.Virus evolution reaches a plateau. Viruses have limited capacity to evolve (limited variations in genome), or cost for virulence is too much (genetic conservation).
5.Virus evolve towards contact transmission as may be occurring in Europe with the evolution of amyxomatous strains of virus. Simultaneous coinfection with bacteria may cause respiratory disease and mask the clinical signs of myxomatosis and by suppressing the rabbit's immune response help to maintain the transmission of very attenuated viruses. Such transmission is likely only to be sustainable where high rabbit densities and close contact prevail.
Viruses have demonstrated a tremendous capacity for evolution, at least more than that of the rabbit population, in such scenario, this could see the emergence of viruses with hypervirulent phenotypes.
Conclusion.