myxoma virus in rabbits - semantic scholar · myxoma virus is a member of the poxvirus family and...

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Myxoma virus in rabbits P.J. Kerr S.M. B e s t ( 2 )

(1) Vertebrate Biacontrol Cooperative Research Centre, Commonwealth Scientific and Industrial Research Organisation, Wildlife and Ecology, P.O. Box 84, Lyneham, ACT 2602, Australia (2) Division of Biochemistry and Molecular Biology, Australian National University, Canberra, ACT 0200, Australia

Summary M y x o m a virus in E u r o p e a n rabbi ts (Oryctolagus cuniculus) is o n e of t h e best d o c u m e n t e d e x a m p l e s of host -v i rus c o - e v o l u t i o n . In t h e na tura l hosts (Sylvilagus brasiliensis or S. bachmani rabbi ts in t h e A m e r i c a s ) , m y x o m a virus c a u s e s a ben ign c u t a n e o u s f i b r o m a . In E u r o p e a n rabbi ts , h o w e v e r , m y x o m a virus causes the fu lminant d i s e a s e , myxomatos is . W h e n i n t r o d u c e d into w i l d E u r o p e a n rabbit populat ions in A u s t r a l i a , Europe and G r e a t Br i ta in , t h e v i rus w a s init ial ly highly le tha l , killing in e x c e s s of 9 9 % of in fec ted rabbi ts . D e v e l o p m e n t of r e s i s t a n c e w a s e n c o u r a g e d by t h e e m e r g e n c e of a t t e n u a t e d v i rus s t ra ins w h i c h a l l o w e d the survival o f m o d e r a t e l y res is tant rabbi ts . Th is m a y h a v e o c c u r r e d m o r e rapidly in hot c l ima tes , as h i g h a m b i e n t t e m p e r a t u r e s i n c r e a s e t h e survival ra te of infected rabbi ts . Res is tant rabbi ts are less e f fec t ive t r a n s m i t t e r s of t h e v i rus and this may e n c o u r a g e the e m e r g e n c e of m o r e v i ru lent v i rus s t ra ins . Little is k n o w n of the m e c h a n i s m of r e s i s t a n c e . T h e r e h a v e b e e n s u g g e s t i o n s of non-gene t ic r e s i s t a n c e . H o w e v e r , t h e s e a r e y e t to be c o n f i r m e d e x p e r i m e n t a l l y .

Keywords Disease resistance - Genet ics - M y x o m a v i rus - M y x o m a t o s i s - Rabbi ts - V i ru lence.

Introduction The co-evolution of infectious and parasitic diseases with their hosts may be one of the major causes of genetic polymorphisms and hence drivers of evolution in animal populations (3). However, there are very few opportunities to study this form of evolution as it occurs. The release of virulent myxoma virus, which had evolved in Syhilagus brasiliensis rabbits in South America, into completely naive populations of European rabbits (Oryctolagus cuniculus) in Australia and Europe, and the subsequent natural selection of attenuated strains of virus and resistant rabbits, provided one of the best documented natural studies of host-pathogen co-evolution in mammals (14, 2 1 , 22) . In this paper, the authors describe the development of resistance to myxoma virus in populations of European rabbits and suggest that this was dependent on the emergence of attenuated virus strains. The pathogenesis of myxoma virus is then discussed, in relation to viral virulence genes and possible mechanisms for resistance, and the implications of resistance for co-evolution of the virus and the rabbit.

Myxoma virus and myxomatosis Myxoma virus is a member of the poxvirus family and is classified in the genus Leporipoxvirus (43) . The myxoma vims is a large virus with a double-stranded DNA genome of 163 kilobases (kb) which replicates in the cytoplasm of infected cells. There are two major geographic types of the virus: South American (natural host: S. brasiliensis) and Californian (natural host: S. bachmani). In the natural hosts, the native virus causes a benign cutaneous fibroma (21) .

Natural isolates of both types of myxoma virus are lethal for European rabbits. However, it was the South American viruses that were released into European rabbit populations and on which this review focuses. These viruses cause a disease which is characterised by swelling of the face and head, together with mucoid cutaneous tumours, and which is termed 'myxomatosis' for the mucoid nature of the cut surface of the lesions. The virus is spread by blood-feeding arthropod vectors, such as mosquitoes or fleas. Transmission is passive: the virus adheres to the mouthparts of the vector but does not replicate within the vector. Epidemics occur annually or less

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frequently, depending on the emergence of large numbers of susceptible kittens in the spring and summer and the availability of vectors (21 , 22) .

The use of myxoma virus as a biological control for the European rabbit The lethal nature of myxomatosis for European rabbits suggested that the myxoma virus could be used as a biological control agent for rabbits in countries such as Australia, where the introduced European rabbit had caused environmental devastation and major agricultural losses. Several trials were conducted in the 1930s in both Australia and Europe using the Moses' strain of the Brazilian myxoma virus (later referred to as the 'standard laboratory strain' or 'SLS'), to evaluate the effectiveness of myxoma virus for this purpose (8, 39 ) . However, the virus failed to become established, possibly because there were insufficient arthropod vectors to spread it beyond the sites of introduction. Further trials were conducted in Australia after the Second World War, and in the summer of 1 9 5 0 - 1 9 5 1 , myxoma virus spread explosively from an experimental site in the Murray Valley in south-eastern Australia. This spread was driven by mosquitoes, predominantly Culex annulirostris but also Anopheles annulipes, which were present in plague proportions that summer (44) . Myxomatosis has been endemic in Australia since this release (21) .

A separate strain of myxoma virus which originated in Brazil was obtained from a laboratory in Lausanne in Switzerland and hence is referred to as the 'Lausanne strain'. It was released in France at Mallebois in the summer of 1952. From this initial single release site, myxoma virus spread across the entire rabbit range in Europe. In the autumn of 1953, virus from France was illegally released into Great Britain, where myxoma virus is now also endemic (22) .

Myxomatosis in rabbits in Australia: development of resistance associated wi th the attenuation of virus strains In the initial epidemic in Australia in the summer of 1950-1951, myxoma virus was estimated to have killed as many as 9 9 . 8 % of infected wild rabbits, and many populations were reduced by more than 9 0 % . Although predominantly transmitted by mosquitoes, the virus overwintered and reappeared the following summer in epidemics of myxomatosis which were augmented by

intensive release campaigns (15, 54) . Attenuated strains of myxoma virus emerged during these early epidemics ( 3 6 , 4 7 ) . Some of these viruses allowed survival of a few infected rabbits in laboratory studies and this was confirmed by serological observations in the field (15, 36 , 45 ) . The fact that there would be an opportunity for selection of genetically resistant rabbits in the field became apparent, and studies were set up ' for long-term monitoring of both the development of genetic resistance and the virulence of field strains of virus (54).

In the virulence studies, myxoma virus isolates were grouped into five levels of virulence (I-V), based on the survival rates and survival times of small groups of laboratory and hence unselected rabbits (Table I) (18) . Grade I viruses were the most virulent, killing essentially 100% of infected rabbits with an average survival time of less than 13 days; grade V viruses were the least virulent, with mortality rates of less than 50%.

Table I Virulence grades of myxoma virus

Virus grade Average survival time Mortality (%)

1 < 13 days 100 II 13-16 days 95-99 III 17-28 days 70-95 IV 29-50 days 50-70 V Not relevant <50

a) Table adapted from Fennerand Marshall (18)

Virulence and transmission of the virus were strongly linked because transmission depends on arthropod vectors probing through infected epidermis and virus adhering to the mouthparts of the vector. This is most likely to occur when virus titres are over 1 0 7 infectious units per gram of skin (17) . As shown in Figure 1, highly lethal viruses reached this infectivity threshold for only a few days before the rabbit died, whereas moderately attenuated viruses, such as grade 111 or grade IV strains, allowed infected rabbits to survive longer and increased the period for which they were infectious for mosquitoes (17) . 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 in Australia (Fig. 2) (18) .

This evolution of attenuated virus strains was probably critical for the establishment of myxoma virus in the new host as, unlike South America, where S. brasiliensis was available as a reservoir host, there was no reservoir host in Australia. Thus, highly lethal viruses which left no survivors were likely to reduce the density of rabbit populations to such an extent that the virus became extinct locally; this appears to have been the case with earlier attempts at introduction.

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Days post inoculation

Fig. 1 Mosquito infectivity of myxoma virus strains Virus titres in the skin at the inoculation site of rabbits infected with strains of myxoma virus of different virulence grades are shown over time post inoculation of a small dose of virus intradermally. The threshold for mosquito infectivity is shown at 10 7 plaque-forming units (PFU)/g. Data for the grade I, III and IV strains are taken from Fenner et al. (17). Data for the grade V strain are taken from S.M. Best and P.J. Kerr (unpublished data)

To assess the development of genetic resistance to myxomatosis in wild rabbit populations, rabbit kittens were collected from field sites and challenged with myxoma virus strains of defined virulence. Many such studies were performed but, as an example, a longitudinal data set from Lake Urana in New South Wales, where annual spring/summer epidemics of myxomatosis occurred from the

Fig. 2 Virulence of myxoma virus in Australia Data adapted from Fenner (14) The percentage of isolates of myxoma virus from Australia assigned to each virulence grade from 1952 to 1981. The number of isolates tested for each period is shown above the grade III bar. Virulence grades are shown in Table I

summer of 1951-1952 , is used here (37, 38 ) . Following the first epidemic at this site, rabbit kittens were captured each spring prior to the annual epidemic and taken to a central laboratory. Seronegative animals were held until at least four months of age and then were challenged with the mildly attenuated KM 13 (the prototype grade III) strain of myxoma virus.

The mortality rates in unselected wild and domestic rabbits challenged with this virus were 8 8 % and 8 9 % , respectively, and similar mortality rates were seen in rabbits from Lake Urana challenged with KM 13 following the first two epidemics. After the fourth epidemic, however, the mortality rate had dropped to approximately 5 0 % and after the seventh epidemic, mortality due to challenge was reduced to 26% (Fig. 3) . A similar change was observed in the proportion of rabbits which showed severe clinical signs. In the trials following the first two epidemics, only 0% to 2% of rabbits showed mild clinical signs; however, after seven epidemics, 3 0 % of rabbits showed mild clinical signs on challenge with KM13 (21 , 37, 38) .

Number of epidemics

Fig. 3 Development of innate resistance to myxoma virus at Lake Urana, Australia Data adapted from Marshall and Fenner (37) and Marshall and Douglas (38) The percentage mortality rate of rabbits trapped at Lake Urana after two, three, four, five or seven epidemics of myxomatosis and challenged with the grade III KM13 strain of myxoma virus is shown as a histogram. The number of rabbits tested at each timepoint is shown above the bars

Using the data from Lake Urana as an example (37) , Table II demonstrates how selection for innate resistance and attenuation of myxoma virus occurred concurrendy. Following the initial epidemic at Lake Urana, which reduced the population in one area from an estimated 5,000 rabbits to 50 rabbits (15) , a large proportion of kittens would have been bom to the 7 8 % of parents which were seronegative. Antibodies are detectable for at least two to three years following infection, so these animals must have avoided infection with myxoma virus during the first epidemic (15).

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Thus, there was relatively little selection pressure for resistance. However, in the following years there was a predominance of attenuated strains of myxoma virus which allowed survival of more infected rabbits. This may have been aided by high ambient temperatures (see below). Table II shows that from the second epidemic onwards, virtually all kittens were the offspring of parents which had survived myxomatosis. Thus, there was a very high selection pressure at the population level, and animals which had avoided myxomatosis were almost unrepresented in the breeding population. In addition, in the Mediterranean climate of Lake Urana, most rabbits only bred for one season, although four to five litters might be produced in this time, so that the breeding population was essentially being replaced annually (46) .

Table II Proportion of breeding animals which survived myxomatosis at Lake Urana Data adapted from Marshall and Fenner (37)

Epizootic Number of immune

adults/number tested ( a |

Immune adults 1%)

Virulence (and number)

of virus strains isolated

1 25/114* 22 KD 2 61/61 100 IKD

I I I IR\

3 201/201 100 I I I [Oj

Ill-ID. 4 82/84 98 (bi5 40/42 95 ll (2)

III (5) IV (5) V(4)

a) The number of immune animals Is indicated as a proportion of the number of animals tested

b) In this epizootic, the highly virulent Lausanne strain of myxoma virus was extensively released at Lake Urana (19) and therefore the results of virus isolations have been disregarded

Initially, resistance to myxoma virus in rabbit populations seems to have developed fairly uniformly and quite rapidly in different geographic areas, although the degree of resistance in different populations may have varied somewhat. As an example, the survival rates of rabbits collected in 1959 from Maryvale station in the Victorian Wimmera region, Ouyen in the Victorian Mallee and Penshurst in south-western Victoria and challenged with the KM13 2a strain (67% lethal in unselected rabbits) are shown in Table III. Approximately 60% to 8 0 % of rabbits survived challenge under laboratory conditions, with a higher proportion surviving from the Mallee (21 , 38 ) .

Survival rates under laboratory conditions may have led to an underestimation of the effect of resistance on survival in the field. This was emphasised when the results of animal-house challenge were compared with challenge in outdoor pens located in the collecting areas. Over 9 0 % of rabbits from both

Table III Testing rabbits from different geographic areas for resistance to myxoma virus Data taken from Fenner and Ratcliffe (21 ) and Marshall and Douglas (38)

Location

Rabbits recovered from challenge

with KM 13 2a (%) Climate and epidemic history

Laboratory Outdoor pens

Ouyen 79 94 Semi-arid Annual epidemics from 1951

Maryvale 62 93 Hot summers Annual epidemics from 1951

Penshurst 73 Not tested Cooler tow-level epidemics from 1952

Maryvale and Ouyen survived challenge with KM13 2a when housed in outdoor pens during the summer (Table III). The critical difference appears to have been the high ambient temperatures during summer in the field pens. Temperatures in the animal house ranged from 17°C to 23°C while temperatures in the field ranged from 15°C to 38°C (38) . This sparing effect of high environmental temperatures on the clinical disease caused by attenuated strains of myxoma virus was experimentally demonstrated (35) . Unselected laboratory rabbits were housed in hot (26°C to 39°C), temperate (20°C to 22°C) or cold (-3°C to 27°C) environments and infected with the attenuated KM13 2a strain of myxoma virus. In the hot environment, 10% to 3 0 % of rabbits died from virus infection, compared to 9 2 % of those in the cold and 6 3 % in the temperate environment. This temperature effect may have been important in allowing rabbits in Australia to survive infection with moderately attenuated virus strains during the early evolution of resistance, and may have aided selection of resistant rabbits in hotter climates.

Resistance in a population is a graduated effect, the manifestation of which depends on the individual rabbit, the population from which the rabbit is drawn and the virus strain. For example, on challenging rabbits from Maryvale, Ouyen and Penshurst with SLS, 9 0 % , 8 6 % and 8 5 % to 9 0 % of rabbits were killed, i.e., a 10% to 15% survival rate (21 , 38) . However, a longer survival time was noted compared to that of unselected rabbits. Testing of rabbits from these populations with the more virulent 'Glenfield' strain of virus showed that all the rabbits tested were completely susceptible to this virus (21) . More recent data suggest that resistance has not continued to develop uniformly and, for example, may be more advanced in the hot Mallee region than in the cooler Gippsland region of Victoria. For rabbits from the Mallee tested with three grade I strains of myxoma virus, SLS was 6 0 % lethal, Glenfield 9 1 % lethal and Lausanne 9 8 % lethal, whereas the corresponding figures for Gippsland rabbits were: SLS, 7 9 % lethal; Glenfield, 9 5 % lethal and Lausanne, 100% lethal (22) .

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Development of resistance to myxoma virus in Europe and Great Britain As in Australia, the initial epidemics of myxomatosis in France and Great Britain were highly lethal and rabbit numbers were greatly reduced. As shown above, the Lausanne strain of myxoma virus released in France and subsequently in Great Britain is inherently more virulent than the SLS released in Australia - although this could only be demonstrated in genetically resistant rabbits. The virus spread more slowly across Great Britain than Australia and France, but by the end of 1955, most parts of Great Britain were affected (22). Similarly to Australia, strains which allowed some infected rabbits to survive emerged in Great Britain within a year or two of the initial release (25) . By 1962, grade III viruses predominated in the field, although virulent grade I and II viruses were much more prevalent than in Australia and grade II virus prevalence has increased with time (Fig. 4) (20, 57) . This increase has occurred despite the fact that further releases of virulent virus have not been made in any organised sense in Great Britain (or in France), whereas widespread releases of grade I viruses were made in Australia for many years and some release of the Lausanne strain still occurs.

Fig. 4 Virulence of myxoma virus in Great Britain Data adapted from Fenner and Chappie (20) and Ross and Sanders (57)

The percentage of isolates of myxoma virus in Great Britain assigned to each virulence grade for the years 1962,1975 and 1981 is shown, together with the number of isolates tested at each time

Resistance to myxoma virus was slower to develop in Great Britain than in Australia. Testing of wild rabbits from one location in Norfolk, where annual epidemics of myxomatosis occurred from at least 1960, revealed very little resistance to myxomatosis between 1966 and 1969 (55). These rabbits were challenged with the mildly attenuated Brecon strain (grade III) which killed essentially 100% of unselected rabbits. However, Vaughan and Vaughan pointed to extended survival times in challenged wild rabbits as an indicator of the early development of resistance in populations of rabbits (69). Between 1970 and 1976, a dramatic decrease in mortality

rates was observed (from over 8 0 % to approximately 20%) (Fig. 5) . Among the 5 0 survivors of challenge with Brecon in 1976, 10 showed only a primary lesion at the inoculation site with no signs of generalised disease (55) . When rabbits from this area were challenged with the grade I Cornwall strain in 1974 and 1975, there were no recoveries, although survival times were prolonged (11 to 26 days) compared to those of domestic rabbits (11 to 14 days) (55) . These observations on resistance in Norfolk were extended by testing rabbits from other areas of Great Britain. This showed that in four widely separated populations between 1978 and 1980, approximately 5 0 % of rabbits survived challenge with myxoma virus, including grade I and grade II virus strains (56) .

Fig. 5 Innate resistance to myxoma virus in Great Britain Data adapted from Ross and Sanders (55)

Rabbit kittens were captured from a site in Norfolk which had experienced annual epidemics of myxomatosis since 1960. The kittens were held in captivity until over three months old and then challenged with the grade III Brecon strain of myxoma virus. The percentage mortality rate following challenge for each year and the number of rabbits tested are shown

The reasons for the slower development of resistance in Great Britain compared with Australia are unclear. Perhaps resistance development was linked with the more lethal virus introduced into Great Britain and the slower selection of attenuated virus strains, although, as shown in Figure 4, there were large numbers of attenuated virus strains in the field which could have enhanced selection: this may also reflect the ability of mosquitoes to disseminate virus strains widely in Australia compared with the more local and less seasonal dissemination which occurs with European rabbit fleas (Spilopsj/llus cuniculi), the predominant vector in Great Britain. Another possible reason is the generally milder summer temperatures in Great Britain compared with those in Australia, which may have decreased survival rates and slowed down selection. Similarly, in the winter, very attenuated viruses could have proved lethal due to the very cold conditions.

In France, where both mosquitoes and rabbit fleas were available as vectors, attenuated strains of myxoma virus were recovered from the field within two years of the initial virus


release (27) . However, ten years after release, 3 0 % of strains were still grade I or II (compared with < 15% in Australia) (Fig. 2) . By 1968, this figure had dropped to 6%. There are few data available on resistance to myxomatosis in Europe. Fenner and Ross quote a study conducted by Galaup in 1988, who reported that 1/7, 1/4 and 7/7 rabbits from three sites in France survived challenge with the Lausanne strain of myxoma .virus (22) . This indicated that resistance was present, but the numbers of animals from each area were too small to make conclusions about geographic variability.

Selection of domestic rabbits for resistance to myxomatosis An obvious experimental approach to studying the evolution' of genetic resistance to myxoma virus was to attempt to replicate the selection for genetic resistance in laboratory rabbits. Clearly this selection could not be performed on a scale comparable to that which occurred in field populations on a continent-wide basis. However, from 1954 to 1976, domestic rabbits were selected for resistance by challenging males with strains of myxoma virus of different virulences and breeding from the survivors; the survival rate of challenged rabbits was too low to use selection on the female line. An apparent response to selection for resistance to myxoma virus was achieved with an estimated heritability of 3 5 % to 4 0 % (61). This peaked after about six generations of selection and after 1968 no further response to selection was achieved. The trends in resistance were similar to those observed in the field but comparable levels of resistance were not reached. For example, after approximately four generations of selection, the grade III KM13 virus still killed around 8 0 % of the selected rabbits compared with 9 0 % to 9 5 % of unselected rabbits (61) . This survival rate is similar to that observed in rabbits from Lake Urana challenged with KM 13 after three epidemics (Fig. 3 ) . After approximately six generations of selection, around 2 0 % of selected rabbits also survived challenge with SLS (61) .

Genetic resistance versus acquired resistance (sire effect) Reanalysis of these selection experiments suggested that the resistance observed could largely be explained by some factor, transmitted from the sire to the dam, which conferred a temporary resistance to myxomatosis on the offspring which was not associated with maternal antibody (63). This non-genetic, 'acquired' resistance enhanced survival of kittens to myxoma virus challenge if the kittens were born to does which had mated with males that had 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 myxoma virus were also protected. This enhanced survival of kittens was termed the 'sire effect'.

In this analysis, and on retrospective analysis of other data from Australia (50, 71) , the risk of death of progeny following challenge with myxoma virus was reduced by 2 0 % to 2 5 % if b o m within seven months of infection of the male, and was enhanced when the strain of virus used to challenge the buck was the same as that used to challenge the progeny. The effect, however, was temporary, with domestic kittens infected prior to 18 weeks of age having a higher recovery rate than those infected later. The protection was claimed to last up to 60 weeks of age in wild rabbits (71) .

The suggestion has been made that in areas with annual epidemics of myxomatosis, as most kittens are born to females which have mated with males which had survived myxomatosis during the previous epidemic, the sire effect could explain much of the apparent resistance observed in the field (63, 71) . However, no experimental test of this hypothesis has been performed and a mechanism by which it might operate remains difficult to imagine. If the hypothesis is correct, there would be fundamental implications for understanding the infectious disease biology of mammals, especially in species with a short generation time. Meanwhile, there is no doubt that a significant component (and perhaps the most important component) of the resistance to myxomatosis observed in wild rabbits in Australia is genetically acquired. The authors have shown this using animal-house-bred wild rabbits as part of the mechanistic studies of genetic resistance. Neither sires nor dams of these rabbits have had any exposure to myxomatosis and the rabbits have a very high level of resistance to the grade I SLS (S.M. Best and P.J. Kerr, in preparation).

The phenotype of resistance and possible genotypes The clinical effect on the rabbit of challenge with myxoma virus depends on a series of variables. These include the immune status, age, nutritional status, intercurrent disease status and ambient temperature, as well as the innate resistance of the animal. If effects other than innate resistance are controlled within a population of wild rabbits in which selection for resistance has been operating, there can be a range of clinical outcomes following challenge with myxoma virus. Some rabbits will develop generalised myxomatosis with death occurring within two to three weeks of inoculation (low resistance but prolonged survival compared to domestic rabbits). Some may have moderate to severe clinical signs with eventual recovery (moderate resistance). The third group show very mild clinical signs; sometimes only a primary lesion at the site of inoculation or, in some cases, no evidence of infection apart from seroconversion (strong resistance).


The proportion of animals in each group will vary according to the virulence of the virus used for challenge and the overall level of resistance in the population. Clearly, development of resistance in a population is not an 'all or nothing' effect but involves a series of steps. If the virus is virulent enough, it appears that resistance may be overcome in many cases. Within a population, there may be individuals with any of these phenotypes: in fact, two or three rabbits per thousand survived infection during the initial epidemics in Australia (15).

Development of resistance must have required 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 a short time period. However, the genetic loci involved in resistance to myxoma virus have not been identified. The resistance phenotypes generalised above could possibly be explained by polymorphisms at a single locus with multiple alleles which encode for different grades of resistance. Alternatively, and perhaps more likely, the phenotypes could represent multiple unlinked loci, such as those which occur in genetic resistance to mousepox virus ( 7 , 1 0 ) . In mousepox resistance, protection is encoded by a major dominant autosomal gene and one or more other genes provide some protection, depending on the virulence of the virus and perhaps the route of inoculation.

The survival of rabbits within a challenged group will represent gene frequencies within the population from which these rabbits were drawn. At each resistance locus, a rabbit could be either homozygous or heterozygous. If a particular polymorphism was in some way disadvantageous, there may be advantages to heterozygotes and thus homozygote-susceptible rabbits would also be maintained in the population. Unlike mousepox and some other murine models (7, 5 1 , 53 , 70) , the sex of the animal appears to have no influence on survival from myxomatosis (15, 62) .

Virus interactions with the host Like other poxviruses, myxoma virus encodes proteins which bind host antiviral and proinflammatory factors such as interferon-Y (IFN-y) (68) , interleukin-1 (IL-1) (33) , tumour necrosis factor (TNF) (58) and chemokines (24, 30) . These proteins significantly modulate the host immune and inflammatory responses (Table IV) (33, 34) . Other proteins, such as M11L (23) and Serp 1 (31) , are strongly anti-inflammatory but the cellular targets of these proteins have not been identified. By inhibiting apoptosis (cell death), M11L, T5 and T2 (32, 41) are critical for virus replication in lymphocytes and thus in dissemination of the virus within the host (see below). Serp 2, which inhibits IL-1, converting enzyme (52) , is also likely to be important in inhibiting apoptosis (29) . Disruption of any of the genes encoding these proteins may dramatically attenuate the virus for European rabbits, leading these genes to be termed 'virulence genes'.

Myxoma virus also modulates the host immune response by downregulating major histocompatibility complex (MHC)-I molecules on the surface of infected cells and thus potentially inhibiting recognition by cytotoxic T lymphocytes (5), and downregulating CD-4 (cluster of differentiation antigen) molecules on the surface of infected T lymphocytes (4). Myxoma virus may also encode proteins which inhibit the action of type II interferons and complements, as these are encoded by other poxviruses which have homologues of some or most of the myxoma virus virulence genes (1) .

The roles of the proteins encoded by virulence genes can provide some clues to important host factors in resistance, although the fact that these viruses evolved in S. brasiliensis (and thus the genes were not selected specifically for virulence in European rabbits) must be remembered.

Pathogenesis of myxomatosis and understanding resistance The pathogenesis of myxoma virus in laboratory rabbits is shown in Figure 6. Following intradermal inoculation of a small dose of virulent virus, initial replication of virus occurs at the inoculation site. Within two days of inoculation, virus is found in the draining lymph node and high titres of virus are found in the node three to four days after infection. Systemic spread occurs in leucocytes (virus is not found free in the serum), while replication can be detected in distal lymph nodes, spleen, lung, testis and other organs and at mucocutaneous junctions, such as the conjunctiva, three to five days after infection. At this stage, the main sign of disease is a red, raised swelling at the inoculation site and slightly swollen eyelids. Secondary lesions begin to appear in the skin

Fig. 6 Pathogenesis of myxoma virus Diagrammatic representation of the spread of myxoma virus in the rabbit, showing the main tissues in which the virus replicates and the critical cells for dissemination


Table IV Identified virulence genes in myxoma virus

Gene Protein Function identified Reference

T1* Secreted 35 kDa Chemokine binding (24) T2 Secreted 55-60 kDa glycoprotein TNFa/B binding

Inhibition of apoptosis in lymphocytes (58, 67) (32)

T5 55 kDa poxvirus host-range superfamily Inhibition of apoptosis in lymphocytes (41) T7 Secreted 37 kDa IFN-y binding

Chemokine binding (42, 68) (30)

Serpi Secreted serine protease inhibitor; 55 kDa glycoprotein ' Inhibition of inflammation (31,661 M11L Type II membrane protein, 166 amino acids Inhibition of inflammation, inhibition of apoptosis in lymphocytes (23,32, 48| MGF Secreted 85 amino acid peptide EGF/TGF-a homologue (49, 65) Serp 2* 34 kDa; cytoplasmic IL-1 p-converting enzyme inhibition (52)

* Role in virulence not yet determined kDa : kiloDaltons TNF : tumour necrosis factor IFN : interferon EGF : epidermal growth factor TGF : transforming growth factor It : interleukin

of the ears and margins of the eyelids and subsequently over much of the body, if the animal lives long enough (16, 21) .

The major sites of pathology are in the lymphoid tissues, skin and mucocutaneous junctions and in the testes in the male (26). The cause of death is obscure; Mims could not attribute death to damage of any specific organ (40) , while others have suggested that death is due to superinfection with Gram-negative bacteria complemented by immunosuppression of the host immune system (64) . However, following infection with highly virulent viruses, death frequently occurs with minimal evidence of secondary bacterial infection, particularly with Californian strains of virus (21) .

Possible mechanisms of resistance Conceptually, resistance can be viewed as the control of virus replication and spread within the host. Comparison with the natural hosts of myxoma virus suggests that the virus has evolved virulence genes to survive within the dermis/ epidermis long enough to ensure transmission, but the host is able to prevent the systemic spread of the virus. These viral factors are presumed to overwhelm 0. cuniculus, but the ability to replicate and spread in host leucocytes is also likely to be critical. This is supported by observations on rabbit fibroma virus, a Leporipoxvirus closely related to myxoma virus but the natural host of which is S. floridanus. In European rabbits, rabbit fibroma virus causes only a cutaneous fibroma. The virus replicates to high titres in the skin at the inoculation site, but is unable to replicate in rabbit lymphocytes in vitro. Instead, infected lymphocytes undergo apoptosis and this is believed to be a key event in controlling the spread of the virus and thus the development of systemic disease ( 3 2 , 4 1 , 6 4 ) .

As shown in Figure 6, resistance to myxoma virus 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 permissivity, as occurs in flavivirus-resistant mice (6) , 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, natural killer cells (NK cells) and cytotoxic T lymphocytes or to make cells non-permissive for replication by the action of interferon. Myxoma virus actively suppresses apoptosis in infected lymphocytes and the early inflammatory response to infection (Fig. 6) . 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 rmp (resistance to mousepox) 1 gene in mousepox-virus-resistant mice (10) . Ultimately, as in any acute virus infection, the outcome will depend on whether the host can slow replication and dissemination of the virus enough to enable the immune response to control and clear the infection.

When genetically resistant wild rabbits were compared with non-resistant domestic rabbits infected with either a grade I (SLS) or a grade V strain of myxoma virus, the authors found that virus titres in the draining lymph node were significantly reduced in the wild rabbits compared to domestic rabbits, but that skin titres were similar in both groups. Similarly, titres in distal lymph nodes were much reduced in wild rabbits compared to domestic rabbits, indicating a reduced dissemination within the body (S.M. Best and P.J. Kerr, unpublished data). Thus, the draining lymph node or spread from the skin to the lymph node appears to be the key controlling the progress of infection. Limitation of virus spread within the body also appeared to be the key


mechanism by which high ambient temperatures exerted an attenuating effect (35) , but the molecular and cellular basis for this is unclear.

Conclusion: host-virus co-evolution now and in the future The association of myxoma virus with the original host, S. brasiliensis, is a good example of a successful parasite which causes minimal harm to the host. European rabbits and myxoma virus might be expected to evolve to a climax association, with attenuation of the virus such that a transmissible fibroma similar to that seen in S. brasiliensis is induced. However, theoretical modelling studies indicate that for a general host-parasite interaction, this is likely to occur only if transmission is not positively linked to virulence (2). For this to happen in myxoma virus infections of European rabbits, skin titres of virus would have to be independent of dissemination within the host.

Using the data on myxoma virus and rabbits to develop models, it has been predicted that, as rabbits are selected for resistance, field strains of virus will be selected for enhanced virulence ( 2 , 1 2 , 59) . There is some evidence of this occurring in Great Britain (Fig. 4 ) , where increasing numbers of grade II strains of virus are emerging, and perhaps also in Australia (Fig. 3) . Regions where genetic resistance is highest, such as the Mallee region of Australia, seem to have predominant virus strains of higher virulence (13, 22) . No detailed assessments of virulence have been performed in Australia in the last ten years but in other studies, 7/11 field strains isolated in Australia since 1990 were of grade I virulence, indicating that there may well be a shift towards highly virulent viruses in the field (P.J. Kerr, unpublished findings). Perhaps the most likely scenario was proposed by Fenner and Ross (22) , who suggested that most of the changes in viral or host genotypes which can be readily selected for have already occurred, and that myxomatosis will remain a moderately severe disease with 'an appreciable mortality', similar to smallpox in Asia prior to eradication. This assumes that the absolute resistance occasionally seen in some rabbits will not become dominant in the field. These rabbits may be selected

against in some situations and the attenuated virus strains may limit selection pressure for this degree of resistance.

Interestingly, in France, the so-called 'amyxomatous' strains of myxoma virus appeared (28) . These strains had a predilection for the respiratory tract and appeared to be transmitted by the respiratory route (as was smallpox). The question of whether selection. for resistance of rabbits to vector-transmitted myxoma virus has led to selection for virus strains which are transmitted by other routes is fascinating, with relevance to host-pathogen evolution in many situations.

Even over relatively short time-frames, and excluding normal climatic fluctuations, the environment in which selection of rabbits and virus occurs has not remained constant. Since 1970, the European rabbit flea has become established in the temperate areas of Australia, thus providing an additional vector. More recently, the Spanish rabbit flea has been extensively released in the arid zones of Australia. The European rabbit flea altered the epidemiology of myxomatosis in Australia (9, 11, 60) , and the Spanish flea is also likely to affect epidemiology in the arid zones, but the effects of these new vectors on the evolution of viral virulence and host resistance are unclear. Recently the calicivirus, viral haemorrhagic disease of rabbits, has significantly reduced populations of rabbits in Europe and Australia, and the effects that this may have on resistance to myxomatosis have not been studied.

Acknowledgements This work on genetic resistance to myxoma virus is partially supported by funding from the Anti-Rabbit Research Foundation of Australia. Dr R. Seamark and Dr R. Jackson critically read the manuscript.


Le virus de la myxomatose du lapin P.J. Kerr & S.M. Best

Résumé Le virus de la m y x o m a t o s e du lapin e u r o p é e n (Oryctolagus cuniculus) est l'un des

e x e m p l e s les mieux décr i ts d 'évolut ion conjo inte de l 'hôte et du v irus. Chez les

hôtes nature ls ( lapins Sylvilagus brasiliensis ou S. bachmani du c o n t i n e n t

a m é r i c a i n ) , le virus de la m y x o m a t o s e p r o v o q u e un f i b r o m e c u t a n é bén in . Chez le

lapin e u r o p é e n , e n r e v a n c h e , il d é c l e n c h e u n e m y x o m a t o s e f o u d r o y a n t e . A u

début de l 'épizoot ie , le virus provoqua i t un t a u x de morta l i té t r ès é l e v é , s u p é r i e u r

à 9 9 % c h e z le lapin e u r o p é e n en Aus t ra l i e , en Europe c o n t i n e n t a l e et en

G r a n d e - B r e t a g n e . L 'appari t ion de s o u c h e s v i ra les a t t é n u é e s a pe rmis le

d é v e l o p p e m e n t d 'une ce r ta ine r é s i s t a n c e et , par tan t , la survie de lapins a s s e z

rés istants . Cette évolut ion a été sur tout sens ib le d a n s les c l imats c h a u d s , où la

t e m p é r a t u r e é l e v é e a a u g m e n t é le t a u x de survie des a n i m a u x in fec tés . Les lapins

rés is tants t r a n s m e t t a n t moins f a c i l e m e n t le v i rus , l 'appar i t ion de s o u c h e s v i ra les

plus v i ru lentes p e u t s 'en t r o u v e r f a v o r i s é e . Les m é c a n i s m e s de la r é s i s t a n c e sont

en g r a n d e part ie m é c o n n u s . Les h y p o t h è s e s qui ont é té a v a n c é e s c o n c e r n a n t la

rés is tance non g é n é t i q u e res ten t à con f i rmer e x p é r i m e n t a l e m e n t .

Mots-clés Génét ique - Lapins - M y x o m a t o s e - Résistance aux ma lad ies - V i ru lence - V i rus de la

myxomatose.

El v i rus del mixoma en el conejo P.J. Kerr & S.M. Best

Resumen La re lac ión en t re el v i rus del m ixoma y el cone jo e u r o p e o (Oryctolagus cuniculus).

es uno de los e jemplos de c o e v o l u c i ó n en t re h u é s p e d y virus d o c u m e n t a d o s con

m á s profus ión. En sus h u é s p e d e s n a t u r a l e s (los c o n e j o s a m e r i c a n o s de las

e s p e c i e s Sylvilagus brasiliensis o S. bachmani), el v irus del m i x o m a c a u s a un

f i b r o m a c u t á n e o de c a r á c t e r ben igno . En el cone jo e u r o p e o , sin e m b a r g o , e s e

v i rus p rovoca una e n f e r m e d a d f u l m i n a n t e , la mixomatos is . En las f a s e s in ic ia les

q u e s igu ieron a su in t roducc ión en las p o b l a c i o n e s sa lva jes de cone jo e u r o p e o de

Aus t ra l i a , Europa cont inenta l y Gran B r e t a ñ a , el v i rus se reve ló letal en g r a d o

s u m o , con una t a s a de mor ta l idad super ior al 9 9 % de los cone jos i n f e c t a d o s . La

a p a r i c i ó n de c e p a s v í r icas a t e n u a d a s , al fac i l i ta r la s u p e r v i v e n c i a de a n i m a l e s

m o d e r a d a m e n t e res is ten tes , a len tó el desarro l lo de la res is tenc ia al v i rus .

Cons iderando que una e l e v a d a t e m p e r a t u r a a m b i e n t e i n c r e m e n t a la t a s a de

superv ivenc ia de los c o n e j o s i n f e c t a d o s , es posible que a q u e l p r o c e s o se d iera

con m á s rap idez e n c l imas cá l idos . Los c o n e j o s res is ten tes son t r a n s m i s o r e s

m e n o s e f i c a c e s del v i rus , h e c h o que p u e d e f a v o r e c e r la a p a r i c i ó n de c e p a s m á s

v i ru lentas . M u y poco se s a b e sobre el m e c a n i s m o de res is tenc ia : a u n q u e se ha

suger ido una res is tenc ia de t ipo no g e n é t i c o , fa l ta aún c o n f i r m a c i ó n e x p e r i m e n t a l

de ta l supos ic ión .

Palabras clave Conejos - Genét ica - M i xoma tos i s - Resistencia a la en fe rmedad - V i ru lenc ia - V i rus del

m ixoma.


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myxoma virus in rabbits - semantic scholar · myxoma virus is a member of the poxvirus family and...

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