Genome Scale Evolution of Myxoma Virus Reveals Host-Pathogen Adaptation and Rapid Geographic Spread

Kerr, Peter J.; Rogers, Matthew B.; Fitch, Adam; DePasse, Jay V.; Cattadori, Isabella M.; Twaddle, Alan; Hudson, Peter J.; Tscharke, David C.; Read, Andrew F.; Holmes, Edward C.; Ghedin, Elodie

doi:10.1128/jvi.02060-13

Cited by 31 publications

(64 citation statements)

References 57 publications

(72 reference statements)

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“…Peng et al now show that one such mutation in M156 (L98P) abolishes its ability to inhibit PKR and cannot rescue replication of a M156-deficient MYXV in rabbit cells (2). Remarkably, this mutation lies within the region predicted to interact with PKR and is present in more than half of wild viral samples tested (11), supporting the notion that it is a determinant of attenuation.…”

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confidence: 58%

“…Duplications of the M156 gene were also identified in several wild myxoma isolates (11), perhaps foreshadowing the appearance of betteradapted variants. In support of this possibility, genomic duplications involving the K3L gene were recovered in laboratory evolution studies using VACV, accelerating the emergence of adaptive variants better able to counteract PKR (12).…”

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confidence: 99%

“…However, the underlying molecular basis of MYXV attenuation has hitherto remained unclear. Although the recent comparison of wild Australian MYXV isolates from the 1990s with the experimental strain released more than 50 y ago identified many changes in the MYXV genome (11), identifying which of these are associated with the observed attenuation of virulence posed a significant challenge. Peng et al now show that one such mutation in M156 (L98P) abolishes its ability to inhibit PKR and cannot rescue replication of a M156-deficient MYXV in rabbit cells (2).…”

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Evolutionary clash between myxoma virus and rabbit PKR in Australia

Burgess

Mohr

2016

Proc. Natl. Acad. Sci. U.S.A.

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The success of a virus in defeating or evading cellintrinsic immune responses contributes to its virulence, pathogenesis, and host range. A central tenet of virology holds that virus and host coevolve as each adapts to survive. Rarely, however, do we have the chance to observe this principal at play in the real world. The deliberate and repeated release of myxoma virus (MYXV) to control feral European rabbits introduced into Australia provides one such exceptional opportunity. Myxoma is a member of the poxvirus family, though unlike its more famous cousin variola, the agent of small pox, is unable to infect humans and is instead limited to infection of rabbits and hares. Following the release of a MYXV reference strain into the wild that exhibited 99.8% fatality rates in laboratory rabbits, attenuated strains were recovered from the field that had begun to outcompete the virulent parental strain. In addition, the resistance of rabbits to MYXV increased (1). The underlying molecular mechanism of both rabbit resistance and MYXV attenuation, however, remained elusive. Armed with the recently compiled genome sequence of 21 myxoma field isolates, a new study by Peng et al. in PNAS reveals that genetic alterations to the MYXV M156 protein correlate with both MYXV host specificity and changes in virulence observed in the field (2). Remarkably, more than 50% of MYXV field isolates produce an M156 variant that is no longer able to antagonize the rabbit double-stranded RNA (dsRNA)-activated protein kinase PKR, a critical component of IFN-stimulated defenses that controls protein synthesis. This not only provides the first mechanistic explanation for each of these facets of myxoma biology, but also elegantly illustrates the coevolution of host innate defense and viral virulence factors since the first release of MYXV in 1950.In response to virus infection, a key arm of antiviral host defenses acts to cripple the infected cell's capacity to produce the polypeptides required for virus replication and spread. This is achieved by globally inhibiting the initiation of mRNA translation and is triggered by accumulation of dsRNA, a pathogenassociated molecular pattern produced by many different viruses during their replication cycle. Upon sensing dsRNA, host PKR, which resides in uninfected cells as an inactive, unphosphorylated monomer, becomes activated as a phosphorylated dimer bound to dsRNA (Fig. 1). The ensuing site-specific phosphorylation of the eukaryotic translation initiation factor eIF2 α-subunit prevents methionine-initiator tRNA charging of 40S small ribosome subunits, inhibiting the initiation of protein synthesis and effectively preventing virus replication (3). The extraordinary efforts and diverse molecular tactics many different viruses rely upon to counteract PKR and preserve the activity of the critical initiation factor eIF2 underscore the significant role PKR plays in host defense.To safeguard eIF2 function and effectively contain PKR, viruses frequently enlist multiple molecular strategies. MYXV is no excep...

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Evolutionary clash between myxoma virus and rabbit PKR in Australia

Burgess

Mohr

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Recently, the complete genomes of 24 MYXV strains that were collected in the field in Australia were reported. Although a number of mutations were discovered, it was not immediately clear which mutations led to changes in MYXV virulence (6,7). Two candidate genes that might contribute to changes in virulence are M029L and M156R, the MYXV orthologs of vaccinia virus (VACV) E3L and K3L, respectively.…”

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Myxoma virus M156 is a specific inhibitor of rabbit PKR but contains a loss-of-function mutation in Australian virus isolates

Chen

Haller

Rahman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Myxoma virus (MYXV) is a rabbit-specific poxvirus, which is highly virulent in European rabbits. The attenuation of MYXV and the increased resistance of rabbits following the release of MYXV in Australia is one of the best-documented examples of host-pathogen coevolution. To elucidate the molecular mechanisms that contribute to the restriction of MYXV infection to rabbits and MYXV attenuation in the field, we have studied the interaction of the MYXV protein M156 with the host antiviral protein kinase R (PKR). In yeast and cell-culture transfection assays, M156 only inhibited rabbit PKR but not PKR from other tested mammalian species. Infection assays with human HeLa PKR knock-down cells, which were stably transfected with human or rabbit PKR, revealed that only human but not rabbit PKR was able to restrict MYXV infection, whereas both PKRs were able to restrict replication of a vaccinia virus (VACV) strain that lacks the PKR inhibitors E3 and K3. Inactivation of M156R led to MYXV virus attenuation in rabbit cells, which was rescued by the ectopic expression of VACV E3 and K3. We further show that a mutation in the M156 encoding gene that was identified in more than 50% of MYXV field isolates from Australia resulted in an M156 variant that lost its ability to inhibit rabbit PKR and led to virus attenuation. The species-specific inhibition of rabbit PKR by M156 and the M156 loss-of-function in Australian MYXV field isolates might thus contribute to the species specificity of MYXV and to the attenuation in the field, respectively.oxviruses are large double-stranded DNA viruses that exclusively replicate in the cytoplasm of infected cells. Members of the Poxviridae family can productively infect a wide variety of animal hosts. Interestingly, the binding and entry of poxviruses into cells is largely independent of host species after which virus replication is initiated. The successful completion of virus replication, however, depends on the effective subversion of the host cell's innate immune responses (1). Even closely related poxviruses can exhibit drastic differences in their host ranges. Whereas some poxviruses have only one host species, such as variola virus, the causative agent of smallpox, which is restricted to humans, others, such as cowpox and monkeypox viruses, can infect many different species and thus display very broad host ranges (2). A number of poxvirus genes have been discovered that influence the host range and cell tropism of poxviruses and have therefore been termed "host range genes" (3, 4). Although the molecular mechanisms responsible for their host range functions have not been elucidated in detail, it is clear that most poxviral host range proteins interact with components of the host immune system and that host species-specific interactions likely play a major role.Myxoma virus (MYXV) is a poxvirus that belongs to the genus leporipoxvirus and shows a restricted host range infecting only leporids (rabbits and hares). MYXV is highly lethal to European (E.) rabbits causing case fatality rate...

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“…However, we emphasize that a prominent role of myxomatosis under current conditions in Australia is unlikely because of only moderate virulence of common circulating field genotypes of MYXV and an rsif.royalsocietypublishing.org J. R. Soc. Interface 12: 20141184 overriding effect of RHD [30,55]. Importantly, the actual impact of the two diseases under natural conditions will depend on the seasonal timing of disease introduction, as a later introduction of MYXV into a host population will dampen the positive effect on disease severity and population extirpation in relation to delayed susceptibility to RHDV.…”

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confidence: 99%

Timing and severity of immunizing diseases in rabbits is controlled by seasonal matching of host and pathogen dynamics

Wells

Brook

Lacy

et al. 2015

J. R. Soc. Interface.

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Infectious diseases can exert a strong influence on the dynamics of host populations, but it remains unclear why such disease-mediated control only occurs under particular environmental conditions. We used 16 years of detailed field data on invasive European rabbits (Oryctolagus cuniculus) in Australia, linked to individual-based stochastic models and Bayesian approximations, to test whether (i) mortality associated with rabbit haemorrhagic disease (RHD) is driven primarily by seasonal matches/mismatches between demographic rates and epidemiological dynamics and (ii) delayed infection (arising from insusceptibility and maternal antibodies in juveniles) are important factors in determining disease severity and local population persistence of rabbits. We found that both the timing of reproduction and exposure to viruses drove recurrent seasonal epidemics of RHD. Protection conferred by insusceptibility and maternal antibodies controlled seasonal disease outbreaks by delaying infection; this could have also allowed escape from disease. The persistence of local populations was a stochastic outcome of recovery rates from both RHD and myxomatosis. If susceptibility to RHD is delayed, myxomatosis will have a pronounced effect on population extirpation when the two viruses coexist. This has important implications for wildlife management, because it is likely that such seasonal interplay and disease dynamics has a strong effect on long-term population viability for many species.

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Genome Scale Evolution of Myxoma Virus Reveals Host-Pathogen Adaptation and Rapid Geographic Spread

Cited by 31 publications

References 57 publications

Evolutionary clash between myxoma virus and rabbit PKR in Australia

Evolutionary clash between myxoma virus and rabbit PKR in Australia

Myxoma virus M156 is a specific inhibitor of rabbit PKR but contains a loss-of-function mutation in Australian virus isolates

Timing and severity of immunizing diseases in rabbits is controlled by seasonal matching of host and pathogen dynamics

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