Abstract
The success of a virus in defeating or evading cell-intrinsic 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 pathogen-associated 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.