Expression of rabbit IL-4 by recombinant myxoma viruses enhances virulence and overcomes genetic resistance to myxomatosis.

Rabbit IL-4 was expressed in the virulent standard laboratory strain (SLS) and the attenuated Uriarra (Ur) strain of myxoma virus with the aim of creating a Th2 cytokine environment and inhibiting the development of an antiviral cell-mediated response to myxomatosis in infected rabbits. This allowed testing of a model for genetic resistance to myxomatosis in wild rabbits that have undergone 50 years of natural selection for resistance to myxomatosis. Expression of IL-4 significantly enhanced virulence of both virulent and attenuated virus strains in susceptible (laboratory) and resistant (wild) rabbits. SLS-IL-4 completely overcame genetic resistance in wild rabbits. The pathogenesis of SLS-IL-4 was compared in susceptible and resistant rabbits. The results support a model for resistance to myxomatosis of an enhanced innate immune response controlling virus replication and allowing an effective antiviral cell-mediated immune response to develop in resistant rabbits. Expression of IL-4 did not overcome immunity to myxomatosis induced by immunization.

Coevolution of host and virus: cellular localization of virus in myxoma virus infection of resistant and susceptible European rabbits.

The coevolution of myxoma virus and the wild European rabbit in Australia and the development of resistance to myxomatosis in wild rabbits have been well described. However, the mechanism of resistance to myxomatosis in wild rabbits is not understood. To determine the basis of resistance, the pathogenesis of the virulent standard laboratory strain (SLS) and the attenuated Uriarra (Ur) strain of myxoma virus were examined in Australian wild rabbits that have been naturally selected in the field for resistance to myxomatosis and in laboratory rabbits which have never been selected for resistance. Virus was localized in tissue sections by immunofluorescence. In all cases virus antigen was initially present in dendritic cells of the dermis before localizing predominantly to the epidermis by Day 6. Antigen-containing cells were detected in the lymph nodes by 24 h after inoculation. Virus replication occurred predominantly in T lymphocytes of the paracortex but SLS also replicated in germinal centers. SLS replication induced loss of most lymphocytes from the lymph nodes of susceptible rabbits. Apoptosis of lymphocytes within the lymph nodes was a major feature of all infections. These apoptotic cells did not contain detectable viral antigen but were often adjacent to infected cells. Ongoing apoptosis of lymphocytes within lymph nodes was also a feature of the recovery phase when very few or no virus-infected cells could be detected. Differences between virulent and attenuated viruses in the wild and laboratory rabbits were predominantly in the degree of tissue pathology in the draining lymph node and distal lymph node and in the type of inflammatory responses, particularly in the skin. SLS infection of laboratory rabbits was associated with a very mild inflammatory response, often distant from the site of virus replication and comprised predominantly of neutrophils. In contrast, Ur-infected rabbits and SLS-infected wild rabbits had an intense inflammatory response adjacent to the site of virus replication and this was comprised predominantly of mononuclear cells. Both the initial infection of dendritic cells and the ongoing destruction of lymphocytes provide obvious mechanisms for the suppression of the immune response by myxoma virus.