Murine gammaherpesvirus 68 infection of IFNγ unresponsive mice: a small animal model for gammaherpesvirus-associated B cell lymphoproliferative disease

摘要

Gammaherpesviruses are tightly controlled by the host immune response, with gammaherpesvirus-associated malignancies prevalent in immune-suppressed individuals. Previously, infection of IFNγ unresponsive mice with gammaherpesvirus 68 (γHV68) showed that IFNγ controlled chronic infection, limiting chronic diseases including arteritis and pulmonary fibrosis. Here we demonstrate that γHV68-infected IFNγ receptor (IFNγR)-deficient mice uniformly develop angiocentric inflammatory lesions in the lung. Prolonged infection revealed a range of outcomes, from spontaneous regression to pulmonary lymphoma. By 12 months of infection, 80% of mice had lymphoid hyperplasia or pulmonary lymphoma. 45% of infected mice developed frank tumors between five and 12 months post-infection, with some mice showing systemic involvement. Lymphomas were composed of B lymphocytes and contained latently infected cells. Although IFNγR−/− mice control chronic γHV68 infection poorly, both early and late pathologies were indistinguishable between wildtype and reactivation-defective virus infection, indicating that, in contrast to other previously described γHV68-associated pathologies, these chronic diseases were not dependent on reactivation of latent infection. This distinct combination of latent infection and defined host defect led to a specific and consistent lymphoproliferative disease. Significantly, this mouse model of virus-associated pulmonary B cell lymphoma closely mimics the full spectrum of human lymphomatoid granulomatosis, an Epstein-Barr virus-associated malignancy with no effective treatment.