Murine gammaherpesvirus 68 infection of IFNgamma unresponsive mice: a small animal model for gammaherpesvirus-associated B-cell lymphoproliferative disease.
Gammaherpesviruses are tightly controlled by the host immune response, with gammaherpesvirus-associated malignancies prevalent in immune-suppressed individuals. Previously, infection of IFNgamma-unresponsive mice with gammaherpesvirus 68 (gammaHV68) showed that IFNgamma controlled chronic infection, limiting chronic diseases including arteritis and pulmonary fibrosis. Here, we show that gammaHV68-infected IFNgamma receptor-deficient (IFNgammaR(-/-)) 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 5 and 12 months postinfection, with some mice showing systemic involvement. Lymphomas were composed of B lymphocytes and contained latently infected cells. Although IFNgammaR(-/-) mice control chronic gammaHV68 infection poorly, both early and late pathologies were indistinguishable between wild-type and reactivation-defective virus infection, indicating that, in contrast with other previously described gammaHV68-associated pathologies, these chronic diseases were not dependent on the 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 EBV-associated malignancy with no effective treatment.
Lee
Katherine S
KS
Department of Microbiology, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA.
Groshong
Steve D
SD
Cool
Carlyne D
CD
Kleinschmidt-DeMasters
Bette K
BK
van Dyk
Linda F
LF
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000821:virology; D018142:Gammaherpesvirinae / Q000235:genetics; D006566:Herpesviridae Infections / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000821:virology; D007371:Interferon-gamma / Q000494:pharmacology*; D008168:Lung / Q000821:virology*; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000821:virology*; D051379:Mice; D009369:Neoplasms / Q000821:virology*; D011652:Pulmonary Circulation; D014779:Virus Replication
D007371:Interferon-gamma