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. 2009 Jul 1;69(13):5481-9.
doi: 10.1158/0008-5472.CAN-09-0291. Epub 2009 Jun 16.

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

Katherine S Lee  1 , Steve D Groshong, Carlyne D Cool, Bette K Kleinschmidt-DeMasters, Linda F van Dyk
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Murine gammaherpesvirus 68 infection of IFNgamma unresponsive mice: a small animal model for gammaherpesvirus-associated B-cell lymphoproliferative disease (VSports在线直播)

"V体育官网入口" Katherine S Lee et al. Cancer Res. .

Abstract

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 VSports手机版. .

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Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1
Figure 1. Lungs of γHV68-infected IFNγR−/− mice reveal significant inflammation marked by multiple angiocentric infiltrates
H&E staining of lung sections from γHV68-infected IFNγR−/− mice showing (A, left) the presence of angiocentric infiltrates (A, right) characterized by lymphocytes, histiocytes (arrows) and hemosiderin (brown areas), (B) mock-infected IFNγR−/− mice and (C) human LyG patient with early stage disease (courtesy of S.D.G.). Original magnifications ×20 (A left, B, C) and ×40 (A right). (D) The mean vascular score, an indicator of the severity of inflammation, was significantly higher in γHV68-infected IFNγR−/− mice (* p≤ 0.001) than all other groups.
Figure 2
Figure 2. Angiocentric infiltrates are comprised mainly of B cells and latently infected cells
(A) Immunofluorescent staining of lung sections with DAPI (blue) and antibody to B220 (red) from WT-infected IFNγR−/− mice. Dotted lines outline vessels. (B) Analysis of lung tissue from WT-infected C57BL/6 (open bars), cycKO-infected C57BL/6 (horizontally lined bars), WT-infected IFNγR−/− (filled bars) or cycKO-infected IFNγR−/−(vertically lined bars) mice based on quantification of cytopathic effect (CPE). Data shown represent the mean ± SEM of independent experiments, as indicated. (C) In situ hybridization for viral transcripts polIII-1, polIII-4, polIII-5 and M2 in lung sections from WT-infected IFNγR−/− mice (left panel). Positive (top right, day 16 infected spleen) and negative (bottom right, mock-infected lung) controls are included. Brown staining is hemosiderin. Original magnifications ×10 (A, C right panels) and ×20 (C, left panel).
Figure 3
Figure 3. Resolution of pulmonary inflammation in chronically infected IFNγR−/−mice is variable
(A) Mean vascular score of mice infected between 4.5 and 12.5 months. Examples of H&E staining of lung tissue from 90 day (B) and long-term infected (C, D) mice with the mean vascular score indicated. Original magnifications ×20.
Figure 4
Figure 4. Long-term infected IFNγR−/− develop pulmonary lymphomas with evidence of systemic involvement
(A) The percentage of B cell lymphoma-free mice. The numbers in parentheses indicate B cell lymphoma-free mice of the total number analyzed in each group. H&E staining of lymphoma in lung (B, C), heart (D, left) and brain (D, right) of WT-infected (B) and cycKO-infected (C, D) IFNγR−/− mice. Dotted circles in (C) indicate mitoses. Inset in (C) shows evidence of necrosis. Original magnification ×10 (B, D left), ×60 (C) and ×40 (D right). Inset in (C) is ×20.
Figure 5
Figure 5. Lymphomas of long-term γHV68-infected IFNγR−/− mice are of B cell origin and contain abundant virus
(A, B) Immunofluorescent staining of lymphomas with DAPI (blue) and antibody to B220 (red). (C, D) In situ hybridization for viral transcripts polIII-1, polIII-4, polIII-5 and M2. Lung from WT-infected (A, C) and brain from cycKO-infected (B, D) IFNγR−/− mice. (E) Positive (day 16 infected spleen) and (F) negative (mock-infected lung) controls are included. Original magnifications ×10 (A, B, E, F) and ×20 (C, D).
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