30 research outputs found
Production of a Natural Antibody to the Mouse Polyoma Virus Is a Multigenic Trait
MA/MyJ mice express a natural antibody to the highly oncogenic polyoma virus. C57BR/cdJ mice lack this antibody but mount an adaptive T-cell response to the virus. Analysis of F2 progeny of a cross between these strains reveals a pattern of inheritance of expression of the natural antibody involving two genes in an epistatic relationship
Receptor-Binding and Oncogenic Properties of Polyoma Viruses Isolated from Feral Mice
Laboratory strains of the mouse polyoma virus differ markedly in their abilities to replicate and induce tumors in newborn mice. Major determinants of pathogenicity lie in the sialic binding pocket of the major capsid protein Vp1 and dictate receptor-binding properties of the virus. Substitutions at two sites in Vp1 define three prototype strains, which vary greatly in pathogenicity. These strains replicate in a limited fashion and induce few or no tumors, cause a disseminated infection leading to the development of multiple solid tumors, or replicate and spread acutely causing early death. This investigation was undertaken to determine the Vp1 type(s) of new virus isolates from naturally infected mice. Compared with laboratory strains, truly wild-type viruses are constrained with respect to their selectivity and avidity of binding to cell receptors. Fifteen of 15 new isolates carried the Vp1 type identical to that of highly tumorigenic laboratory strains. Upon injection into newborn laboratory mice, the new isolates induced a broad spectrum of tumors, including ones of epithelial as well as mesenchymal origin. Though invariant in their Vp1 coding sequences, these isolates showed considerable variation in their regulatory sequences. The common Vp1 type has two essential features: 1) failure to recognize “pseudoreceptors” with branched chain sialic acids binding to which would attenuate virus spread, and 2) maintenance of a hydrophobic contact with true receptors bearing a single sialic acid, which retards virus spread and avoids acute and potentially lethal infection of the host. Conservation of these receptor-binding properties under natural selection preserves the oncogenic potential of the virus. These findings emphasize the importance of immune protection of neonates under conditions of natural transmission
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Receptor-Binding and Oncogenic Properties of Polyoma Viruses Isolated from Feral Mice
Laboratory strains of the mouse polyoma virus differ markedly in their abilities to replicate and induce tumors in newborn mice. Major determinants of pathogenicity lie in the sialic binding pocket of the major capsid protein Vp1 and dictate receptor-binding properties of the virus. Substitutions at two sites in Vp1 define three prototype strains, which vary greatly in pathogenicity. These strains replicate in a limited fashion and induce few or no tumors, cause a disseminated infection leading to the development of multiple solid tumors, or replicate and spread acutely causing early death. This investigation was undertaken to determine the Vp1 type(s) of new virus isolates from naturally infected mice. Compared with laboratory strains, truly wild-type viruses are constrained with respect to their selectivity and avidity of binding to cell receptors. Fifteen of 15 new isolates carried the Vp1 type identical to that of highly tumorigenic laboratory strains. Upon injection into newborn laboratory mice, the new isolates induced a broad spectrum of tumors, including ones of epithelial as well as mesenchymal origin. Though invariant in their Vp1 coding sequences, these isolates showed considerable variation in their regulatory sequences. The common Vp1 type has two essential features: 1) failure to recognize “pseudoreceptors” with branched chain sialic acids binding to which would attenuate virus spread, and 2) maintenance of a hydrophobic contact with true receptors bearing a single sialic acid, which retards virus spread and avoids acute and potentially lethal infection of the host. Conservation of these receptor-binding properties under natural selection preserves the oncogenic potential of the virus. These findings emphasize the importance of immune protection of neonates under conditions of natural transmission
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Ganglioside and Non-ganglioside Mediated Host Responses to the Mouse Polyomavirus
Gangliosides serve as receptors for internalization and infection by members of the polyomavirus family. Specificity is determined by recognition of carbohydrate moieties on the ganglioside by the major viral capsid protein VP1. For the mouse polyomavirus (MuPyV), gangliosides with terminal sialic acids in specific linkages are essential. Although many biochemical and cell culture experiments have implicated gangliosides as MuPyV receptions, the role of gangliosides in the MuPyV-infected mouse has not been investigated. Here we report results of studies using ganglioside-deficient mice and derived cell lines. Knockout mice lacking complex gangliosides were completely resistant to the cytolytic and pathogenic effects of the virus. Embryo fibroblasts from these mice were likewise resistant to infection, and supplementation with specific gangliosides restored infectibility. Although lacking receptors for viral infection, cells from ganglioside-deficient mice retained the ability to respond to the virus. Ganglioside-deficient fibroblasts responded rapidly to virus exposure with a transient induction of c-fos as an early manifestation of a mitogenic response. Additionally, splenocytes from ganglioside-deficient mice responded to MuPyV by secretion of IL-12, previously recognized as a key mediator of the innate immune response. Thus, while gangliosides are essential for infection in the animal, gangliosides are not required for mitogenic responses and innate immune responses to the virus
Polyoma Virus-Induced Osteosarcomas in Inbred Strains of Mice: Host Determinants of Metastasis
The mouse polyoma virus induces a broad array of solid tumors in mice of many inbred strains. In most strains tumors grow rapidly but fail to metastasize. An exception has been found in the Czech-II/Ei mouse in which bone tumors metastasize regularly to the lung. These tumors resemble human osteosarcoma in their propensity for pulmonary metastasis. Cell lines established from these metastatic tumors have been compared with ones from non-metastatic osteosarcomas arising in C3H/BiDa mice. Osteopontin, a chemokine implicated in migration and metastasis, is known to be transcriptionally induced by the viral middle T antigen. Czech-II/Ei and C3H/BiDa tumor cells expressed middle T and secreted osteopontin at comparable levels as the major chemoattractant. The tumor cell lines migrated equally well in response to recombinant osteopontin as the sole attractant. An important difference emerged in assays for invasion in which tumor cells from Czech-II/Ei mice were able to invade across an extracellular matrix barrier while those from C3H/BiDa mice were unable to invade. Invasive behavior was linked to elevated levels of the metalloproteinase MMP-2 and of the transcription factor NFAT. Inhibition of either MMP-2 or NFAT inhibited invasion by Czech-II/Ei osteosarcoma cells. The metastatic phenotype is dominant in F1 mice. Osteosarcoma cell lines from F1 mice expressed intermediate levels of MMP-2 and NFAT and were invasive. Osteosarcomas in Czech-II/Ei mice retain functional p53. This virus-host model of metastasis differs from engineered models targeting p53 or pRb and provides a system for investigating the genetic and molecular basis of bone tumor metastasis in the absence of p53 loss
Susceptibility to Polyomavirus-Induced Tumors in Inbred Mice: Role of Innate Immune Responses
Mice of the PERA/Ei strain (PE mice) are highly susceptible to tumor induction by polyomavirus and transmit their susceptibility in a dominant manner in crosses with resistant C57BR/cdJ mice (BR mice). BR mice respond to polyomavirus infection with a type 1 cytokine response and develop effective cell-mediated immunity to the virus-induced tumors. By enumerating virus-specific CD8(+) T cells and measuring cytokine responses, we show that the susceptibility of PE mice is due to the absence of a type 1 cytokine response and a concomitant failure to sustain virus-specific cytotoxic T lymphocytes. (PE × BR)F(1) mice showed an initial type 1 response that became skewed toward type 2. Culture supernatants of splenocytes from infected PE mice stimulated in vitro contained high levels of interleukin-10 and no detectable gamma interferon, while those from BR mice showed the opposite pattern. Differences in the innate immune response to polyomavirus by antigen-presenting cells in PE mice and BR mice led to polarization of T-cell cytokine responses. Adherent cells from spleens of infected BR mice produced high levels of interleukin-12, while those from infected PE and F(1) mice produced predominantly interleukin-10. PE and F(1) mice infected by polyomavirus responded with increases in antigen-presenting cells expressing B7.2 costimulatory molecules, whereas BR mice responded with increased expression of B7.1. Administration of recombinant interleukin-12 along with virus resulted in partial protection of PE mice and provided complete protection against tumor development in F(1) animals
Lewis(x)-containing oligosaccharide attenuates schistosome egg antigen-induced immune depression in human schistosomiasis
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Previous issue date: 2000Department of Immunology and Infectious Diseases. Harvard School of Public Health. Boston, MA, USA.Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil.Department of Immunology and Infectious Diseases. Harvard School of Public Health. Boston, MA, USA.The proliferative and interleukin (IL)-10 responses to Lacto-n-fucopentaose III (LNFPIII) that contains Lewis(x)(Le(x))-trisaccharide was assessed in PBMC from humans infected with Schistosoma mansoni. All patient groups with low, medium, and high egg counts in their feces responded to polyvalent LNFPIII-HSA (where HSA = human serum albumin) conjugate. PBMC of all subjects showed a significant proliferative response to this sugar conjugate. However, the levels of interleukin (IL)-10 induced by LNFPIII-HSA were higher in groups with low and medium egg counts than those with high egg. Soluble egg antigens (SEA) also induced IL-10 production by PBMC from infected patients. Interestingly, the SEA-induced IL-10 production was remarkably inhibited by pretreatment of PBMC with free ligands of LNFPIII (monovalent form). These LNFPIII-pretreated PBMC displayed appreciable increase in the level of proliferation to SEA stimulation. We propose that the observed bystander immune potentiation rendered by free LNFPIII is due to the reduced IL-10 level which, presumably, up-regulate expression of co-stimulatory molecules on APC. The ensemble of results indicates that the Le(x)-containing LNFPIII is a potent immunoreactive epitope in SEA that negatively influences PBMC response against this parasite antigens via IL-10