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Ganglioside and Non-ganglioside Mediated Host Responses to the Mouse Polyomavirus.

You J, O'Hara SD, Velupillai P, Castle S, Levery S, Garcea RL, Benjamin T - PLoS Pathog. (2015)

Bottom Line: Specificity is determined by recognition of carbohydrate moieties on the ganglioside by the major viral capsid protein VP1.Ganglioside-deficient fibroblasts responded rapidly to virus exposure with a transient induction of c-fos as an early manifestation of a mitogenic 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States of America.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Characterization of St8 and B4 KO mice.A. Kaplan-Meier survival curves for wild-type and ganglioside-knockout mice. Newborn mice were inoculated intraperitoneally with ~106 PFU of the LID strain of virus and followed using death as an endpoint. B. Susceptibility of wild-type, ST8, and B4 MEFs to infection. Large T-antigen immunofluorescence of MuPyV-infected mouse embryo fibroblasts from wild-type and ganglioside-deficient mice. Cells were infected with the RA virus at an MOI of 1–2 PFU/cell.
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ppat.1005175.g002: Characterization of St8 and B4 KO mice.A. Kaplan-Meier survival curves for wild-type and ganglioside-knockout mice. Newborn mice were inoculated intraperitoneally with ~106 PFU of the LID strain of virus and followed using death as an endpoint. B. Susceptibility of wild-type, ST8, and B4 MEFs to infection. Large T-antigen immunofluorescence of MuPyV-infected mouse embryo fibroblasts from wild-type and ganglioside-deficient mice. Cells were infected with the RA virus at an MOI of 1–2 PFU/cell.

Mentions: The LID strain of MuPyV induces a rapidly lethal infection of newborn mice of most backgrounds [23, 27]. Mice typically succumb within a few weeks due to a widely disseminated infection with extensive destruction of the kidney and other vital tissues. LID owes its virulence to an amino acid substitution in the major capsid protein VP1 that reduces hydrophobic interactions with the sialic acid ring. This lower avidity binding of virus to cells facilitates release from cell debris and promotes virus spread. To establish the importance of gangliosides in mediating this infection, newborn mice from a cross of heterozygous B4 KO mice were inoculated with LID. Mice were followed daily and death was used as an endpoint (Fig 2A). Genotyping was carried out retrospectively, i.e., at time of death or at the end of the experiment.


Ganglioside and Non-ganglioside Mediated Host Responses to the Mouse Polyomavirus.

You J, O'Hara SD, Velupillai P, Castle S, Levery S, Garcea RL, Benjamin T - PLoS Pathog. (2015)

Characterization of St8 and B4 KO mice.A. Kaplan-Meier survival curves for wild-type and ganglioside-knockout mice. Newborn mice were inoculated intraperitoneally with ~106 PFU of the LID strain of virus and followed using death as an endpoint. B. Susceptibility of wild-type, ST8, and B4 MEFs to infection. Large T-antigen immunofluorescence of MuPyV-infected mouse embryo fibroblasts from wild-type and ganglioside-deficient mice. Cells were infected with the RA virus at an MOI of 1–2 PFU/cell.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608836&req=5

ppat.1005175.g002: Characterization of St8 and B4 KO mice.A. Kaplan-Meier survival curves for wild-type and ganglioside-knockout mice. Newborn mice were inoculated intraperitoneally with ~106 PFU of the LID strain of virus and followed using death as an endpoint. B. Susceptibility of wild-type, ST8, and B4 MEFs to infection. Large T-antigen immunofluorescence of MuPyV-infected mouse embryo fibroblasts from wild-type and ganglioside-deficient mice. Cells were infected with the RA virus at an MOI of 1–2 PFU/cell.
Mentions: The LID strain of MuPyV induces a rapidly lethal infection of newborn mice of most backgrounds [23, 27]. Mice typically succumb within a few weeks due to a widely disseminated infection with extensive destruction of the kidney and other vital tissues. LID owes its virulence to an amino acid substitution in the major capsid protein VP1 that reduces hydrophobic interactions with the sialic acid ring. This lower avidity binding of virus to cells facilitates release from cell debris and promotes virus spread. To establish the importance of gangliosides in mediating this infection, newborn mice from a cross of heterozygous B4 KO mice were inoculated with LID. Mice were followed daily and death was used as an endpoint (Fig 2A). Genotyping was carried out retrospectively, i.e., at time of death or at the end of the experiment.

Bottom Line: Specificity is determined by recognition of carbohydrate moieties on the ganglioside by the major viral capsid protein VP1.Ganglioside-deficient fibroblasts responded rapidly to virus exposure with a transient induction of c-fos as an early manifestation of a mitogenic 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States of America.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus