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Pivotal components of the IFN response to virus infection include the IFN receptors (IFNR), and the downstream factor signal transducer and activator of transcription 1 (Stat1). Mice deficient for Stat1 and IFNR (Stat1(-/-) and IFNαßγR(-/-) mice) lack responsiveness to IFN and exhibit high sensitivity to various pathogens. Here we examined herpes simplex virus type 1 (HSV-1) pathogenesis in Stat1(-/-) mice and in IFNαßγR(-/-) mice following corneal infection and bioluminescent imaging. Two divergent and paradoxical patterns of infection were observed. Mice with an N-terminal deletion in Stat1 (129Stat1(-/-) (N-term)) had transient infection of the liver and spleen, but succumbed to encephalitis by day 10 post-infection. In stark contrast, infection of IFNαßγR(-/-) mice was rapidly fatal, with associated viremia and fulminant infection of the liver and spleen, with infected infiltrating cells being primarily of the monocyte/macrophage lineage. To resolve the surprising difference between Stat1(-/-) and IFNαßγR(-/-) mice, we infected an additional Stat1(-/-) strain deleted in the DNA-binding domain (129Stat1(-/-) (DBD)). These 129Stat1(-/-) (DBD) mice recapitulated the lethal pattern of liver and spleen infection seen following infection of IFNαßγR(-/-) mice. This lethal pattern was also observed when 129Stat1(-/-) (N-term) mice were infected and treated with a Type I IFN-blocking antibody, and immune cells derived from 129Stat1(-/-) (N-term) mice were shown to be responsive to Type I IFN. These data therefore show significant differences in viral pathogenesis between two commonly-used Stat1(-/-) mouse strains. The data are consistent with the hypothesis that Stat1(-/-) (N-term) mice have residual Type I IFN receptor-dependent IFN responses. Complete loss of IFN signaling pathways allows viremia and rapid viral spread with a fatal infection of the liver. This study underscores the importance of careful comparisons between knockout mouse strains in viral pathogenesis, and may also be relevant to the causation of HSV hepatitis in humans, a rare but frequently fatal infection.
Pubmed ID: 21915277 RIS Download
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Core facility that provides the following services: Medium-density speed congenic backcross service, Medium-density genetic background check service, DNA extraction. DartMouse is a not-for-profit core facility funded by the National Institutes of Health''s National Center for Research Resources. The mission of DartMouse is to facilitate the development of congenic mice in support of pre-clinical projects across the United States. Use of DartMouse allows the generation of congenic mice in 5 generations (~1.5 years), versus the 10 generations (~3 years) required by conventional back-crossing. Facility staff provides expert advice on mouse speed congenic development, mouse genetic background analysis, and mouse genetic mapping. Investigators provide us with mouse tail clippings. From these, DartMouse isolates genomic DNA and performs and analyzes complete genome-wide scans. We return data in graphical and spreadsheet formats, and make specific recommendations on breeder selection. We operate an Illumina BeadStation 500. Chips use a 1449 SNP array covering the mouse genome with an average density of <5 cM.
View all literature mentionsCell line Vero is a Spontaneously immortalized cell line with a species of origin Chlorocebus sabaeus
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
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