[Show abstract][Hide abstract]ABSTRACT: Genetic makeup of the host plays a significant role in the course and outcome of infection. Inbred strains of mice display a wide range of sensitivities to Listeria monocytogenes infection and thus serve as a good model for analysis of the effect of genetic polymorphism. The outcome of L. monocytogenes infection in mice is influenced by the ability of this bacterium to induce expression of interferon beta mRNA, encoded in mouse by the Ifnb1 (interferon beta 1, fibroblast) gene. Mouse strains that lack components of the IFN beta signaling pathway are substantially more resistant to infection. We found that macrophages from the ByJ substrain of the common C57BL/6 inbred strain of mice are impaired in their ability to induce Ifnb1 expression in response to bacterial and viral infections. We mapped the locus that controls differential expression of Ifnb1 to a region on Chromosome 7 that includes interferon regulatory factor 3 (Irf3), which encodes a transcription factor responsible for early induction of Ifnb1 expression. In C57BL/6ByJ mice, Irf3 mRNA was inefficiently spliced, with a significant proportion of the transcripts retaining intron 5. Analysis of the Irf3 locus identified a single base-pair polymorphism and revealed that intron 5 of Irf3 is spliced by the atypical U12-type spliceosome. We found that the polymorphism disrupts a U12-type branchpoint and has a profound effect on the efficiency of splicing of Irf3. We demonstrate that a naturally occurring change in the splicing control element has a dramatic effect on the resistance to L. monocytogenes infection. Thus, the C57BL/6ByJ mouse strain serves as an example of how a mammalian host can counter bacterial virulence strategies by introducing subtle alteration of noncoding sequences.
[Show abstract][Hide abstract]ABSTRACT: Levels of Ifnb1 mRNA in Tissues of Infected Animals
Ifnb1 mRNA was not detectable in livers and spleens of animals infected with 1 × 105 L. monocytogenes until the 24-h time point. Forty-eight hours after infection, spleens of C57BL/6J animals had 6-fold higher levels of Ifnb1 mRNA than C57BL/6ByJ animals.
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[Show abstract][Hide abstract]ABSTRACT: Survival of C57BL/6J and C57BL/6ByJ Mice following Intravenous Infection with 1 × 105 cfu L. monocytogenes Strain 10403S
The majority of C57BL/6ByJ mice survive for more then 10 d following infection.
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[Show abstract][Hide abstract]ABSTRACT: High Levels of Spliced Irf3 mRNA Induce Death of BMMs
Survival of C57BL/6J Irf3−/− BMMs following 24-h transfection of in vitro transcribed Irf3 mRNAs was monitored by the release of the cytosolic enzyme LDH into the supernatant.
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