Irf3 polymorphism alters induction of interferon beta in response to Listeria monocytogenes infection.
Journal - PLoS genetics (United States )
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.
|ISSN : ||1553-7404|
|Mesh Heading : ||Animals Cell Line Interferon Regulatory Factor-3 Interferon-beta Listeria Infections Mice Mice, Inbred BALB C Mice, Inbred C57BL RNA, Messenger Reverse Transcriptase Polymerase Chain Reaction Signal Transduction genetics genetics genetics|
|Mesh Heading Relevant : ||Polymorphism, Genetic genetics biosynthesis metabolism|
Listeria monocytogenes as a probe of immune function.
Journal - Briefings in functional genomics & proteomics (England )
For almost half a century, the mouse model of Listeria monocytogenes infection has been used to analyse both innate and adaptive components of immunity and to discover key immune genes. Vast accumulated knowledge about the disease in mice provides a unique framework for identifying and characterising immune molecules using a variety of experimental approaches. To illustrate the range of questions that can be addressed using modern genetics and genomics tools, the authors provide an overview of the analysis of components of immune signalling networks using the mouse model of L. monocytogenes infection.
|ISSN : ||1473-9550|
|Mesh Heading : ||Animals Complement C5 Genetic Variation Genetics Genome Genomics Humans Immune System Immunity, Active Immunity, Innate Listeria Infections Listeria monocytogenes Mice Mutation Oligonucleotide Array Sequence Analysis Promoter Regions, Genetic Signal Transduction Transgenes genetics pathology genetics|
|Mesh Heading Relevant : ||metabolism|