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Restriction of L egionella pneumophila Replication in Macrophages Requires Concerted Action of the Transcriptional Regulators Irf1 and Irf8 and Nod...
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| Zeitschriftentitel: | Infection and Immunity |
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| Personen und Körperschaften: | , , , , |
| In: | Infection and Immunity, 77, 2009, 11, S. 4794-4805 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society for Microbiology
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| Schlagwörter: |
| Zusammenfassung: | <jats:title>ABSTRACT</jats:title> <jats:p> The unique permissiveness of A/J mouse macrophages for replication of <jats:italic>Legionella pneumophila</jats:italic> is caused by a deficiency in the Nod-like receptor (NLR) protein and intracellular sensor for <jats:italic>L. pneumophila</jats:italic> flagellin ( <jats:italic>Naip5</jats:italic> ). The signaling pathways and proteins activated by Naip5 sensing in macrophages were investigated. Transcript profiling of macrophages from susceptible A/J mice and from resistant A/J mice harboring a transgenic wild-type copy of <jats:italic>Naip5</jats:italic> at 4 h following <jats:italic>L. pneumophila</jats:italic> infection suggested that two members of the Irf transcriptional regulator family, Irf1 and Irf8, are regulated in response to Naip5 sensing of <jats:italic>L. pneumophila</jats:italic> . We show that macrophages having defective alleles of either <jats:italic>Irf1</jats:italic> ( <jats:italic>Irf1</jats:italic> <jats:sup>−</jats:sup> <jats:sup>/</jats:sup> <jats:sup>−</jats:sup> ) or its heterodimerization partner gene <jats:italic>Irf8</jats:italic> ( <jats:italic> Irf8 <jats:sup>R294C</jats:sup> </jats:italic> ) become permissive for <jats:italic>L. pneumophila</jats:italic> replication, indicating that both the Irf1 and Irf8 proteins are essential for macrophage defense against <jats:italic>L. pneumophila</jats:italic> . Moreover, macrophages doubly heterozygous ( <jats:italic> Naip5 <jats:sup>AJ/WT</jats:sup> Irf8 <jats:sup>R294C/WT</jats:sup> </jats:italic> or <jats:italic>Nlrc4</jats:italic> <jats:sup>−/+</jats:sup> <jats:italic> Irf8 <jats:sup>R294C/WT</jats:sup> </jats:italic> ) for combined loss-of-function mutations in <jats:italic>Irf8</jats:italic> and in either <jats:italic>Naip5</jats:italic> or <jats:italic>Nlrc4</jats:italic> are highly susceptible to <jats:italic>L. pneumophila</jats:italic> , indicating that there is a strong genetic interaction between <jats:italic>Irf8</jats:italic> and the NLR protein family in the macrophage response to <jats:italic>L. pneumophila. Legionella</jats:italic> -containing phagosomes (LCPs) formed in permissive <jats:italic>Irf1</jats:italic> <jats:sup>−</jats:sup> <jats:sup>/</jats:sup> <jats:sup>−</jats:sup> or <jats:italic> Irf8 <jats:sup>R294C</jats:sup> </jats:italic> macrophages behave like LCPs formed in <jats:italic>Naip5</jats:italic> -insufficient and <jats:italic>Nlrc4</jats:italic> -deficient macrophages which fail to acidify. These results suggest that, in addition to <jats:italic>Naip5</jats:italic> and <jats:italic>Nlrc4</jats:italic> , <jats:italic>Irf1</jats:italic> and <jats:italic>Irf8</jats:italic> play a critical role in the early response of macrophages to infection with <jats:italic>L. pneumophila</jats:italic> , including antagonizing the ability of <jats:italic>L. pneumophila</jats:italic> to block phagosome acidification. They also suggest that flagellin sensing by the NLR proteins Naip5 and Nlrc4 may be coupled to Irf1-Irf8-mediated transcriptional activation of key effector genes essential for macrophage resistance to <jats:italic>L. pneumophila</jats:italic> infection. </jats:p> |
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| Umfang: | 4794-4805 |
| ISSN: |
0019-9567
1098-5522 |
| DOI: | 10.1128/iai.01546-08 |