{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T06:13:24Z","timestamp":1790489604174,"version":"4.1.0"},"reference-count":57,"publisher":"American Society for Microbiology","issue":"11","license":[{"start":{"date-parts":[[2009,11,1]],"date-time":"2009-11-01T00:00:00Z","timestamp":1257033600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Infect Immun"],"published-print":{"date-parts":[[2009,11]]},"abstract":"ABSTRACT<\/jats:title>\n \n The unique permissiveness of A\/J mouse macrophages for replication of\n Legionella pneumophila<\/jats:italic>\n is caused by a deficiency in the Nod-like receptor (NLR) protein and intracellular sensor for\n L. pneumophila<\/jats:italic>\n flagellin (\n Naip5<\/jats:italic>\n ). 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\n Naip5<\/jats:italic>\n at 4 h following\n L. pneumophila<\/jats:italic>\n infection suggested that two members of the Irf transcriptional regulator family, Irf1 and Irf8, are regulated in response to Naip5 sensing of\n L. pneumophila<\/jats:italic>\n . We show that macrophages having defective alleles of either\n Irf1<\/jats:italic>\n (\n Irf1<\/jats:italic>\n \u2212<\/jats:sup>\n \/<\/jats:sup>\n \u2212<\/jats:sup>\n ) or its heterodimerization partner gene\n Irf8<\/jats:italic>\n (\n \n Irf8\n R294C<\/jats:sup>\n <\/jats:italic>\n ) become permissive for\n L. pneumophila<\/jats:italic>\n replication, indicating that both the Irf1 and Irf8 proteins are essential for macrophage defense against\n L. pneumophila<\/jats:italic>\n . Moreover, macrophages doubly heterozygous (\n \n Naip5\n AJ\/WT<\/jats:sup>\n Irf8\n R294C\/WT<\/jats:sup>\n <\/jats:italic>\n or\n Nlrc4<\/jats:italic>\n \u2212\/+<\/jats:sup>\n \n Irf8\n R294C\/WT<\/jats:sup>\n <\/jats:italic>\n ) for combined loss-of-function mutations in\n Irf8<\/jats:italic>\n and in either\n Naip5<\/jats:italic>\n or\n Nlrc4<\/jats:italic>\n are highly susceptible to\n L. pneumophila<\/jats:italic>\n , indicating that there is a strong genetic interaction between\n Irf8<\/jats:italic>\n and the NLR protein family in the macrophage response to\n L. pneumophila. Legionella<\/jats:italic>\n -containing phagosomes (LCPs) formed in permissive\n Irf1<\/jats:italic>\n \u2212<\/jats:sup>\n \/<\/jats:sup>\n \u2212<\/jats:sup>\n or\n \n Irf8\n R294C<\/jats:sup>\n <\/jats:italic>\n macrophages behave like LCPs formed in\n Naip5<\/jats:italic>\n -insufficient and\n Nlrc4<\/jats:italic>\n -deficient macrophages which fail to acidify. These results suggest that, in addition to\n Naip5<\/jats:italic>\n and\n Nlrc4<\/jats:italic>\n ,\n Irf1<\/jats:italic>\n and\n Irf8<\/jats:italic>\n play a critical role in the early response of macrophages to infection with\n L. pneumophila<\/jats:italic>\n , including antagonizing the ability of\n L. pneumophila<\/jats:italic>\n 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\n L. pneumophila<\/jats:italic>\n infection.\n <\/jats:p>","DOI":"10.1128\/iai.01546-08","type":"journal-article","created":{"date-parts":[[2009,9,1]],"date-time":"2009-09-01T00:58:42Z","timestamp":1251766722000},"page":"4794-4805","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":36,"title":["Restriction of\n L<\/i>\n egionella pneumophila<\/i>\n Replication in Macrophages Requires Concerted Action of the Transcriptional Regulators Irf1 and Irf8 and Nod-Like Receptors Naip5 and Nlrc4"],"prefix":"10.1128","volume":"77","author":[{"given":"Anne","family":"Fortier","sequence":"first","affiliation":[{"name":"Department of Biochemistry"},{"name":"Center for the Study of Host Resistance, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Doiron","sequence":"additional","affiliation":[{"name":"Department of Biochemistry"},{"name":"Center for the Study of Host Resistance, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Saleh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry"},{"name":"Center for the Study of Host Resistance, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Grinstein","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Hospital for Sick Children, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Gros","sequence":"additional","affiliation":[{"name":"Department of Biochemistry"},{"name":"Center for the Study of Host Resistance, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M604933200"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.1994.tb01317.x"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01382-08"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.181.1.257"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2007.00963.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.72.11.6221-6229.2004"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s003359900536"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1065"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2006.00839.x"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2005.05.007"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1346"},{"key":"e_1_3_2_13_2","first-page":"1","volume":"10","year":"2008","unstructured":"Franchi, L., J. 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