{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T07:19:44Z","timestamp":1790752784947,"version":"4.1.0"},"reference-count":47,"publisher":"National Academy of Sciences","issue":"6","license":[{"start":{"date-parts":[[2019,7,18]],"date-time":"2019-07-18T00:00:00Z","timestamp":1563408000000},"content-version":"vor","delay-in-days":181,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-10-LABX-62-IBEID"],"award-info":[{"award-number":["ANR-10-LABX-62-IBEID"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche Medicale","doi-asserted-by":"crossref","award":["DEQ20120323697"],"award-info":[{"award-number":["DEQ20120323697"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,2,5]]},"abstract":"<jats:p>\n                    The genus\n                    <jats:italic>Legionella<\/jats:italic>\n                    comprises 65 species, among which\n                    <jats:italic>Legionella pneumophila<\/jats:italic>\n                    is a human pathogen causing severe pneumonia. To understand the evolution of an environmental to an accidental human pathogen, we have functionally analyzed 80\n                    <jats:italic>Legionella<\/jats:italic>\n                    genomes spanning 58 species. Uniquely, an immense repository of 18,000 secreted proteins encoding 137 different eukaryotic-like domains and over 200 eukaryotic-like proteins is paired with a highly conserved type IV secretion system (T4SS). Specifically, we show that eukaryotic Rho- and Rab-GTPase domains are found nearly exclusively in eukaryotes and\n                    <jats:italic>Legionella<\/jats:italic>\n                    . Translocation assays for selected Rab-GTPase proteins revealed that they are indeed T4SS secreted substrates. Furthermore, F-box, U-box, and SET domains were present in &gt;70% of all species, suggesting that manipulation of host signal transduction, protein turnover, and chromatin modification pathways are fundamental intracellular replication strategies for legionellae. In contrast, the Sec-7 domain was restricted to\n                    <jats:italic>L. pneumophila<\/jats:italic>\n                    and seven other species, indicating effector repertoire tailoring within different amoebae. Functional screening of 47 species revealed 60% were competent for intracellular replication in THP-1 cells, but interestingly, this phenotype was associated with diverse effector assemblages. These data, combined with evolutionary analysis, indicate that the capacity to infect eukaryotic cells has been acquired independently many times within the genus and that a highly conserved yet versatile T4SS secretes an exceptional number of different proteins shaped by interdomain gene transfer. Furthermore, we revealed the surprising extent to which legionellae have coopted genes and thus cellular functions from their eukaryotic hosts, providing an understanding of how dynamic reshuffling and gene acquisition have led to the emergence of major human pathogens.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1808016116","type":"journal-article","created":{"date-parts":[[2019,1,18]],"date-time":"2019-01-18T20:36:00Z","timestamp":1547843760000},"page":"2265-2273","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":256,"title":["More than 18,000 effectors in the\n                    <i>Legionella<\/i>\n                    genus genome provide multiple, independent combinations for replication in human cells"],"prefix":"10.1073","volume":"116","author":[{"given":"Laura","family":"Gomez-Valero","sequence":"first","affiliation":[{"name":"Institut Pasteur, Biologie des Bact\u00e9ries Intracellulaires, 75724 Paris, France;"},{"name":"CNRS UMR 3525, 75724 Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Rusniok","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Biologie des Bact\u00e9ries Intracellulaires, 75724 Paris, France;"},{"name":"CNRS UMR 3525, 75724 Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Carson","sequence":"additional","affiliation":[{"name":"Medical Research Council Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Mondino","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Biologie des Bact\u00e9ries Intracellulaires, 75724 Paris, France;"},{"name":"CNRS UMR 3525, 75724 Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana 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Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Reuter","sequence":"additional","affiliation":[{"name":"Pathogen Genomics, Wellcome Trust Sanger Institute, CB10 1SA Cambridge, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmin","family":"Demirtas","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Biologie des Bact\u00e9ries Intracellulaires, 75724 Paris, France;"},{"name":"CNRS UMR 3525, 75724 Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Crumbach","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Biologie des Bact\u00e9ries Intracellulaires, 75724 Paris, France;"},{"name":"CNRS UMR 3525, 75724 Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephane","family":"Descorps-Declere","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Center of Bioinformatics, Biostatistics and Integrative Biology, 75724 Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth L.","family":"Hartland","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia;"},{"name":"Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia;"},{"name":"Department of Molecular and Translational Science, Monash University, Clayton, VIC 3168, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Jarraud","sequence":"additional","affiliation":[{"name":"International Center for Infectiology Research, INSERM, U1111, CNRS, UMR 5308, Universit\u00e9 Lyon 1, \u00c9cole Normale Sup\u00e9rieure de Lyon, F-69008 Lyon, France;"},{"name":"National Reference Centre of Legionella, Hospices Civils de Lyon, 69317 Lyon, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon","family":"Dougan","sequence":"additional","affiliation":[{"name":"Pathogen Genomics, Wellcome Trust Sanger Institute, CB10 1SA Cambridge, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnar N.","family":"Schroeder","sequence":"additional","affiliation":[{"name":"Medical Research Council Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom;"},{"name":"Centre for Experimental Medicine, Queen\u2019s University Belfast, Belfast BT9 7BL, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gad","family":"Frankel","sequence":"additional","affiliation":[{"name":"Medical Research Council Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College London, London SW7 2AZ, United 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