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These processes include motility, biofilm formation, cell division, differentiation, and virulence. The role of cyclic diguanylate signaling in the lifestyle of<jats:named-content content-type=\"genus-species\">Legionella pneumophila<\/jats:named-content>, the causative agent of Legionnaires\u2019 disease, has not previously been examined. The<jats:named-content content-type=\"genus-species\">L. pneumophila<\/jats:named-content>genome encodes 22 predicted proteins containing domains related to cyclic diguanylate synthesis, hydrolysis, and recognition. We refer to these genes as<jats:italic>cdgS<\/jats:italic>(<jats:italic>c<\/jats:italic>yclic<jats:italic>d<\/jats:italic>iguanylate<jats:italic>s<\/jats:italic>ignaling) genes. Strains of<jats:named-content content-type=\"genus-species\">L. pneumophila<\/jats:named-content>containing deletions of all individual<jats:italic>cdgS<\/jats:italic>genes were created and did not exhibit any observable growth defect in growth medium or inside host cells. However, when overexpressed, several<jats:italic>cdgS<\/jats:italic>genes strongly decreased the ability of<jats:named-content content-type=\"genus-species\">L. pneumophila<\/jats:named-content>to grow inside host cells. Expression of these<jats:italic>cdgS<\/jats:italic>genes did not affect the Dot\/Icm type IVB secretion system, the major determinant of intracellular growth in<jats:named-content content-type=\"genus-species\">L. pneumophila<\/jats:named-content>.<jats:named-content content-type=\"genus-species\">L. pneumophila<\/jats:named-content>strains overexpressing these<jats:italic>cdgS<\/jats:italic>genes were less cytotoxic to THP-1 macrophages than wild-type<jats:named-content content-type=\"genus-species\">L. pneumophila<\/jats:named-content>but retained the ability to resist grazing by amoebae. In many cases, the intracellular-growth inhibition caused by<jats:italic>cdgS<\/jats:italic>gene overexpression was independent of diguanylate cyclase or phosphodiesterase activities. Expression of the<jats:italic>cdgS<\/jats:italic>genes in a<jats:named-content content-type=\"genus-species\">Salmonella enterica<\/jats:named-content>serovar Enteritidis strain that lacks all diguanylate cyclase activity indicated that several<jats:italic>cdgS<\/jats:italic>genes encode potential cyclases. These results indicate that components of the cyclic diguanylate signaling pathway play an important role in regulating the ability of<jats:named-content content-type=\"genus-species\">L. pneumophila<\/jats:named-content>to grow in host cells.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>All bacteria must sense and respond to environmental cues. Intracellular bacterial pathogens must detect and respond to host functions that limit their ability to carry out a successful infection. Small-molecule second messengers play key roles in transmitting signals from environmental receptors to the proteins and other components that respond to signals. Cyclic diguanylate is a ubiquitous bacterial second messenger known to play an important role in many sensing and signaling systems in bacteria. The causative agent of Legionnaires\u2019 disease,<jats:named-content content-type=\"genus-species\">Legionella pneumophila<\/jats:named-content>, is an intracellular pathogen that grows inside environmental protists and human macrophages by subverting the normal processes that these cells use to capture and destroy bacteria. We show that the several cyclic diguanylate signaling components in<jats:italic>Legionella<\/jats:italic>play a role in the ability to grow inside both kinds of host cells. This work highlights the role of cyclic diguanylate signaling during intracellular growth.<\/jats:p>","DOI":"10.1128\/mbio.00316-10","type":"journal-article","created":{"date-parts":[[2011,1,12]],"date-time":"2011-01-12T03:20:32Z","timestamp":1294802432000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":49,"title":["Cyclic Diguanylate Signaling Proteins Control Intracellular Growth of Legionella pneumophila"],"prefix":"10.1128","volume":"2","author":[{"given":"Assaf","family":"Levi","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Folcher","sequence":"additional","affiliation":[{"name":"ETH Z\u00fcrich, Department of Biosystems Science and Engineering (D-BSSE), Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urs","family":"Jenal","sequence":"additional","affiliation":[{"name":"Biozentrum, University of Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard A.","family":"Shuman","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0966-842X(96)10041-X"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2002.tb00607.x"},{"key":"e_1_3_2_4_2","first-page":"32","article-title":"Community-acquired Legionnaires\u2019 disease","volume":"4","author":"Muder R. 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