{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:46:11Z","timestamp":1791294371527,"version":"4.1.0"},"reference-count":51,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2013,5,28]],"date-time":"2013-05-28T00:00:00Z","timestamp":1369699200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2013,7,1]],"date-time":"2013-07-01T00:00:00Z","timestamp":1372636800000},"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":["mBio"],"published-print":{"date-parts":[[2013,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    <jats:named-content content-type=\"genus-species\">Listeria monocytogenes<\/jats:named-content>\n                    infection leads to robust induction of an innate immune signaling pathway referred to as the cytosolic surveillance pathway (CSP), characterized by expression of beta interferon (IFN-\u03b2) and coregulated genes. We previously identified the IFN-\u03b2 stimulatory ligand as secreted cyclic di-AMP. Synthesis of c-di-AMP in\n                    <jats:named-content content-type=\"genus-species\">L. monocytogenes<\/jats:named-content>\n                    is catalyzed by the diadenylate cyclase DacA, and multidrug resistance transporters are necessary for secretion. To identify additional bacterial factors involved in\n                    <jats:named-content content-type=\"genus-species\">L. monocytogenes<\/jats:named-content>\n                    detection by the CSP, we performed a forward genetic screen for mutants that induced altered levels of IFN-\u03b2. One mutant that stimulated elevated levels of IFN-\u03b2 harbored a transposon insertion in the gene\n                    <jats:italic>lmo0052<\/jats:italic>\n                    . Lmo0052, renamed here PdeA, has homology to a cyclic di-AMP phosphodiesterase, GdpP (formerly YybT), of\n                    <jats:named-content content-type=\"genus-species\">Bacillus subtilis<\/jats:named-content>\n                    and is able to degrade c-di-AMP to the linear dinucleotide pApA. Reduction of c-di-AMP levels by conditional depletion of the di-adenylate cyclase DacA or overexpression of PdeA led to marked decreases in growth rates, both\n                    <jats:italic>in vitro<\/jats:italic>\n                    and in macrophages. Additionally, mutants with altered levels of c-di-AMP had different susceptibilities to peptidoglycan-targeting antibiotics, suggesting that the molecule may be involved in regulating cell wall homeostasis. During intracellular infection, increases in c-di-AMP production led to hyperactivation of the CSP. Conditional depletion of\n                    <jats:italic>dacA<\/jats:italic>\n                    also led to increased IFN-\u03b2 expression and a concomitant increase in host cell pyroptosis, a result of increased bacteriolysis and subsequent bacterial DNA release. These data suggest that c-di-AMP coordinates bacterial growth, cell wall stability, and responses to stress and plays a crucial role in the establishment of bacterial infection.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    <jats:named-content content-type=\"genus-species\">Listeria monocytogenes<\/jats:named-content>\n                    is a Gram-positive intracellular pathogen and the causative agent of the food-borne illness listeriosis. Upon infection,\n                    <jats:named-content content-type=\"genus-species\">L. monocytogenes<\/jats:named-content>\n                    stimulates expression of IFN-\u03b2 and coregulated genes dependent upon host detection of a secreted bacterial signaling nucleotide, c-di-AMP. Using a forward genetic screen for mutants that induced high levels of host IFN-\u03b2 expression, we identified a c-di-AMP phosphodiesterase, PdeA, that degrades c-di-AMP. Here we characterize\n                    <jats:named-content content-type=\"genus-species\">L. monocytogenes<\/jats:named-content>\n                    mutants that express enhanced or diminished levels of c-di-AMP. Decreased c-di-AMP levels by conditional depletion of the diadenylate cyclase (DacA) or overexpression of PdeA attenuated bacterial growth and led to bacteriolysis, suggesting that its production is essential for viability and may regulate cell wall metabolism. Mutants lacking PdeA had a distinct transcriptional profile, which may provide insight into additional roles for the molecule. This work demonstrates that c-di-AMP is a critical signaling molecule required for bacterial replication, cell wall stability, and pathogenicity.\n                  <\/jats:p>","DOI":"10.1128\/mbio.00282-13","type":"journal-article","created":{"date-parts":[[2013,5,29]],"date-time":"2013-05-29T00:23:49Z","timestamp":1369787029000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":187,"title":["Cyclic di-AMP Is Critical for Listeria monocytogenes Growth, Cell Wall Homeostasis, and Establishment of Infection"],"prefix":"10.1128","volume":"4","author":[{"given":"Chelsea E.","family":"Witte","sequence":"first","affiliation":[{"name":"Graduate Group in Microbiology, School of Public Health, University of California, Berkeley, Berkeley, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron T.","family":"Whiteley","sequence":"additional","affiliation":[{"name":"Graduate Group in Infectious Diseases and Immunity, School of Public Health, University of California, Berkeley, Berkeley, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas P.","family":"Burke","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John-Demian","family":"Sauer","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel A.","family":"Portnoy","sequence":"additional","affiliation":[{"name":"Graduate Group in Microbiology, School of Public Health, University of California, Berkeley, Berkeley, California, USA"},{"name":"Graduate Group in Infectious Diseases and Immunity, School of Public Health, University of California, Berkeley, Berkeley, California, USA"},{"name":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua J.","family":"Woodward","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1413"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-394590-7.00002-6"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2010.04.004"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.202476699"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00999-10"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10429"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2460"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1189801"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0804170105"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.040238"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00390-08"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/9781555816513"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.73.8.5065-5073.2005"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2011.77"},{"key":"e_1_3_2_16_2","doi-asserted-by":"crossref","unstructured":"CorriganRM AbbottJC BurhenneH KaeverV Gr\u00fcndlingA . 2011. c-di-AMP is a new second messenger in Staphylococcus aureus with a role in controlling cell size and envelope stress. 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