{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:55:10Z","timestamp":1790744110730,"version":"4.1.0"},"reference-count":48,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2015,3,10]],"date-time":"2015-03-10T00:00:00Z","timestamp":1425945600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2015,5,1]],"date-time":"2015-05-01T00:00:00Z","timestamp":1430438400000},"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":[[2015,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The M1T1 clone of group A Streptococcus (GAS) is associated with severe invasive infections, including necrotizing fasciitis and septicemia. During invasive M1T1 GAS disease, mutations in the\n            <jats:italic>covRS<\/jats:italic>\n            regulatory system led to upregulation of an ADP-ribosyltransferase, SpyA. Surprisingly, a GAS \u0394\n            <jats:italic>spyA<\/jats:italic>\n            mutant was resistant to killing by macrophages and caused higher mortality with impaired bacterial clearance in a mouse intravenous challenge model. GAS expression of SpyA triggered macrophage cell death in association with caspase-1-dependent interleukin 1\u03b2 (IL-1\u03b2) production, and differences between wild-type (WT) and \u0394\n            <jats:italic>spyA<\/jats:italic>\n            GAS macrophage survival levels were lost in cells lacking caspase-1, NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), or pro-IL-1\u03b2. Similar\n            <jats:italic>in vitro<\/jats:italic>\n            findings were identified in macrophage studies performed with pseudomonal exotoxin A, another ADP-ribosylating toxin. Thus, SpyA triggers caspase-1-dependent inflammatory cell death in macrophages, revealing a toxin-triggered IL-1\u03b2-dependent innate immune response pathway critical in defense against invasive bacterial infection.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            Group A Streptococcus (GAS) is a leading human pathogen capable of producing invasive infections even in healthy individuals. GAS bacteria produce a toxin called SpyA that modifies host proteins through a process called ADP ribosylation. We describe how macrophages, frontline defenders of the host innate immune system, respond to SpyA by undergoing a specialized form of cell death in which they are activated to release the proinflammatory cytokine molecule interleukin 1\u03b2 (IL-1\u03b2). Release of IL-1\u03b2 activates host immune cell clearance of GAS, as we demonstrated in tissue culture models of macrophage bacterial killing and\n            <jats:italic>in vivo<\/jats:italic>\n            mouse infectious-challenge experiments. Similar macrophage responses to a related toxin of\n            <jats:italic>Pseudomonas<\/jats:italic>\n            bacteria were also shown. Thus, macrophages recognize certain bacterial toxins to activate a protective immune response in the host.\n          <\/jats:p>","DOI":"10.1128\/mbio.00133-15","type":"journal-article","created":{"date-parts":[[2015,3,11]],"date-time":"2015-03-11T01:13:22Z","timestamp":1426036402000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":40,"title":["A Group A Streptococcus ADP-Ribosyltransferase Toxin Stimulates a Protective Interleukin 1\u03b2-Dependent Macrophage Immune Response"],"prefix":"10.1128","volume":"6","author":[{"given":"Ann E.","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico C.","family":"Beasley","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Keller","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Hollands","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodolfo","family":"Urbano","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily R.","family":"Troemel","sequence":"additional","affiliation":[{"name":"Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hal M.","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, California, USA"},{"name":"Department of Medicine, University of California, San Diego, La Jolla, California, USA"},{"name":"Rady Children's Hospital, San Diego, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Nizet","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, California, USA"},{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA"},{"name":"Rady Children's Hospital, San Diego, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(05)70267-X"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1410.071660"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.0020005"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2648"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1612"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00191-10"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1159\/000317640"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2004.04262.x"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2012.07979.x"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01191-10"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.micro.62.081307.162848"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.370791"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2231"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2013.11.008"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032712-095944"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2070"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2012.11.009"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1202688"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000661"},{"key":"e_1_3_2_21_2","doi-asserted-by":"crossref","unstructured":"Dinarello CA. 1996. 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