{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T01:10:52Z","timestamp":1791421852778,"version":"4.3.3"},"reference-count":46,"publisher":"Rockefeller University Press","issue":"5","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54 AI057159"],"award-info":[{"award-number":["U54 AI057159"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AI070999"],"award-info":[{"award-number":["R01 AI070999"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,5,1]]},"abstract":"<jats:p>The spores of pathogenic bacteria are involved in host entry and the initial encounter with the host immune system. How bacterial spores interact with host immunity, however, remains poorly understood. Here, we show that the spores of Bacillus anthracis (BA), the etiologic agent of anthrax, possess an intrinsic ability to induce host immune responses. This immunostimulatory activity is attributable to high amounts of RNA present in the spore surface layer. RNA-sensing TLRs, TLR7, and TLR13 in mice and their human counterparts, are responsible for detecting and triggering the host cell response to BA spores, whereas TLR2 mediates the sensing of vegetative BA. BA spores, but not vegetative BA, induce type I IFN (IFN-I) production. Although TLR signaling in itself affords protection against BA, spore RNA\u2013induced IFN-I signaling is disruptive to BA clearance. Our study suggests a role for bacterial spore\u2013associated RNA in microbial pathogenesis and illustrates a little known aspect of interactions between the host and spore-forming bacteria.<\/jats:p>","DOI":"10.1084\/jem.20161141","type":"journal-article","created":{"date-parts":[[2017,4,11]],"date-time":"2017-04-11T10:20:38Z","timestamp":1491906038000},"page":"1297-1311","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["TLR sensing of bacterial spore-associated RNA triggers host immune responses with detrimental effects"],"prefix":"10.1084","volume":"214","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1492-7539","authenticated-orcid":true,"given":"Min-Kyung","family":"Choo","sequence":"first","affiliation":[{"name":"Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuyo","family":"Sano","sequence":"additional","affiliation":[{"name":"Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1087-0424","authenticated-orcid":true,"given":"Changhoon","family":"Kim","sequence":"additional","affiliation":[{"name":"Macrogen Inc., Seoul 08511, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6791-4531","authenticated-orcid":true,"given":"Kei","family":"Yasuda","sequence":"additional","affiliation":[{"name":"Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4349-6996","authenticated-orcid":true,"given":"Xiao-Dong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0956-3654","authenticated-orcid":true,"given":"Xin","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Stenzel-Poore","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4619-697X","authenticated-orcid":true,"given":"Lena","family":"Alexopoulou","sequence":"additional","affiliation":[{"name":"Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Universit\u00e9, UM2, 13288 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3227-0588","authenticated-orcid":true,"given":"Sankar","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1488-5666","authenticated-orcid":true,"given":"Eicke","family":"Latz","sequence":"additional","affiliation":[{"name":"Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2674-3991","authenticated-orcid":true,"given":"Ian R.","family":"Rifkin","sequence":"additional","affiliation":[{"name":"Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijian J.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4766-160X","authenticated-orcid":true,"given":"George C.","family":"Stewart","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology and Bond Life Science Center, University of Missouri, Columbia, MO 65211"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyonyong","family":"Chong","sequence":"additional","affiliation":[{"name":"Macrogen Inc., Seoul 08511, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3458-5583","authenticated-orcid":true,"given":"Jin Mo","family":"Park","sequence":"additional","affiliation":[{"name":"Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2017,4,11]]},"reference":[{"key":"2020012721470303600_bib1","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1038\/nature12331","article-title":"Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota","volume":"500","author":"Atarashi","year":"2013","journal-title":"Nature."},{"key":"2020012721470303600_bib2","doi-asserted-by":"publisher","first-page":"2351","DOI":"10.1128\/IAI.01982-06","article-title":"Role of Bacillus anthracis spore structures in macrophage cytokine responses","volume":"75","author":"Basu","year":"2007","journal-title":"Infect. Immun."},{"key":"2020012721470303600_bib3","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1038\/nature17645","article-title":"Culturing of \u2018unculturable\u2019 human microbiota reveals novel taxa and extensive sporulation","volume":"533","author":"Browne","year":"2016","journal-title":"Nature."},{"key":"2020012721470303600_bib4","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1056\/NEJM199909093411107","article-title":"Anthrax","volume":"341","author":"Dixon","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"2020012721470303600_bib5","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1128\/JB.87.2.323-328.1964","article-title":"Ribonucleic acids of Bacillus subtilis spores and sporulating cells","volume":"87","author":"Doi","year":"1964","journal-title":"J. Bacteriol."},{"key":"2020012721470303600_bib6","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1016\/j.clnu.2012.05.016","article-title":"Spores from two distinct colony types of the strain Bacillus subtilis PB6 substantiate anti-inflammatory probiotic effects in mice","volume":"31","author":"Folign\u00e9","year":"2012","journal-title":"Clin. Nutr."},{"key":"2020012721470303600_bib7","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1128\/IAI.05988-11","article-title":"Differential role of the interleukin-17 axis and neutrophils in resolution of inhalational anthrax","volume":"80","author":"Garraud","year":"2012","journal-title":"Infect. Immun."},{"key":"2020012721470303600_bib8","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1084\/jem.20111044","article-title":"Identification of modifications in microbial, native tRNA that suppress immunostimulatory activity","volume":"209","author":"Gehrig","year":"2012","journal-title":"J. Exp. Med."},{"key":"2020012721470303600_bib9","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1128\/JB.00921-06","article-title":"Morphogenesis of the Bacillus anthracis spore","volume":"189","author":"Giorno","year":"2007","journal-title":"J. Bacteriol."},{"key":"2020012721470303600_bib10","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1111\/j.1462-5822.2006.00806.x","article-title":"Murine splenocytes produce inflammatory cytokines in a MyD88-dependent response to Bacillus anthracis spores","volume":"9","author":"Glomski","year":"2007","journal-title":"Cell. Microbiol."},{"key":"2020012721470303600_bib11","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.immuni.2011.02.006","article-title":"Type I interferon inhibits interleukin-1 production and inflammasome activation","volume":"34","author":"Guarda","year":"2011","journal-title":"Immunity."},{"key":"2020012721470303600_bib12","doi-asserted-by":"publisher","first-page":"1680","DOI":"10.1172\/JCI33342","article-title":"The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice","volume":"118","author":"Guo","year":"2008","journal-title":"J. Clin. Invest."},{"key":"2020012721470303600_bib13","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1146\/annurev.micro.61.080706.093224","article-title":"Structure, assembly, and function of the spore surface layers","volume":"61","author":"Henriques","year":"2007","journal-title":"Annu. Rev. Microbiol."},{"key":"2020012721470303600_bib14","doi-asserted-by":"publisher","first-page":"2717","DOI":"10.4049\/jimmunol.1200898","article-title":"Cutting edge: TLR13 is a receptor for bacterial RNA","volume":"189","author":"Hidmark","year":"2012","journal-title":"J. Immunol."},{"key":"2020012721470303600_bib15","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1111\/j.1574-695X.2008.00415.x","article-title":"Immunostimulatory activity of Bacillus spores","volume":"53","author":"Huang","year":"2008","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"2020012721470303600_bib16","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1016\/j.cell.2009.09.033","article-title":"Induction of intestinal Th17 cells by segmented filamentous bacteria","volume":"139","author":"Ivanov","year":"2009","journal-title":"Cell."},{"key":"2020012721470303600_bib17","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1038\/ni.3123","article-title":"Control of adaptive immunity by the innate immune system","volume":"16","author":"Iwasaki","year":"2015","journal-title":"Nat. Immunol."},{"key":"2020012721470303600_bib18","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1128\/JB.119.2.514-521.1974","article-title":"Messenger ribonucleic acid of dormant spores of Bacillus subtilis","volume":"119","author":"Jeng","year":"1974","journal-title":"J. Bacteriol."},{"key":"2020012721470303600_bib19","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1084\/jem.20111075","article-title":"The 2\u2032-O-methylation status of a single guanosine controls transfer RNA-mediated Toll-like receptor 7 activation or inhibition","volume":"209","author":"J\u00f6ckel","year":"2012","journal-title":"J. Exp. Med."},{"key":"2020012721470303600_bib20","doi-asserted-by":"publisher","first-page":"1656","DOI":"10.15252\/embr.201540861","article-title":"Human TLR8 senses UR\/URR motifs in bacterial and mitochondrial RNA","volume":"16","author":"Kr\u00fcger","year":"2015","journal-title":"EMBO Rep."},{"key":"2020012721470303600_bib21","doi-asserted-by":"publisher","first-page":"1647","DOI":"10.1128\/CVI.00135-10","article-title":"Development of a Bacillus subtilis-based rotavirus vaccine","volume":"17","author":"Lee","year":"2010","journal-title":"Clin. Vaccine Immunol."},{"key":"2020012721470303600_bib22","doi-asserted-by":"publisher","first-page":"e00102","DOI":"10.7554\/eLife.00102","article-title":"Sequence specific detection of bacterial 23S ribosomal RNA by TLR13","volume":"1","author":"Li","year":"2012","journal-title":"eLife."},{"key":"2020012721470303600_bib23","doi-asserted-by":"publisher","first-page":"aaa2630","DOI":"10.1126\/science.aaa2630","article-title":"Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation","volume":"347","author":"Liu","year":"2015","journal-title":"Science."},{"key":"2020012721470303600_bib24","doi-asserted-by":"publisher","first-page":"4801","DOI":"10.1128\/IAI.72.8.4801-4809.2004","article-title":"Murine model of pulmonary anthrax: kinetics of dissemination, histopathology, and mouse strain susceptibility","volume":"72","author":"Lyons","year":"2004","journal-title":"Infect. Immun."},{"key":"2020012721470303600_bib25","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1128\/JB.101.1.196-201.1970","article-title":"Chemical composition of exosporium from spores of Bacillus cereus","volume":"101","author":"Matz","year":"1970","journal-title":"J. Bacteriol."},{"key":"2020012721470303600_bib26","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/nrmicro2921","article-title":"The Bacillus subtilis endospore: assembly and functions of the multilayered coat","volume":"11","author":"McKenney","year":"2013","journal-title":"Nat. Rev. Microbiol."},{"key":"2020012721470303600_bib27","doi-asserted-by":"publisher","first-page":"e1001222","DOI":"10.1371\/journal.ppat.1001222","article-title":"Inflammasome sensor Nlrp1b-dependent resistance to anthrax is mediated by caspase-1, IL-1 signaling and neutrophil recruitment","volume":"6","author":"Moayeri","year":"2010","journal-title":"PLoS Pathog."},{"key":"2020012721470303600_bib28","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1146\/annurev-micro-091014-104523","article-title":"Anthrax Pathogenesis","volume":"69","author":"Moayeri","year":"2015","journal-title":"Annu. Rev. Microbiol."},{"key":"2020012721470303600_bib29","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1126\/science.1220363","article-title":"TLR13 recognizes bacterial 23S rRNA devoid of erythromycin resistance-forming modification","volume":"337","author":"Oldenburg","year":"2012","journal-title":"Science."},{"key":"2020012721470303600_bib30","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1016\/j.tim.2014.04.003","article-title":"Clostridium difficile spore biology: sporulation, germination, and spore structural proteins","volume":"22","author":"Paredes-Sabja","year":"2014","journal-title":"Trends Microbiol."},{"key":"2020012721470303600_bib31","doi-asserted-by":"publisher","first-page":"3257","DOI":"10.4049\/jimmunol.1301886","article-title":"Cutting edge: the UNC93B1 tyrosine-based motif regulates trafficking and TLR responses via separate mechanisms","volume":"193","author":"Pelka","year":"2014","journal-title":"J. Immunol."},{"key":"2020012721470303600_bib32","doi-asserted-by":"publisher","first-page":"E898","DOI":"10.1073\/pnas.1118155109","article-title":"Spontaneous mutation of the Dock2 gene in Irf5\u2212\/\u2212 mice complicates interpretation of type I interferon production and antibody responses","volume":"109","author":"Purtha","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2020012721470303600_bib33","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1126\/science.1254790","article-title":"Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon","volume":"345","author":"Reboldi","year":"2014","journal-title":"Science."},{"key":"2020012721470303600_bib34","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1038\/nmeth.3047","article-title":"Improved vectors and genome-wide libraries for CRISPR screening","volume":"11","author":"Sanjana","year":"2014","journal-title":"Nat. Methods."},{"key":"2020012721470303600_bib35","doi-asserted-by":"publisher","first-page":"17005","DOI":"10.1074\/jbc.M412584200","article-title":"The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signaling","volume":"280","author":"Schoenemeyer","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2020012721470303600_bib36","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/j.mam.2009.06.004","article-title":"Dr. Jekyll and Mr. Hyde: a short history of anthrax","volume":"30","author":"Schwartz","year":"2009","journal-title":"Mol. Aspects Med."},{"key":"2020012721470303600_bib37","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.immuni.2008.05.008","article-title":"Engagement of the type I interferon receptor on dendritic cells inhibits T helper 17 cell development: role of intracellular osteopontin","volume":"29","author":"Shinohara","year":"2008","journal-title":"Immunity."},{"key":"2020012721470303600_bib38","doi-asserted-by":"publisher","first-page":"3266","DOI":"10.1016\/j.vaccine.2012.03.016","article-title":"Killed Bacillus subtilis spores as a mucosal adjuvant for an H5N1 vaccine","volume":"30","author":"Song","year":"2012","journal-title":"Vaccine."},{"key":"2020012721470303600_bib39","doi-asserted-by":"publisher","first-page":"13145","DOI":"10.1073\/pnas.1412008111","article-title":"Commensal bacteria protect against food allergen sensitization","volume":"111","author":"Stefka","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2020012721470303600_bib40","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1128\/MMBR.00050-15","article-title":"The exosporium layer of bacterial spores: a connection to the environment and the infected host","volume":"79","author":"Stewart","year":"2015","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"2020012721470303600_bib41","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1084\/jem.20132183","article-title":"Type I IFN suppresses Cxcr2 driven neutrophil recruitment into the sensory ganglia during viral infection","volume":"211","author":"Stock","year":"2014","journal-title":"J. Exp. Med."},{"key":"2020012721470303600_bib42","doi-asserted-by":"publisher","first-page":"6076","DOI":"10.4049\/jimmunol.176.10.6076","article-title":"Monoclonal antibodies for Bacillus anthracis spore detection and functional analyses of spore germination and outgrowth","volume":"176","author":"Swiecki","year":"2006","journal-title":"J. Immunol."},{"key":"2020012721470303600_bib43","doi-asserted-by":"publisher","first-page":"17","DOI":"10.4049\/jimmunol.0903114","article-title":"Cutting edge: resistance to Bacillus anthracis infection mediated by a lethal toxin sensitive allele of Nalp1b\/Nlrp1b","volume":"184","author":"Terra","year":"2010","journal-title":"J. Immunol."},{"key":"2020012721470303600_bib44","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1016\/j.cell.2015.02.047","article-title":"Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis","volume":"161","author":"Yano","year":"2015","journal-title":"Cell."},{"key":"2020012721470303600_bib45","doi-asserted-by":"publisher","first-page":"6876","DOI":"10.4049\/jimmunol.178.11.6876","article-title":"Murine dendritic cell type I IFN production induced by human IgG-RNA immune complexes is IFN regulatory factor (IRF)5 and IRF7 dependent and is required for IL-6 production","volume":"178","author":"Yasuda","year":"2007","journal-title":"J. Immunol."},{"key":"2020012721470303600_bib46","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1093\/intimm\/dxs114","article-title":"Phenotype and function of B cells and dendritic cells from interferon regulatory factor 5-deficient mice with and without a mutation in DOCK2","volume":"25","author":"Yasuda","year":"2013","journal-title":"Int. Immunol."}],"container-title":["The Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/rupress.org\/jem\/article-pdf\/214\/5\/1297\/1792\/jem_20161141.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/rupress.org\/jem\/article-pdf\/214\/5\/1297\/1792\/jem_20161141.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,1,27]],"date-time":"2020-01-27T21:47:10Z","timestamp":1580161630000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/214\/5\/1297\/175\/TLR-sensing-of-bacterial-sporeassociated-RNA"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,11]]},"references-count":46,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2017,5,1]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20161141","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,11]]}}}