{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:24:08Z","timestamp":1790663048816,"version":"4.1.0"},"reference-count":39,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2015,1,20]],"date-time":"2015-01-20T00:00:00Z","timestamp":1421712000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2015,2,27]],"date-time":"2015-02-27T00:00:00Z","timestamp":1424995200000},"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":[[2015,2,27]]},"abstract":"<jats:title>ABSTRACT\u2002<\/jats:title>\n          <jats:p>\n            <jats:named-content content-type=\"genus-species\">Streptococcus pneumoniae<\/jats:named-content>\n            is a leading pathogen with an extracellular lifestyle; however, it is detected by cytosolic surveillance systems of macrophages. The innate immune response that follows cytosolic sensing of cell wall components results in recruitment of additional macrophages, which subsequently clear colonizing organisms from host airways. In this study, we monitored cytosolic access by following the transit of the abundant bacterial surface component capsular polysaccharide, which is linked to the cell wall. Confocal and electron microscopy visually characterized the location of cell wall components in murine macrophages outside membrane-bound organelles. Quantification of capsular polysaccharide through cellular fractionation demonstrated that cytosolic access of bacterial cell wall components is dependent on phagocytosis, bacterial sensitivity to the host\u2019s degradative enzyme lysozyme, and release of the pore-forming toxin pneumolysin. Activation of p38 mitogen-activated protein kinase (MAPK) signaling is important for limiting access to the cytosol; however, ultimately, these are catastrophic events for both the bacteria and the macrophage, which undergoes cell death. Our results show how expression of a pore-forming toxin ensures the death of phagocytes that take up the organism, although cytosolic sensing results in innate immune detection that eventually allows for successful host defense. These findings provide an example of how cytosolic access applies to an extracellular microbe and contributes to its pathogenesis.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            \u2002\n            <jats:named-content content-type=\"genus-species\">Streptococcus pneumoniae<\/jats:named-content>\n            (the pneumococcus) is a bacterial pathogen that is a leading cause of pneumonia. Pneumococcal disease is preceded by colonization of the nasopharynx, which lasts several weeks before being cleared by the host\u2019s immune system. Although S.\u00a0pneumoniae is an extracellular microbe, intracellular detection of pneumococcal components is critical for bacterial clearance. In this study, we show that following bacterial uptake and degradation by phagocytes, pneumococcal products access the host cell cytosol via its pore-forming toxin. This phenomenon of cytosolic access results in phagocyte death and may serve to combat the host cells responsible for clearing the organism. Our results provide an example of how intracellular access and subsequent immune detection occurs during infection with an extracellular pathogen.\n          <\/jats:p>","DOI":"10.1128\/mbio.02110-14","type":"journal-article","created":{"date-parts":[[2015,1,21]],"date-time":"2015-01-21T04:58:11Z","timestamp":1421816291000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":47,"title":["Degradation Products of the Extracellular Pathogen Streptococcus pneumoniae Access the Cytosol via Its Pore-Forming Toxin"],"prefix":"10.1128","volume":"6","author":[{"given":"Jamie K.","family":"Lemon","sequence":"first","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey N.","family":"Weiser","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","unstructured":"O\u2019Brien KL Wolfson LJ Watt JP Henkle E Deloria-Knoll M McCall N Lee E Mulholland K Levine OS Cherian T the Hib and Pneumococcal Global Burden of Disease Study Team. 2009. Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet 374:893\u2013902. doi:10.1016\/S0140-6736(09)61204-6.","DOI":"10.1016\/S0140-6736(09)61204-6"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(04)00938-7"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20011576"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI36731"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200207-698OC"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI57761"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C200651200"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M008072200"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600175"},{"key":"e_1_3_2_11_2","doi-asserted-by":"crossref","unstructured":"Korchev YE Bashford CL Pederzolli C Pasternak CA Morgan PJ Andrew PW Mitchell TJ. 1998. A conserved tryptophan in pneumolysin is a determinant of the characteristics of channels formed by pneumolysin in cells and planar lipid bilayers. Biochem J 329:571\u2013577.","DOI":"10.1042\/bj3290571"},{"key":"e_1_3_2_12_2","doi-asserted-by":"crossref","unstructured":"Walker JA Allen RL Falmagne P Johnson MK Boulnois GJ. 1987. Molecular cloning characterization and complete nucleotide sequence of the gene for pneumolysin the sulfhydryl-activated toxin of Streptococcus pneumoniae. Infect Immun 55:1184\u20131189.","DOI":"10.1128\/iai.55.5.1184-1189.1987"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000241"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2006.00878.x"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/0882-4010(90)90091-4"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0911581107"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0435928100"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00579-13"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0404073101"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.03.241"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M511431200"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400133"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.73.10.6199-6209.2005"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00198-2"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.167.4.1459"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0904958106"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01710-14"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.12.6985"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.2.719"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00077-11"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2009.06673.x"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00016-11"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100381"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1003143"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C114.548982"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxn071"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2009.06.007"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.9.6246"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.67.11.5190-5196.2001"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.47661-0"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.02110-14","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.02110-14","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T02:02:37Z","timestamp":1646704957000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mBio.02110-14"}},"subtitle":[],"editor":[{"given":"Larry S.","family":"McDaniel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2015,2,27]]},"references-count":39,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2015,2,27]]}},"alternative-id":["10.1128\/mBio.02110-14"],"URL":"https:\/\/doi.org\/10.1128\/mbio.02110-14","relation":{},"ISSN":["2161-2129","2150-7511"],"issn-type":[{"value":"2161-2129","type":"print"},{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,2,27]]},"assertion":[{"value":"2014-10-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-12-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-01-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e02110-14"}}