{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T22:10:09Z","timestamp":1790115009168,"version":"4.0.1"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2014,5,1]],"date-time":"2014-05-01T00:00:00Z","timestamp":1398902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Nasopharyngeal carriage of Streptococcus pneumoniae is a prerequisite for invasive disease, but the majority of carriage episodes are asymptomatic and self-resolving. Interactions determining the development of carriage versus invasive disease are poorly understood but will influence the effectiveness of vaccines or therapeutics that disrupt nasal colonization.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>We sought to elucidate immunological mechanisms underlying noninvasive pneumococcal nasopharyngeal carriage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Pneumococcal interactions with human nasopharyngeal and bronchial fibroblasts and epithelial cells were investigated in vitro. A murine model of nasopharyngeal carriage and an experimental human pneumococcal challenge model were used to characterize immune responses in the airways during carriage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>We describe the previously unknown immunological basis of noninvasive carriage and highlight mechanisms whose perturbation may lead to invasive disease. We identify the induction of active transforming growth factor (TGF)-\u03b21 by S. pneumoniae in human host cells and highlight the key role for TGF-\u03b21 and T regulatory cells in the establishment and maintenance of nasopharyngeal carriage in mice and humans. We identify the ability of pneumococci to drive TGF-\u03b21 production from nasopharyngeal cells in vivo and show that an immune tolerance profile, characterized by elevated TGF-\u03b21 and high nasopharyngeal T regulatory cell numbers, is crucial for prolonged carriage of pneumococci. Blockade of TGF-\u03b21 signaling prevents prolonged carriage and leads to clearance of pneumococci from the nasopharynx.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These data explain the mechanisms by which S. pneumoniae colonize the human nasopharynx without inducing damaging host inflammation and provide insight into the role of bacterial and host constituents that allow and maintain carriage.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201401-0128oc","type":"journal-article","created":{"date-parts":[[2014,4,21]],"date-time":"2014-04-21T13:09:11Z","timestamp":1398085751000},"page":"1250-1259","source":"Crossref","is-referenced-by-count":56,"title":["Density and Duration of Pneumococcal Carriage Is Maintained by Transforming Growth Factor \u03b21 and T Regulatory Cells"],"prefix":"10.1093","volume":"189","author":[{"given":"Daniel R.","family":"Neill","sequence":"first","affiliation":[{"name":"Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William R.","family":"Coward","sequence":"additional","affiliation":[{"name":"Centre of Respiratory Research, Biomedical Research Unit, University of Nottingham, Nottingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna F.","family":"Gritzfeld","sequence":"additional","affiliation":[{"name":"Respiratory Infection Group, Liverpool School of Tropical Medicine, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Richards","sequence":"additional","affiliation":[{"name":"School of Veterinary and Medical Sciences, University of Nottingham, Leicestershire, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesc J.","family":"Garcia-Garcia","sequence":"additional","affiliation":[{"name":"Centre of Respiratory Research, Biomedical Research Unit, University of Nottingham, Nottingham, United Kingdom"},{"name":"Immunoall\u00e8rgia Respirat\u00f2ria Cl\u00ednica i Experimental, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; 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