title: Density and duration of pneumococcal carriage is maintained by transforming growth factor β1 and T regulatory cells.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  We sought to elucidate immunological mechanisms underlying noninvasive pneumococcal nasopharyngeal carriage.
  
  
  METHODS
  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.
  
  
  RESULTS
  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)-β1 by S. pneumoniae in human host cells and highlight the key role for TGF-β1 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-β1 production from nasopharyngeal cells in vivo and show that an immune tolerance profile, characterized by elevated TGF-β1 and high nasopharyngeal T regulatory cell numbers, is crucial for prolonged carriage of pneumococci. Blockade of TGF-β1 signaling prevents prolonged carriage and leads to clearance of pneumococci from the nasopharynx.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 1 Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Neill
authors.forename: William R
authors.initials: WR
authors.lastname: Coward
authors.forename: Jenna F
authors.initials: JF
authors.lastname: Gritzfeld
authors.forename: Luke
authors.initials: L
authors.lastname: Richards
authors.forename: Francesc J
authors.initials: FJ
authors.lastname: Garcia-Garcia
authors.forename: Javier
authors.initials: J
authors.lastname: Dotor
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gordon
authors.forename: Aras
authors.initials: A
authors.lastname: Kadioglu
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D002353:Carrier State / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009305:Nasopharynx / Q000276:immunology; D011008:Pneumococcal Infections / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D013296:Streptococcus pneumoniae / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000276:immunology*
chemical_list: D015415:Biomarkers; D053773:Transforming Growth Factor beta1
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