Density and Duration of Pneumococcal Carriage Is Maintained by Transforming Growth Factor β1 and T Regulatory Cells

Neill, Daniel R., Coward, William R., Gritzfeld, Jenna, Richards, Luke, Garcia-Garcia, Francesc J., Dotor, Javier, Gordon, Stephen ORCID: https://orcid.org/0000-0001-6576-1116 and Kadioglu, Aras (2014) 'Density and Duration of Pneumococcal Carriage Is Maintained by Transforming Growth Factor β1 and T Regulatory Cells'. American Journal of Respiratory and Critical Care Medicine, Vol 189, Issue 10, pp. 1250-1259.

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Abstract

Rationale:
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.

Objectives:
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.
Measurements and Main 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.

Item Type:	Article
Subjects:	QW Microbiology and Immunology > Reference Works. General Immunology > QW 504 General works WC Communicable Diseases > Infection. Bacterial Infections > Bacterial Infections > WC 204 Pneumococcal pneumonia. Staphylococcal pneumonia WC Communicable Diseases > Infection. Bacterial Infections > Bacterial Infections > WC 217 Pneumococcal infections WF Respiratory System > WF 140 Diseases of the respiratory system (General) WV Otolaryngology > Pharyngeal Region > WV 400 General works
Faculty: Department:	Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI):	https://doi.org/10.1164/rccm.201401-0128OC
Depositing User:	Martin Chapman
Date Deposited:	23 Jul 2014 13:51
Last Modified:	07 Oct 2019 08:23
URI:	https://archive.lstmed.ac.uk/id/eprint/3797

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