Article Text

A decoy receptor 3 analogue reduces localised defects in phagocyte function in pneumococcal pneumonia
  1. Helen M Marriott1,
  2. Marc Daigneault1,
  3. Alfred A R Thompson1,2,
  4. Sarah R Walmsley1,2,
  5. Sharonjit K Gill1,
  6. Derrick R Witcher3,
  7. Victor J Wroblewski4,
  8. Paul G Hellewell5,
  9. Moira K B Whyte1,2,
  10. David H Dockrell1,2
  1. 1Department of Infection and Immunity, University of Sheffield, Sheffield, UK
  2. 2Sheffield Teaching Hospitals, Sheffield, UK
  3. 3Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly & Company, Lilly Corporate Center, Indianapolis, Indiana, USA
  4. 4Department of Drug Disposition Development/Commercialization, Lilly Research Laboratories, Eli Lilly & Company, Lilly Corporate Center, Indianapolis, Indiana, USA
  5. 5Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
  1. Correspondence to Dr Helen Marriott, Department of Infection and Immunity, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK; h.m.marriott{at}sheffield.ac.uk

Abstract

Background Therapeutic strategies to modulate the host response to bacterial pneumonia are needed to improve outcomes during community-acquired pneumonia. This study used mice with impaired Fas signalling to examine susceptibility to pneumococcal pneumonia and decoy receptor 3 analogue (DcR3-a) to correct factors associated with increased susceptibility.

Methods Wild-type mice and those with varying degrees of impairment of Fas (lpr) or Fas ligand signalling (gld) were challenged with Streptococcus pneumoniae and microbiological and immunological outcomes measured in the presence or absence of DcR3-a.

Results During established pneumonia, neutrophils became the predominant cell in the airway and gld mice were less able to clear bacteria from the lungs, demonstrating localised impairment of pulmonary neutrophil function in comparison to lpr or wild-type mice. T-cells from gld mice had enhanced activation and reduced apoptosis in comparison to wild-type and lpr mice during established pneumonia. Treatment with DcR3-a reduced T-cell activation and corrected the defect in pulmonary bacterial clearance in gld mice.

Conclusions The results suggest that imbalance in tumour necrosis factor superfamily signalling and excessive T-cell activation can impair bacterial clearance in the lung but that DcR3-a treatment can reduce T-cell activation, restore optimal pulmonary neutrophil function and enhance bacterial clearance during S pneumoniae infection.

  • Streptococcus pneumoniae
  • pneumococcal pneumonia
  • aFas/Fas ligand
  • T-cell activation
  • murine models of pneumococcal infection

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

View Full Text

Statistics from Altmetric.com

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Files in this Data Supplement:

Footnotes

  • Funding This work was supported by a grant from the Sheffield Hospitals Charitable Trust Research Grant (No. 7843), a Wellcome Trust Senior Clinical Fellowship to DHD (No. 076945) and a British Lung Foundation fellowship to HMM (F05/7). SRW is a Wellcome Clinician Scientist (No. 078244) and AART an MRC Clinical Research Training Fellow (G0802255).

  • Competing interests DRW and VJW are employees and have stock in Eli Lilly & Company.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.