Effects of the Streptococcus pneumoniae capsule on interactions with macrophages and during early lung infection

Lead Research Organisation: University College London
Department Name: Medicine

Abstract

Streptococcus pneumoniae (also known as the pneumococcus) is a bacteria that is a common cause of severe diseases like pneumonia and meningitis. One reason why pneumococcus is able to cause severe infections is that it is coated with a layer of material made of sugars that is called the capsule. This capsule seems to act like a coat of armour, preventing the immune system from killing the bacteria and thereby allowing the bacteria to successfully invade the body. Although it is thought the capsule prevents white cells from getting rid of the pneumococcus, surprisingly little is known on exactly how the capsule disguises or protects the pneumococcus from different aspects of the bodies immune system. The aim of this project is to investigate precisely how the capsule helps the pneumococcus cause disease in particular pneumonia, the commonest severe disease it causes. We will identify which proteins on the white cell surface are prevented from recognising the pneumococcus by the capsule, and what are the consequences of this failure to identify properly the bacteria for the immune response and development of lung infection. As all vaccines against the pneumococcus that are in use at present rely on using the capsule, more detailed information on the functions of the capsule during infection will be helpful. Furthermore, the information obtained may allow the design of new effective therapies against the pneumococcus, and will provide more detailed information on how the pneumococcus is able to cause pneumonia even in previously healthy individuals.

Technical Summary

The polysaccharide capsule is a major virulence determinant of Streptococcus pneumoniae as well as the target of the vaccines presently in use. The capsule is thought to aid virulence by preventing phagocytosis, but the exact mechanisms involved are surprisingly poorly understood considering the importance of the capsule for S. pneumoniae disease. Furthermore little is known about how the effects of the capsule on interactions with phagocytes can affect disease development. The existing data on the S. pneumoniae capsule and preliminary data from Dr Brown?s laboratory indicate that the capsule can prevent neutrophil phagocytosis by reducing opsonisation of S. pneumoniae with complement. Furthermore, during early lung infection phagocytosis of unencapsulated S. pneumoniae by alveolar macrophages is considerably more efficient than that of encapsulated bacteria. However, phagocytosis can be mediated by interactions between the pathogen and a range of possible phagocyte cell surface receptors, including complement receptors, antibody receptors, lectins, integrins and scavenger receptors, and how the S. pneumoniae capsule affects these interactions with macrophages is poorly defined. We propose to use encapsulated and unencapsulated strains of two S. pneumoniae capsular serotypes to investigate the effect of the capsule on S. pneumoniae interactions with macrophages in more detail. In addition, we will also investigate how the capsule affects S. pneumoniae interactions with the alveolar macrophage in vivo and aids the development of lung infection. By using Dr Brown?s experience in investigating S. pneumoniae immunity and Dr Caron?s expertise in the molecular mechanisms of phagocyosis, we will addresses the hypothesis that the S. pneumoniae capsule increases virulence during the develpment of lung infection mainly by preventing complement opsonisation of the bacteria and thereby indirectly inhibiting phagocytosis by alveolar macrophages. In particular we will use a combination of recent advances in techniques for investigating macrophage cell biology and in the use of animal models to characterise the development of infection to assess the effects of the S. pneumoniae capsule on: (a) the distribution and nature of complement deposition on S. pneumoniae: (b) complement-dependent and -independent interactions of S. pneumoniae with macrophages; (c) which receptors and mechanism(s) are responsible for S. pneumoniae recognition and phagocytosis by macrophages; and (d) how these capsule-dependent effects alter the development of early lung infection. The data obtained will improve our fundamental understanding of the function of the capsule, a major virulence determinant and therapeutic target of S. pneumoniae, and may lead to improved therapies against this important pathogen.
 
Description British Thoracic Society short course in lung infection
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact I co-organised and co-chaired (and delivered a lecture) on a British Thoracic Society sponsored short course in lung infection at the annual summer meeting - by educating the audience this should improve provision of care for patients with lung infection
 
Description Clinical Reference Group membership
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact responsible for the design and implementation of national commissioning for subspecialty care for specific areas of respiratory medicine- implemented subspecialty care for three separate conditions across England
 
Description Lecture to GulfThoracic conference
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
Impact I gave two lectures on the care of pneumonia patients at the GulfThoracic conference, Dubai; by educating the healthcare workforce these should improve provision of care for these patients in the Middle East
 
Description NICE pneumonia guidelines
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
 
Description Royal College Regional training day lectures (three in total, a fourth in Oct 2014)
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact I have given 2012-2013 three lectures to Royal College of Physician regional training days on various aspects of clinical care for patients with pneumonia; a fourth lecture is planned for the national training conference October 2014
 
Description BBSRC PhD fellowship
Amount £60,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2013 
End 09/2016
 
Description Clinical Training PhD Fellowship
Amount £229,000 (GBP)
Funding ID MR/K00168X/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2012 
End 09/2015
 
Description Project grant
Amount £95,000 (GBP)
Organisation The Colt Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2013 
End 02/2014
 
Description Project grant
Amount £30,000 (GBP)
Organisation Rosetrees Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2013 
End 09/2013
 
Description Project grant
Amount £650,000 (GBP)
Organisation Research Council of Norway 
Sector Public
Country Norway
Start 10/2015 
End 10/2018
 
Title bacterial strains 
Description Bacterial strains, both wild-type and mutant 
Type Of Material Cell line 
Provided To Others? Yes  
Impact research using these strains has contributed to multiple papers 
 
Description AFM for evaluating bacterial virulence characteristics 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We have supplied the bacterial mutant strains and microbiological background for the work
Collaborator Contribution My partner (Laurent Bozec) has developed and supervised the use of atomic force microscopy techniques on our bacterial strains
Impact One paper has been published. Another two are in preparation.The work directly led to an additional project student from the BBSRC LIDO network working with Dr Bozec and yself in this area
Start Year 2015
 
Description Capsule effects on inflammation 
Organisation University College London
Department Division of Infection and Immunity
Country United Kingdom 
Sector Academic/University 
PI Contribution Joint research project funded by the MRC for a clinical training fellow; the work is largely in my lab
Collaborator Contribution Support for macrophage biology experiments
Impact MRC PhD training fellowship. Importance of the pro-inflammatory effects of the capsule during invasive Streptococcus pneumoniae infection. Dr J.Persileris, M.Noursadeghi, J.S.Brown (£228,751), 2012-15 Additional grant: Roseberry's Trust project grant. Identification of targets for immunomodulation treatment during severe Streptococcus pneumoniae infections. Prof JS Brown Dr Noursadeghi £30000.
Start Year 2012
 
Description Comparative virulence of Streptococcous pneumoniae and Streptococcus mitis 
Organisation University College London
Department Division of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Joint BBSRC PhD fellowship with Dr Laurent Bozec
Collaborator Contribution Shared supervision of a PhD student
Impact presentation of various abstracts at conferences; poster prize for best poster at Europneumo July 2015 one paper: Rukke HV, Kalluru RS, Repnik U, Gerlini A, José RJ, Periselneris J, Marshall H, Griffiths G, Oggioni MR, Brown JS, Petersen FC. Protective Role of the Capsule and Impact of Serotype 4 Switching on Streptococcus mitis. Infect Immun. 2014 Sep;82(9):3790-801
Start Year 2013
 
Description Pneumococcus and PAR1 mediated inflammation 
Organisation University College London
Department Division of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Joint research project for a clinical PhD fellow in shared laboratory facilities with my collaborator
Collaborator Contribution About equal contributions to design and planning of experimental work
Impact Wellcome PhD training fellowship. Pro-coagulant signalling in Streptococcus pneumoniae induced acute lung injury. Dr R.Jose and J.S.Brown, Professor R.Chambers (approx.. £250,000) 2012-15
Start Year 2012
 
Description Protection to Streptococcus pneumoniae by commensal streptococci 
Organisation University of Oslo
Department Department of Oral Biology
Country Norway 
Sector Academic/University 
PI Contribution I am a coPI on a successful grant application to the Research Council of Norway (award £650,000)
Collaborator Contribution they led the application
Impact none as yet
Start Year 2015
 
Description Welding fumes and lung immunity 
Organisation Queen Mary University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborative research - we do mainly the animal models of infection work
Collaborator Contribution The in vitro assessment; the researcher is based at Queen Mary's
Impact Colt foundation project grant. Identification of the mechanism for the association between pneumococcal pneumonia and exposure to welding fumes. Prof J. Grigg, J.S.Brown £95,000
Start Year 2012
 
Description work experience placements 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact During 2011 and 2012 we had work experience placements for four school pupils in my laboratory; two of the students have decided to go forward and apply for university courses in the hope of a biomedical research career.
The drop down categories above do not fit this engagement activity but I have had to choose something to enable this to be submitted.

I will be giving a talk to the sixth formers at the school which the four pupils attend in the New Year as part of their invited scientific speakers programme
Year(s) Of Engagement Activity 2011,2012