Mechanisms of complement-mediated pulmonary immunity to Streptococcus pneumoniae

Lead Research Organisation: University College London
Department Name: Medicine

Abstract

Pneumonia is one of the most common infections worldwide, and is most often caused by the bacteria Streptococcus pneumoniae (otherwise known as the pneumococcus). As a consequence pneumococcus is an important cause of premature death, killing over a million children per year. We urgently need to understand how the body prevents the pneumococcus from causing lung infections in order to design effective methods of reducing this toll. One important component of the bodies immune system for preventing pneumococcus from causing lung infections is the complement system, a series of proteins that can bind to bacteria and help prevent disease. However, exactly how complement stops the pneumococcus from causing pneumonia is not known, and the aim of this proposal is to identify the mechanisms by which complement helps lung defences control infection by pneumococcus. One possibility is that complement bound to the bacteria help white cells in the lung ingest and kill the pneumococcus, and the other possibility is that activation of complement proteins act as a warning signal that results in the body directing its immune defences to the lung. The proposal will evaluate the degree to which these two possibilities contribute to lung defence against pneumococcus. The effect of complement on the interactions of pneumococcus with two different types of human white cells will be investigated to identify which of these two cell types are likely to use complement during infection to kill the pneumococcus. The results will be reinforced by experiments infecting mice that have been genetically engineered so that they are deficient in complement with pneumococcus. Using these experiments we will be able to assess the effects of loss of complement on white cell functions and the bodies response during the actual development of pneumonia, data which the complexity of the immune response to infection makes impossible to obtain without using animal experiments. The information obtained from the proposal will substantially improve our knowledge of how the lungs defend against the pneumococcus, and should lead to future therapies aimed at preventing or treating this important cause of lethal infection. The results will be published in science journals, and important results disseminated to the general public via the UCL website and publicity office.

Technical Summary

Pneumonia due to Streptococcus pneumoniae is a common and serious disease, responsible for significant morbidity and mortality in otherwise healthy adults and children. Severe pneumonia has a mortality of 25% despite treatment with appropriate antibiotics, and there is an increasing incidence of antibiotic resistance amongst clinical isolates of S. pneumoniae. Hence a comprehensive understanding of the interactions of S. pneumoniae with the host immune system is necessary for the development of better therapeutic and preventative strategies. One important element of host immunity to S. pneumoniae is the complement system. Laboratory and clinical data suggest that complement, as well as preventing systemic infection, also has a significant role in helping control S. pneumoniae infection during the early stages of pneumonia. However which mechanisms mediate complement-dependent immunity to S. pneumoniae within the lungs and which complement pathways are involved has not been defined. Mechanisms of complement-dependent immunity in the lungs are likely to include either improved phagocytosis by alveolar macrophages or neutrophils (which are recruited to the lung within a few hours of S. pneumoniae infection) or enhanced inflammatory responses to the infection. The overall aim of this proposal is to take advantage of new scientific developments to investigate how complement assists immunity during early pneumonia, using assays of phagocyte function and animal models of infection. The contribution and the specific effects of different complement pathways on the interactions of S. pneumoniae with pulmonary phagocytes will be characterised. Bacteria will be incubated in sera deficient in specific complement components, mixed with ex-vivo human neutrophils and alveolar macrophages and assays for phagocytosis, bacterial killing, phagolysosomal maturity, and phagocyte activation performed. Mouse models of infection in complement deficient mice will be used to assess the roles of different complement pathways during early S. pneumoniae pneumonia. The effects of complement deficiencies on C3b deposition on S. pneumoniae in the lungs, phagocytosis by alveolar macrophages and neutrophils, bacterial replication, and the development of the inflammatory response and white cell recruitment will be characterised. Comparing the data obtained from human samples and mouse models of infections will allow a thorough characterisation of the likely effects of complement during early S. pneumoniae pneumonia in humans. The results will provide important insights into complement dependent immunity to pulmonary pathogens, why certain patients with complement deficiencies are susceptible to S. pneumoniae pneumonia, and valuable data for the design of new strategies to prevent this common and serious disease.

Publications

10 25 50

 
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 PhD fellowship
Amount £228,751 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2012 
End 10/2015
 
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
 
Description response mode
Amount £358,711 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 11/2009 
End 10/2012
 
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 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 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