Mechanisms of complement-mediated pulmonary immunity to Streptococcus pneumoniae

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.

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.