Mechanisms of complement-mediated pulmonary immunity to Streptococcus pneumoniae

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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.