The role of immune tolerance and regulation in pneumococcal carriage and invasive disease.

点击翻译按钮获取中文摘要

Streptococcus pneumoniae (the pneumococcus) can cause a range of severe diseases such as pneumonia, meningitis and sepsis (blood poisoning) but it is also part of the normal community of microbes that live in our noses and throat. Therefore, it is very common to harbour the pneumococcus in our airways without suffering any signs or symptoms of disease. However, it is not understood how and why pneumococci spread from these areas into deeper tissues such as the lung or the brain where they cause disease or why the bacteria induce inflammation and strong immune responses in the lungs and brain but little, if any, response in our nose and throat. Understanding the "silent" infection of the upper airways is essential to understand how a normally safe organism can cause severe disease in a minority of individuals. The pneumococcus accounts for around 2 million deaths per year, half of which occur in children under 5 years of age. This is more than HIV/AIDS, measles and malaria combined. The current vaccines against the pneumococcus provide excellent protection against a limited range of the circulating strains of the bacteria but there are concerns that replacement disease may occur as strains that are not covered by the vaccine start to colonise the environment of the upper airways made vacant by vaccination. We believe that this could be avoided by designing a vaccine that protects against pneumococcal diseases such as pneumonia and sepsis, but allows the bacteria to colonise normally in the upper airways, providing additional protection generated by natural immunity. We believe that the process of pneumococcal colonisation of the upper airways might be an important way of training our immune system to provide natural protection against pneumococcal disease. This route to natural immunity would be lost following vaccination with current vaccines that kill off upper airway bacteria. This may in turn leave us more vulnerable to pneumococcal disease caused by non-vaccine type strains.This project aims to improve our understanding of the process of natural colonisation and persistence of Streptococcus pneumoniae in the upper airways. We aim to uncover the interaction of bacteria with host cells in the airways in order to understand how silent infection occurs. Finally, we will determine what factors (bacterial, host or environmental) that lead from upper airway infection to the development of invasive disease. Factors that may predispose us to pneumococcal disease include coinfection with other disease causing organisms, exposure to inhaled pollutants (cigarette smoke, car exhaust fumes etc.) or production of certain toxins by pneumococci. The data generated from this project will help us identify groups or individuals at particular risk of developing invasive pneumococcal disease and will inform the design of future, more effective pneumococcal vaccination strategies.