The bacterium *Streptococcus pneumoniae* lives harmlessly in the noses and throats of most people, yet it kills roughly 2 million people each year—more than HIV/AIDS, measles, and malaria combined—when it spreads to the lungs or brain. Current vaccines work by clearing the bacteria from the upper airways, but they only cover a limited number of bacterial strains. This creates a worrying gap: strains not targeted by the vaccine can move into the vacated space and cause disease, a phenomenon known as replacement disease. Researchers do not understand why the immune system tolerates the bacteria in the nose and throat but attacks it fiercely in deeper tissues. This project will map the molecular interactions between the bacteria and host cells in the upper airways, and identify the bacterial, host, or environmental factors—such as cigarette smoke or co-infection—that trigger the transition from harmless carriage to invasive disease. If successful, the work could inform a new generation of vaccines that allow harmless colonisation of the upper airways while still protecting against pneumonia and sepsis. This would preserve the natural immune training that current vaccines inadvertently destroy, potentially reducing replacement disease and saving hundreds of thousands of lives each year.
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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.
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