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

肺炎链球菌（肺炎球菌）可引起一系列严重疾病，如肺炎、脑膜炎和败血症（血液中毒），但它也是生活在我们鼻子和喉咙中的正常微生物群落的一部分。因此，在我们的呼吸道中窝藏肺炎球菌而没有任何疾病的体征或症状是很常见的。然而，目前尚不清楚肺炎球菌如何以及为什么从这些区域扩散到肺部或大脑等更深的组织，并在那里引起疾病，也不清楚为什么这种细菌会在肺部和大脑中引起炎症和强烈的免疫反应，而在我们的鼻子和喉咙中却几乎没有反应。了解上呼吸道的“无声”感染对于理解通常安全的生物体如何在少数个体中引起严重疾病至关重要。肺炎球菌每年造成约200万人死亡，其中一半发生在5岁以下儿童中。这比艾滋病毒/艾滋病、麻疹和疟疾加起来还要多。目前针对肺炎球菌的疫苗对有限范围的循环细菌菌株提供了极好的保护，但人们担心，当疫苗未覆盖的菌株开始在因疫苗接种而空白的上呼吸道环境中定植时，可能会发生替代疾病。我们相信，这可以通过设计一种疫苗来避免，这种疫苗可以预防肺炎球菌疾病，如肺炎和败血症，但允许细菌在上呼吸道正常定植，提供由自然免疫产生的额外保护。我们相信，肺炎球菌在上呼吸道定植的过程可能是训练我们的免疫系统提供自然保护以对抗肺炎球菌疾病的重要方式。这种自然免疫途径将在接种现有疫苗杀死上呼吸道细菌后丧失。这可能反过来使我们更容易受到由非疫苗型菌株引起的肺炎球菌疾病的伤害。本项目旨在提高我们对肺炎链球菌在上呼吸道自然定植和持续存在过程的理解。我们的目标是揭示细菌与呼吸道宿主细胞的相互作用，以了解无声感染是如何发生的。最后，我们将确定哪些因素（细菌、宿主或环境）导致上呼吸道感染发展为侵袭性疾病。可能使我们易患肺炎球菌疾病的因素包括同时感染其他致病生物体、暴露于吸入污染物（香烟烟雾、汽车尾气等）或肺炎球菌产生某些毒素。该项目产生的数据将帮助我们确定具有侵袭性肺炎球菌疾病特别风险的群体或个人，并将为未来更有效的肺炎球菌疫苗接种策略的设计提供信息。

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.