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

免疫耐受和调节在肺炎球菌携带和侵袭性疾病中的作用。

• 批准号: MR/P011284/1
• 负责人: Aras Kadioglu
• 金额: $ 201.9万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP011284%2F1
• 关键词: role; immune; tolerance; regulation; pneumococcal

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.

肺炎链球菌（肺炎球菌）可以引起一系列严重的疾病，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，在我们的呼吸道中藏匿肺炎球菌而没有任何疾病的迹象或症状是非常常见的。然而，目前还不清楚肺炎球菌如何以及为什么从这些区域传播到更深的组织，如肺或大脑，在那里它们引起疾病，或者为什么细菌在肺和大脑中诱导炎症和强烈的免疫反应，但在我们的鼻子和喉咙中几乎没有反应。了解上呼吸道的“无声”感染对于了解正常情况下安全的微生物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岁以下的儿童中。这比艾滋病毒/艾滋病、麻疹和疟疾的总和还要多。目前针对肺炎球菌的疫苗提供了针对有限范围的细菌的循环菌株的极好保护，但是存在这样的担忧，即当疫苗未覆盖的菌株开始定殖于通过接种而空出的上呼吸道的环境时，可能发生替代疾病。我们认为，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的定植过程可能是训练我们的免疫系统提供天然保护以对抗肺炎球菌疾病的重要途径。这种天然免疫途径在接种杀死上呼吸道细菌的现有疫苗后会丧失。这项研究计划旨在加深我们对肺炎链球菌在上呼吸道自然定植和持续存在的过程的认识。我们的目标是揭示气道中细菌与宿主细胞的相互作用，以了解沉默感染是如何发生的。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与其他致病微生物的共同感染，暴露于吸入的污染物（香烟烟雾，汽车尾气等）。或者肺炎球菌产生某些毒素。该项目产生的数据将帮助我们识别具有发生侵袭性肺炎球菌疾病特定风险的群体或个人，并为未来更有效的肺炎球菌疫苗接种策略的设计提供信息。

项目成果

Bacterial genome-wide association study of hyper-virulent pneumococcal serotype 1 identifies genetic variation associated with neurotropism.

• DOI: 10.1038/s42003-020-01290-9
• 发表时间: 2020-10-08
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Chaguza C;Yang M;Cornick JE;du Plessis M;Gladstone RA;Kwambana-Adams BA;Lo SW;Ebruke C;Tonkin-Hill G;Peno C;Senghore M;Obaro SK;Ousmane S;Pluschke G;Collard JM;Sigaùque B;French N;Klugman KP;Heyderman RS;McGee L;Antonio M;Breiman RF;von Gottberg A;Everett DB;Kadioglu A;Bentley SD
• 通讯作者: Bentley SD

Pseudomonas aeruginosa utilizes the host-derived polyamine spermidine to facilitate antimicrobial tolerance.

• DOI: 10.1172/jci.insight.158879
• 发表时间: 2022-11-22
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Hasan, Chowdhury M.;Pottenger, Sian;Green, Angharad E.;Cox, Adrienne A.;White, Jack S.;Jones, Trevor;Winstanley, Craig;Kadioglu, Aras;Wright, Megan H.;Neill, Daniel R.;Fothergill, Joanne L.
• 通讯作者: Fothergill, Joanne L.

Increased pathogenicity of pneumococcal serotype 1 is driven by rapid autolysis and release of pneumolysin

• DOI: 10.1038/s41467-020-15751-6
• 发表时间: 2020-04-20
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Jacques，Laura C.;Panagiotou，Stavros;Kadioglu，Aras
• 通讯作者: Kadioglu，Aras

Comparative Genomics of Disease and Carriage Serotype 1 Pneumococci.

• DOI: 10.1093/gbe/evac052
• 发表时间: 2022-04-10
• 期刊: GENOME BIOLOGY AND EVOLUTION
• 影响因子: 3.3
• 作者: Chaguza, Chrispin;Ebruke, Chinelo;Senghore, Madikay;Lo, Stephanie W.;Tientcheu, Peggy-Estelle;Gladstone, Rebecca A.;Tonkin-Hill, Gerry;Cornick, Jennifer E.;Yang, Marie;Worwui, Archibald;McGee, Lesley;Breiman, Robert F.;Klugman, Keith P.;Kadioglu, Aras;Everett, Dean B.;Mackenzie, Grant;Croucher, Nicholas J.;Roca, Anna;Kwambana-Adams, Brenda A.;Antonio, Martin;Bentley, Stephen D.
• 通讯作者: Bentley, Stephen D.

Influence of Streptococcus pneumoniae Within-Strain Population Diversity on Virulence and Pathogenesis.

• DOI: 10.1128/spectrum.03103-22
• 发表时间: 2023-02-14
• 期刊: Microbiology spectrum
• 影响因子: 3.7