Temporal changes to cellular bioenergetics, cholesterol metabolism, innate immune responses and microbiota during infection

感染期间细胞生物能、胆固醇代谢、先天免疫反应和微生物群的暂时变化

• 批准号: MR/R020671/1
• 负责人: Gad Frankel
• 金额: $ 247.6万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR020671%2F1
• 关键词: Temporal; changes; cellular; bioenergetics; cholesterol

Bacterial infections are major cause of morbidity and mortality in children under 5 years of age, especially in Low and Middle Income Countries (LMIC). In industrial countries, bacterial infections mainly affect the elderly (both in the community and in hospitals) and the immunocompromised (e.g. patients undergoing chemotherapy or infected with HIV). While the ability to treat bacterial infections with antibiotics is arguably the most important achievement of modern medicine, the extensive misuse and overuse of antibiotics in human medicine and livestock has contributed to the rise and spread of antimicrobial resistance (AMR). The threat of antibiotic resistance is well reported, being sighted in many newspaper articles, high-level government reports and campaigns in recent years. Already responsible for 700,000 deaths per year, antibiotic-resistant bacteria are predicted to cause a staggering 10 million deaths by 2050. Whilst there has been a dramatic rise in the spread of multi-drug resistant bacteria, the discovery rate of new antibiotics has tumbled over the past decades, with only a few new approved drugs reaching the clinic. This highlights the urgent need to complement traditional drug discovery routes with new approaches to treat bacterial infections. Importantly, unintended targets of antibiotics include the normal, beneficial, gut bacteria (microbiota). Accordingly, we need to employ innovative approaches to treat bacterial infections, which minimise both selective pressure-promoting emergence of resistance and impact on the microbiota. The development of effective and novel control measures requires a systematic understanding of the biology of the disease, particularly the complex interactions between bacterial pathogens and their hosts in the context of the gut microbiota. By definition, this type of research relies on utilisation of robust and physiologically relevant animal models.Citrobacter rodentium is mouse specific extracellular pathogen, which shares an infection strategy with human pathogenic E. coli strains (for example E. coli O157). Being a natural mouse pathogen, C. rodentium provides an ideal model to study infections with gut pathogens in the natural host and in the context of the gut microbiota. C. rodentium causes a self-limiting infection and triggers robust immune responses, proliferation of epithelial cells and displacement of the normal gut bacteria which mimic the characteristics observed during human infection with pathogenic E. coli. Recently, by applying state-of-the-art molecular methods to study the interaction of C. rodentium with cells that line the gut we found that the infection causes drastic changes to energy production and central metabolism in the host cells, in what seems to be an attempt to dampen inflammation. While previously the focus has been on immune cells, it is only now that we are starting to realise that controlling metabolism in epithelial cells is another key frontier in host-pathogen interactions. In this project we aim to obtain an unprecedented molecular resolution of host-pathogen interactions over the duration of infection, in the context of a whole organism. Our proof-of-concept studies have already shown deregulation in the production and release of cholesterol during C. rodentium infection. In this project we will use wild type and mutant C. rodentium strains as well as wild type mice and mice deficient in a key controllers of cholesterol metabolism. We will study changes in metabolism over time, from infection to recovery, and match these changes to the presence of specific gut microbiota. The use of selected mutants, both bacterial and host, will allow us to unravel the molecular processes involved. We believe our pioneering approach would lead to conceptual shifts in understanding of host-bacterial infections and thus open new avenues for the development of novel treatment strategies for bacterial infection.

细菌感染是5岁以下儿童发病率和死亡率的主要原因，尤其是在中低收入国家（LMIC）。在工业国家，细菌感染主要影响老年人（在社区和医院中）和免疫功能低下（例如接受化疗或感染HIV的患者）。虽然可以说，用抗生素治疗细菌感染的能力可以说是现代医学的最重要成就，但人类医学和牲畜在人类医学和牲畜中的广泛滥用和过度使用促进了抗菌耐药性（AMR）的兴起和传播。据报道，在许多报纸文章，高级政府报告和运动中都看到了抗生素抗性的威胁。预计到2050年已经造成抗生素耐药性细菌死亡，抗生素耐药性细菌的死亡人数惊人。虽然多药耐药细菌的传播幅度急剧上升，但在过去的几十年中，新抗生素的发现率却急剧增加，只有少数新批准的药物可以涉及新的抗生素。这凸显了迫切需要通过新方法来补充传统的药物发现路线，以治疗细菌感染。重要的是，抗生素的意外靶标包括正常，有益的肠道细菌（微生物群）。因此，我们需要采用创新的方法来治疗细菌感染，从而最大程度地减少了耐药性的选择性促进性促进性和对微生物群的影响。有效和新颖的控制措施的发展需要系统地了解疾病的生物学，尤其是在肠道菌群中细菌病原体与其宿主之间的复杂相互作用。根据定义，这种类型的研究依赖于鲁棒和生理相关的动物模型的利用。核杆菌是小鼠特定的细胞外病原体，该病原体与人类致病性大肠杆菌菌株共享感染策略（例如大肠杆菌O157）。作为天然小鼠病原体，啮齿动物C.提供了一种理想的模型，可以在天然宿主和肠道菌群中研究肠道病原体的感染。 C.啮齿动物会引起自限性感染，并触发可靠的免疫反应，上皮细胞的增殖以及正常肠道细菌的位移，这些肠道细菌模仿了患有致病性大肠杆菌的人类感染过程中观察到的特征。最近，通过应用最先进的分子方法研究啮齿动物念珠菌与肠道细胞的相互作用，我们发现感染会导致宿主细胞中能量产生和中枢代谢的急剧变化，这似乎是试图抑制炎症的尝试。虽然以前的重点是免疫细胞，但直到现在我们才开始意识到，在上皮细胞中控制代谢是宿主 - 病原体相互作用的另一个关键边界。在这个项目中，我们旨在在整个生物体的背景下，在感染期间获得宿主 - 病原体相互作用的前所未有的分子分辨率。我们的概念验证研究已经表明，在啮齿动物念珠菌感染期间胆固醇的生产和释放中失调。在这个项目中，我们将使用野生型和突变型啮齿动物菌株以及野生型小鼠和缺乏胆固醇代谢的关键控制器的小鼠。我们将随着时间的流逝，从感染到恢复，新陈代谢的变化，并将这些变化与特定肠道菌群的存在相匹配。使用细菌和宿主的选定突变体的使用将使我们能够揭示所涉及的分子过程。我们认为，我们的开创性方法将导致理解宿主 - 细菌感染的概念转变，从而为开发新的细菌感染治疗策略开辟了新的途径。

项目成果

Citrobacter amalonaticus Inhibits the Growth of Citrobacter rodentium in the Gut Lumen.

• DOI: 10.1128/mbio.02410-21
• 发表时间: 2021-10-26
• 期刊: mBio
• 影响因子: 6.4
• 作者: Mullineaux-Sanders C;Carson D;Hopkins EGD;Glegola-Madejska I;Escobar-Zepeda A;Browne HP;Lawley TD;Frankel G
• 通讯作者: Frankel G

The type III secretion system effector network hypothesis

III型分泌系统效应网络假说

• DOI: 10.1016/j.tim.2021.10.007
• 发表时间: 2022
• 期刊: Trends in Microbiology
• 影响因子: 15.9
• 作者: Sanchez-Garrido J

Type III secretion system effector subnetworks elicit distinct host immune responses to infection.

III 型分泌系统效应子网络引发不同的宿主对感染的免疫反应。

• DOI: 10.1016/j.mib.2021.08.008
• 发表时间: 2021
• 期刊: Current opinion in microbiology
• 影响因子: 5.4
• 作者: Sanchez-Garrido J

Citrobacter rodentium Infection Induces Persistent Molecular Changes and Interferon Gamma-Dependent Major Histocompatibility Complex Class II Expression in the Colonic Epithelium.

• DOI: 10.1128/mbio.03233-21
• 发表时间: 2021-02-22
• 期刊: mBio
• 影响因子: 6.4
• 作者: Mullineaux-Sanders C;Kozik Z;Sanchez-Garrido J;Hopkins EGD;Choudhary JS;Frankel G
• 通讯作者: Frankel G

The type III secretion system effector EspO of enterohaemorrhagic Escherichia coli inhibits apoptosis through an interaction with HAX-1.

• DOI: 10.1111/cmi.13366
• 发表时间: 2021-09
• 期刊: Cellular microbiology
• 影响因子: 3.4
• 作者: Chatterjee S;Lekmeechai S;Constantinou N;Grzybowska EA;Kozik Z;Choudhary JS;Berger CN;Frankel G;Clements A
• 通讯作者: Clements A