Klebsiella pneumonaie anti-immunology: exploiting mTORC1 to control cell-intrinsic immunity.

肺炎克雷伯菌抗免疫学：利用 mTORC1 控制细胞内在免疫。

• 批准号: MR/V032496/1
• 负责人: Jose Bengoechea
• 金额: $ 71.75万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV032496%2F1
• 关键词: Klebsiella; pneumonaie; anti; immunology; exploiting

The control of bacterial infections is perhaps the most important achievement of modern medicine. However, we have failed to keep pace with microbes becoming increasingly resistant to available treatments. This threat is exemplified by multidrug resistant Klebsiella pneumoniae, resistant to all major front line antibiotic compounds. In fact, the increasing isolation of strains resistant to "last resort" antimicrobials has significantly narrowed, or in some settings completely removed, the therapeutic options. This is particularly alarming in low and middle income countries. Of particular concern is the rise of resistant infections in the community, which can put more people at risk. For example, invasive Klebsiella infections have increased 12% in the UK in the last five years. Unfortunately, new classes of drugs are not being invented and resistance continues to spread inexorably. The stakes are high and we might be entering into a pre-antibiotic era. Public Health England has calculated that the lack of effective antibiotics will render more than the three million operations and cancer treatments life threatening, and more than 90,000 people are estimated to die in the UK over the next 30 years due to antibiotic resistant infections.An attractive appraoch to develop new antimicrobial therapeutics is to boost protective immune responses that, in fact, protect most people. However this is particularly difficult in the case of Klebsiella infections because still we do not know which of such responses are protective and which ones may benefit the microbe. Moreover, we lack a complete understanding of the strategies deployed by Klebsiella to avoid the attack of our defenses. Microbes such as Klebsiella are fascinating because they have evolved to flourish in our body despite the attack of our immune system. By learning how they do it, we can identify the vulnerable hot spots of our defenses while discovering the intricacies of the interaction between our body and a microbe. In this research, we will expose a hitherto unknown Klebsiella evasion strategy directed to counteract the microbicidal function of macrophages. These cells are crucial in our protection against Klebsiella. To turn the tide on Klebsiella infections, we will investigate whether blocking this evasion strategy will help our defenses to clear the infection. Interference with the signalling pathways hijacked by microbes for their own benefit is an especially compelling approach to treat multidrug infections. It is thought that this strategy apply less selective pressure for the development of resistance than traditional antimicrobial therapeutics, which are aimed at killing microbes or preventing their growth. In our work we will use a drug already approved for use in humans targeting the proteins manipulated by Klebsiella but used for purposes unrelated to antimicrobial activity. From the drug discovery point of view, this significantly short cuts the drug development process hence allowing a potential fast-track transition from the basic research to clinical development. We envision that our results will encourage other academics as well as pharmaceutical companies to follow this avenue of research to tackle the problem of lack of therapies for microbes resistant to antibiotics.

控制细菌感染也许是现代医学最重要的成就。然而，我们未能跟上微生物对现有治疗方法越来越耐药的步伐。多药耐药肺炎克雷伯菌就是这一威胁的例证，它对所有主要的一线抗生素化合物都具有耐药性。事实上，对“最后手段”抗微生物药物有耐药性的菌株越来越多地进行隔离，大大缩小了治疗选择范围，或在某些情况下完全消除了治疗选择。这在低收入和中等收入国家尤其令人担忧。特别令人关切的是社区中耐药感染的增加，这可能使更多人处于危险之中。例如，在过去五年中，侵袭性克雷伯氏菌感染在英国增加了12%。不幸的是，没有发明新的药物类别，耐药性继续无情地蔓延。风险很高，我们可能正在进入前抗生素时代。英国公共卫生部计算出，缺乏有效的抗生素将使300多万例手术和癌症治疗危及生命，估计在未来30年里，英国将有9万多人死于抗生素耐药性感染。开发新的抗微生物疗法的一个有吸引力的方法是增强保护性免疫反应，事实上，这保护了大多数人。然而，这在克雷伯氏菌感染的情况下尤其困难，因为我们仍然不知道哪些反应是保护性的，哪些反应可能对微生物有益。此外，我们对克雷伯氏菌为避免我们的防御系统受到攻击而采取的策略缺乏全面的了解。像克雷伯氏菌这样的微生物令人着迷，因为尽管免疫系统受到攻击，它们仍在我们体内进化繁殖。通过了解它们是如何做到的，我们可以识别出我们防御系统的脆弱热点，同时发现我们身体和微生物之间复杂的相互作用。在这项研究中，我们将揭示一种迄今为止未知的克雷伯氏菌逃避策略，旨在抵消巨噬细胞的杀微生物功能。这些细胞对我们抵御克雷伯氏菌至关重要。为了扭转克雷伯氏菌感染的趋势，我们将研究阻断这种逃避策略是否有助于我们的防御系统清除感染。干扰被微生物劫持的信号通路以获取自身利益是治疗多药感染的一种特别引人注目的方法。据认为，与旨在杀死微生物或阻止其生长的传统抗菌药物相比，这种策略对耐药性发展施加的选择性压力较小。在我们的工作中，我们将使用一种已经批准用于人类的药物，针对克雷伯氏菌操纵的蛋白质，但用于与抗菌活性无关的目的。从药物发现的角度来看，这大大缩短了药物开发过程，从而允许从基础研究到临床开发的潜在快速过渡。我们设想，我们的结果将鼓励其他学者和制药公司遵循这一研究途径，以解决缺乏对抗生素耐药微生物治疗的问题。

项目成果

Modelling the gastrointestinal carriage of Klebsiella pneumoniae infections

肺炎克雷伯菌感染的胃肠道运输模型

• DOI: 10.1101/2022.10.03.510744
• 发表时间: 2022
• 作者: Calderon-Gonzalez R

In vivo single-cell transcriptomics reveal Klebsiella pneumoniae skews lung macrophages to promote infection.

• DOI: 10.15252/emmm.202216888
• 发表时间: 2022-12-07
• 期刊: EMBO MOLECULAR MEDICINE
• 影响因子: 11.1
• 作者: Dumigan, Amy;Cappa, Oisin;Morris, Brenda;Pessoa, Joana Sa;Calderon-Gonzalez, Ricardo;Mills, Grant;Lancaster, Rebecca;Simpson, David;Kissenpfennig, Adrien;Bengoechea, Jose A.
• 通讯作者: Bengoechea, Jose A.

A cell-free strategy for profiling of intracellular antibiotic sensitivity and resistance

用于分析细胞内抗生素敏感性和耐药性的无细胞策略

• DOI: 10.21203/rs.3.rs-2923903/v1
• 发表时间: 2023
• 作者: Chengan K