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日益耐药的步伐。这种威胁的例子是多重耐药肺炎克雷伯菌，它对所有主要的一线抗生素化合物都有耐药性。事实上，对“最后手段”抗菌药物耐药的菌株的日益分离已经显着缩小了治疗选择，或者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震惊。特别令人担忧的是社区中耐药感染的增加，这可能使更多的人面临风险。例如，过去 5 年英国的侵袭性克雷伯氏菌感染增加了 12%。不幸的是，新型药物尚未被发明出来，耐药性继续无情地蔓延。风险很高，我们可能正在进入一个前抗生素时代。英国公共卫生部门计算出，由于缺乏有效的抗生素，超过 300 万次手术和癌症治疗将危及生命，预计未来 30 年内英国将有超过 9 万人因抗生素耐药性感染而死亡。开发新的抗菌疗法的方法是增强保护性免疫反应，这实际上可以保护大多数人。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攻击我们的防御而部署的策略缺乏完整的了解。像克雷伯氏菌这样的微生物很令人着迷，因为尽管我们的免疫系统受到攻击，它们仍然能够在我们的体内繁衍生息。通过了解它们是如何做到这一点的，我们可以识别我们防御的脆弱热点，同时发现我们的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菌功能。这些细胞对于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局面，我们将研究阻止这种逃避策略是否有助于我们的防御系统清除感染。干扰微生物为了自身利益而劫持的信号通路是治疗多药感染的一种特别引人注目的方法。人们认为，与旨在杀死微生物或阻止其生长的传统抗菌疗法相比，这种策略对耐药性的产生施加的选择性压力较小。在我们的工作中，我们将使用一种已批准用于人类的药物，该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，从而实现了从基础研究到临床开发的潜在快速过渡。我们预计，我们的研究结果将鼓励其他学者以及制药公司遵循这一研究途径，以解决缺乏抗生素耐药微生物治疗方法的问题。

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

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

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.