Optimising Innate Host Defence to Combat Antimicrobial Resistance

优化宿主先天防御以对抗抗生素耐药性

基本信息

  • 批准号:
    MR/N02995X/1
  • 负责人:
  • 金额:
    $ 366.22万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2016
  • 资助国家:
    英国
  • 起止时间:
    2016 至 无数据
  • 项目状态:
    已结题

项目摘要

The treatment of bacterial infection is complicated by antibiotic resistance. The body's defence against bacteria relies on the immune system and requires blood cells, called macrophages and neutrophils that eat and kill bacteria. Despite being frequently exposed to bacteria that cause serious infections most people rarely become ill due to these bacteria. We can learn from how the immune system protects most people and develop medicines to re-engage this system if it fails. This approach is currently limited by incomplete understanding of the precise mechanisms that kill bacteria in immune cells but our consortium has made great strides to address this. We now wish to refine our understanding of mechanisms that we have already identified and supplement this with further experiments to identify the best approaches with which to modulate these responses in patients. In the body macrophages are the first line of defence against bacteria. We will use techniques that manipulate all the macrophage's genes individually and identify which are most important in regulating bacterial killing. We have also identified that when macrophages commit cell-suicide it helps clear bacteria and we will look for genes that regulate this process. When macrophages are overwhelmed by bacteria neutrophils are important to remove bacteria. For neutrophils we cannot manipulate the cell's genes but we will use an approach that uses antibodies to target all the proteins in the cell and will perform a similar screen to identify factors influencing bacterial killing. We also have some candidates we have already identified which regulate this process. We will then study how important the mechanisms we find are in models of infection where immune cells interact with other cell types. In particular we want to ensure we not only enhance bacterial killing but also minimize the capacity of neutrophil-derived immune factors to cause bystander damage to the body's tissues. Next we will screen panels of chemical structures to enhance the selected mechanisms of bacteria killing. We will work with industry partners to adapt these structures for medical use. In particular we will test how well these target the specific location in the cell where the killing factors are produced using new approaches, termed super-resolution microscopy (SRM), that allow us to measure their production and location in the cell with great precision. We will modify the chemical structures to ensure our medicines target the right mechanism and location in the macrophage or neutrophil. These compounds will then be tested in our models of bacterial infection, including models of bacteria resistant to multiple antibiotics.We will also test how the bacteria respond to attempts by the immune system to kill them. This will also inform understanding of how bacteria escape immune responses and spread between species to establish reservoirs of infection in animals that contribute to human disease with antibiotic resistant bacteria.To confirm our findings are relevant to patients and to test potential medicines that we develop we will study macrophages and neutrophils from healthy volunteers or patients at risk of bacterial infection. Our approach will be significantly enhanced by our ability to image the interaction of bacteria with macrophages and neutrophils, and specifically the factors that regulate or mediate bacterial killing, in the lung of patients. This involves new developments with unique chemical probes and fibre optical imaging. We can potentially translate our findings rapidly to patients because many of the agents we will use to manipulate the innate response are drugs licensed for other medical indications. Our approach will reduce reliance on antibiotics and provide an alternative approach based on modifying the body's immune response that will be active against a range of bacteria, irrespective of their sensitivity to antibiotics.
细菌感染的治疗因抗生素耐药性而变得复杂。人体对细菌的防御依赖于免疫系统,需要被称为巨噬细胞和中性粒细胞的血细胞来吞噬和杀死细菌。尽管经常接触导致严重感染的细菌,但大多数人很少因这些细菌而生病。我们可以从免疫系统如何保护大多数人的过程中学习,并开发药物,以便在免疫系统失灵时重新启动该系统。这种方法目前受到对免疫细胞中杀死细菌的精确机制的不完全理解的限制,但我们的联盟在解决这一问题方面取得了很大进展。我们现在希望完善我们对已经确定的机制的理解,并通过进一步的实验来补充这一点,以确定调节患者这些反应的最佳方法。在体内,巨噬细胞是抵御细菌的第一道防线。我们将使用单独操纵所有巨噬细胞基因的技术,并确定哪些在调节细菌杀伤中最重要。我们还发现,当巨噬细胞自杀时,它有助于清除细菌,我们将寻找调节这一过程的基因。当巨噬细胞被细菌淹没时,中性粒细胞对清除细菌很重要。对于中性粒细胞,我们不能操纵细胞的基因,但我们将使用一种方法,即使用抗体靶向细胞中的所有蛋白质,并将执行类似的筛选,以确定影响细菌杀死的因素。我们也已经确定了一些候选人来规范这一过程。然后,我们将研究我们发现的机制在免疫细胞与其他细胞类型相互作用的感染模型中有多重要。特别是,我们要确保我们不仅能增强细菌杀灭能力,而且还能最大限度地减少中性粒细胞衍生的免疫因子对人体组织造成的旁观者损伤的能力。接下来,我们将筛选化学结构面板,以增强选定的杀死细菌的机制。我们将与行业伙伴合作,使这些结构适应医疗用途。特别是,我们将测试这些靶向细胞中产生杀伤因子的特定位置的效果,使用称为超分辨率显微镜(SRM)的新方法,使我们能够非常精确地测量它们在细胞中的产生和位置。我们将修改化学结构,以确保我们的药物靶向巨噬细胞或中性粒细胞的正确机制和位置。然后,这些化合物将在我们的细菌感染模型中进行测试,包括对多种抗生素具有耐药性的细菌模型。我们还将测试细菌对免疫系统试图杀死它们的反应。这也将有助于了解细菌如何逃避免疫反应并在物种之间传播,从而在动物中建立感染库,从而通过抗生素耐药细菌导致人类疾病。为了证实我们的发现与患者相关,并测试我们开发的潜在药物,我们将研究健康志愿者或有细菌感染风险的患者的巨噬细胞和中性粒细胞。我们的方法将通过我们成像细菌与巨噬细胞和中性粒细胞相互作用的能力,特别是调节或介导细菌杀死的因素,在患者的肺部得到显著增强。这涉及到独特的化学探针和光纤成像的新发展。我们有可能将我们的发现迅速转化为患者,因为我们将用于操纵先天反应的许多药物都是获准用于其他医学适应症的药物。我们的方法将减少对抗生素的依赖,并提供一种基于修改身体免疫反应的替代方法,这种免疫反应将对一系列细菌产生活性,而不管它们对抗生素的敏感性如何。

项目成果

期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
CFTR Protects against Mycobacterium abscessus Infection by Fine-Tuning Host Oxidative Defenses.
  • DOI:
    10.1016/j.celrep.2019.01.071
  • 发表时间:
    2019-02-12
  • 期刊:
  • 影响因子:
    8.8
  • 作者:
    Bernut, Audrey;Dupont, Christian;Kremer, Laurent
  • 通讯作者:
    Kremer, Laurent
Rate of replenishment and microenvironment contribute to the sexually dimorphic phenotype and function of peritoneal macrophages.
  • DOI:
    10.1126/sciimmunol.abc4466
  • 发表时间:
    2020-06-19
  • 期刊:
  • 影响因子:
    24.8
  • 作者:
    Bain CC;Gibson DA;Steers NJ;Boufea K;Louwe PA;Doherty C;González-Huici V;Gentek R;Magalhaes-Pinto M;Shaw T;Bajénoff M;Bénézech C;Walmsley SR;Dockrell DH;Saunders PTK;Batada NN;Jenkins SJ
  • 通讯作者:
    Jenkins SJ
Research priorities to address the global burden of chronic obstructive pulmonary disease (COPD) in the next decade.
  • DOI:
    10.7189/jogh.11.15003
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    7.2
  • 作者:
    Adeloye D;Agarwal D;Barnes PJ;Bonay M;van Boven JF;Bryant J;Caramori G;Dockrell D;D'Urzo A;Ekström M;Erhabor G;Esteban C;Greene CM;Hurst J;Juvekar S;Khoo EM;Ko FW;Lipworth B;López-Campos JL;Maddocks M;Mannino DM;Martinez FJ;Martinez-Garcia MA;McNamara RJ;Miravitlles M;Pinnock H;Pooler A;Quint JK;Schwarz P;Slavich GM;Song P;Tai A;Watz H;Wedzicha JA;Williams MC;Campbell H;Sheikh A;Rudan I
  • 通讯作者:
    Rudan I
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David Dockrell其他文献

Pneumolysin mediates lysosomal changes following internalisation by macrophages
  • DOI:
    10.1016/j.jinf.2008.01.016
  • 发表时间:
    2008-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Martin Bewley;Marc Daigneault;Tim Mitchell;Rob Read;Moira Whyte;David Dockrell
  • 通讯作者:
    David Dockrell
Correction to: Managing pneumonia through facility-based integrated management of childhood management (IMCI) services: an analysis of the service availability and readiness among public health facilities in Bangladesh
  • DOI:
    10.1186/s12913-021-06898-z
  • 发表时间:
    2021-08-26
  • 期刊:
  • 影响因子:
    3.000
  • 作者:
    Ahmed Ehsanur Rahman;Shema Mhajabin;David Dockrell;Harish Nair;Shams El Arifeen;Harry Campbell
  • 通讯作者:
    Harry Campbell
Is FRAX® a valid screening tool for fragility fracture risk assessment in HIV-positive individuals?: Category: Scientific free paper
  • DOI:
    10.1016/j.jinf.2011.04.078
  • 发表时间:
    2011-12-01
  • 期刊:
  • 影响因子:
  • 作者:
    Ben Stone;Eugene McCloskey;Christine Bowman;David Dockrell
  • 通讯作者:
    David Dockrell
The association between Vitamin D deficiency and CD4 T-Lymphocyte depletion in sero-positive individuals: Category: Scientific free paper
  • DOI:
    10.1016/j.jinf.2011.04.090
  • 发表时间:
    2011-12-01
  • 期刊:
  • 影响因子:
  • 作者:
    Alicia Vedio;Benjamin Stone;Anne Tunbridge;David Dockrell
  • 通讯作者:
    David Dockrell

David Dockrell的其他文献

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{{ truncateString('David Dockrell', 18)}}的其他基金

MICA: Mitochondrial dysfunction in macrophages and impaired bacterial clearance in chronic obstructive pulmonary disease (COPD)
MICA:慢性阻塞性肺疾病 (COPD) 中巨噬细胞线粒体功能障碍和细菌清除受损
  • 批准号:
    MR/W028506/1
  • 财政年份:
    2022
  • 资助金额:
    $ 366.22万
  • 项目类别:
    Research Grant

相似国自然基金

Innate-likeB细胞受损介导凋亡细胞的清除障碍在系统性红斑狼疮发病中的作用及机制研究
  • 批准号:
    81860295
  • 批准年份:
    2018
  • 资助金额:
    35.0 万元
  • 项目类别:
    地区科学基金项目

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