Adjunct antibody therapy for severe antibiotic-resistant Acinetobacter baumannii infections

严重抗生素耐药鲍曼不动杆菌感染的辅助抗体治疗

• 批准号: MR/S004394/1
• 负责人: Jeremy Brown
• 金额: $ 144.91万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS004394%2F1
• 关键词: Adjunct; antibody; therapy; severe; antibiotic

Unlike in the UK and other Western countries, the bacteria Acinetobacter baumannii is a common cause of pneumonia and other infections in Asian countries. Unfortunately A. baumannii both often causes severe infections and is frequently highly resistant to antibiotics, including penems and extended spectrum penicillins, and A. baumannii infections therefore have a high mortality and require considerable hospital resources. We will investigate whether antibodies that bind to the surface of A. baumannii bacteria could be used as way of providing additional treatment to patients with an A. baumannii infection along with antibiotics. We will look for several protein targets for an antibody therapy that can increase killing of A. baumannii by human white cells or which by inhibiting mechanisms of antibiotic resistance makes a previously ineffective antibiotic able to kill A. baumannii. To do so we will:Aims 1 and 2. Use information that we have recently obtained on the gene content of 300 Thai A. baumannii strains to identify proteins present in most strains, and use these to construct what is called an antigenome array. Antigenome arrays allow all the proteins that cause an antibody response to be identified, and we will use the A. baumannii conserved protein antigenome array to identify which proteins can cause an antibody response after human or mouse A. baumannii infections.Aims 3. Identify which A. baumannii proteins are abundant on the bacteria during infection or in response to antibiotics using a technology called RNAseq to see which genes are highly expressed during infection or when the bacteria has been stressed by antibiotics; these genes should b particularly good candidates for an antibody therapy.Aim 4. Use the data obtained in aims 1 to 3 to identify which A. baumannii proteins should be investigated further as potential targets for an antibody therapy. We will make each protein antigen and obtain rabbit antibodies to the protein to test the ability of the antibody to recognise and kill different A. baumannii strains using laboratory assays of immune function and mouse models of infection. From these data we select a few protein antigens for use in a protective multivalent antibody therapy that targets several important proteins rather than just individual protein antigens as targeting several proteins should make the treatment more effective as a therapy.Aim 5. To identify which patients with A. baumannii infection and when during infection those patients could benefit from an antibody therapy we will collect data on 100 Thai patients with proven A. baumannii infection. In addition we will purify antibodies developing in these patients as a result of the A. baumannii infection for use in our blood infection model to confirm that antibody therapy can inhibit A. baumannni growth in the blood or resistance to antibiotics. Overall the project will identify which A. baumannii proteins would make good targets for an antibody therapy and confirm the potential of this approach for treating antibiotic resistant A. baumannii infections in Thailand and other Asian countries. By allowing experienced research scientists who work on bacterial infections to start investigating A. baumanii as well, the project will also increase the number of researchers investigating how to combat antibiotic resistant bacteria both in the UK and in Thailand.

与英国和其他西方国家不同，鲍曼不动杆菌是亚洲国家肺炎和其他感染的常见原因。不幸的是，鲍曼不动杆菌经常引起严重感染，并且常常对包括青霉素和广谱青霉素在内的抗生素具有高度耐药性，因此鲍曼不动杆菌感染具有很高的死亡率并且需要大量的医院资源。我们将研究与鲍曼不动杆菌细菌表面结合的抗体是否可以与抗生素一起为鲍曼不动杆菌感染患者提供额外的治疗。我们将寻找抗体疗法的几个蛋白质靶点，以增加人类白细胞对鲍曼不动杆菌的杀伤力，或者通过抑制抗生素耐药性机制，使以前无效的抗生素能够杀死鲍曼不动杆菌。为此，我们将： 目标 1 和 2。利用我们最近获得的 300 个泰国鲍曼不动杆菌菌株的基因内容信息来鉴定大多数菌株中存在的蛋白质，并使用这些信息构建所谓的反基因组阵列。反基因组芯片可以识别引起抗体反应的所有蛋白质，我们将使用鲍曼不动杆菌保守蛋白反基因组芯片来识别哪些蛋白质可以在人或小鼠鲍曼不动杆菌感染后引起抗体反应。目标 3. 识别哪些蛋白质在感染期间或对抗生素产生反应时，鲍曼不动杆菌蛋白在细菌中含量丰富，使用一种名为 RNAseq 的技术来观察哪些基因在感染期间或当细菌受到抗生素应激时高度表达；这些基因应该是抗体治疗的特别好的候选者。目标 4. 使用目标 1 至 3 中获得的数据来确定应进一步研究哪些鲍曼不动杆菌蛋白作为抗体治疗的潜在靶标。我们将制备每种蛋白抗原并获得针对该蛋白的兔抗体，以利用实验室免疫功能测定和小鼠感染模型来测试该抗体识别和杀死不同鲍曼不动杆菌菌株的能力。从这些数据中，我们选择了一些蛋白质抗原用于保护性多价抗体疗法，该疗法针对几种重要的蛋白质，而不仅仅是单个蛋白质抗原，因为针对多种蛋白质应该使治疗更有效。目标 5. 确定哪些患者患有鲍曼不动杆菌感染，当这些患者在感染期间可以从抗体治疗中受益时，我们将收集 100 名已证实感染鲍曼不动杆菌的泰国患者的数据。此外，我们将纯化这些患者因鲍曼不动杆菌感染而产生的抗体，用于我们的血液感染模型，以确认抗体疗法可以抑制鲍曼不动杆菌在血液中的生长或对抗生素的耐药性。总体而言，该项目将确定哪些鲍曼不动杆菌蛋白可以成为抗体治疗的良好靶点，并确认这种方法在泰国和其他亚洲国家治疗抗生素耐药鲍曼不动杆菌感染的潜力。通过允许从事细菌感染研究的经验丰富的研究科学家也开始研究鲍曼不动杆菌，该项目还将增加英国和泰国研究如何对抗抗生素耐药细菌的研究人员数量。

项目成果

Streptococcus pneumoniae interactions with the complement system.

肺炎链球菌与补体系统的相互作用。

• DOI: http://dx.10.3389/fcimb.2022.929483
• 发表时间: 2022
• 期刊: Frontiers in cellular and infection microbiology
• 作者: Gil E

Single-Nucleotide Polymorphisms within the cps Loci: Another Potential Source of Clinically Important Genetic Variation for Streptococcus pneumoniae?

cps 位点内的单核苷酸多态性：肺炎链球菌临床重要遗传变异的另一个潜在来源？

• DOI: http://dx.10.1128/iai.00374-21
• 发表时间: 2021
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Brown JS

Streptococcus pneumoniae meningitis and the CNS barriers.

肺炎链球菌脑膜炎和中枢神经系统障碍。

• DOI: http://dx.10.3389/fcimb.2022.1106596
• 发表时间: 2022
• 期刊: Frontiers in cellular and infection microbiology
• 作者: Gil E

Strain Specific Variations in Acinetobacter baumannii Complement Sensitivity

鲍曼不动杆菌补体敏感性的菌株特异性变异

• DOI: http://dx.10.3389/fimmu.2022.853690
• 发表时间: 2022
• 期刊: Frontiers in Immunology
• 影响因子: 7.3
• 作者: Kamuyu G

Sequential Vaccination With Heterologous Acinetobacter baumannii Strains Induces Broadly Reactive Antibody Responses.

异源鲍曼不动杆菌菌株的序贯疫苗接种可诱导广泛的反应性抗体反应。

• DOI: http://dx.10.3389/fimmu.2021.705533
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 作者: Kamuyu G