A genetically modified nasopharyngeal commensal as a platform for human bacteriotherapy

转基因鼻咽共生体作为人类细菌治疗的平台

• 批准号: MR/N013204/1
• 负责人: Robert Read
• 金额: $ 25.51万
• 依托单位: University of Southampton
• 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
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN013204%2F1
• 关键词: genetically; modified; nasopharyngeal; commensal; platform

Our long term objective is to invent a new type of medicine which consists of living bacteria which would be given as nose drops (akin to the Yacult drink that is commercially available and taken by mouth by people with bowel problems). We have recently published work in which we inoculated a small dose of a `friendly bacterium` - Neisseria lactamica - into the noses of participants and found that the bacterium was still present in their throats 6 months later, and caused no ill effects. Furthermore, the friendly bacterium stopped the paticipants from being infected with a related bacterium which can cause meningitis. This concept of `bacteriotherapy` is rapidly gaining credence as a way to treat bacterial infections - for example we now treat Clostridium difficile diarrhoea with bacteria derived from the stools of donors, and it works very well. We have discovered a way to genetically transform Neisseria lactamica with genes from a very wide range of living things, which means that we could potentially develop a range of bacterial medicines containing genes which exert specific desired effects in the recipients. For example, we could make a bacterial medicine which makes substances which kill harmful bacteria or viruses or which simply out-competes them. One of the problems with our idea is that when we inoculated students with the Neisseria lactamica, we found that 65% of them became colonised, but this was only 35% if we restricted the study to non-smokers. This would not be a very reliable bacteriotherapy and we would need to increase the likelihood of colonisation if this approach is to be of any use. So, in the proposed study, we will use our technology to make a strain of Neisseria lactamica which makes two proteins that are normally used by other bacteria to stick to cells. We will use for this purpose two proteins that are normally made by the related meningitis bacterium Neisseria meningitidis, to stick to stick to the inner surface of the nose when it colonises humans. We will show that the new genetically modified strain has all of the characteristics we expect including the ability to stick better to cells in the laboratory, and that is safe to release into the community (because it is not more resistant to the immune system, or to antibiotics, and does not have increased capacity to gradually change into something more dangerous). We will then apply to the appropriate regulators for permission to repeat our studies with human volunteers to see if the genetically modified strain that we have generated manages to colonise better than the wild type bacterium from which it is derived. This would be the subject of a follow-on study - if that were to be successful this strategy that we have devised would be a future therapy of relevance to any disease process involving colonisation of the nasopharynx, eg pneumonia, Chronic Bronchitis, sinusitis, ear infection, meningitis or MRSA colonisation and disease.

我们的长期目标是发明一种由活细菌组成的新型药物，这种药物可以作为滴鼻剂（类似于市售的Yacult饮料，由肠道问题患者口服）。我们最近发表了一项研究，我们将小剂量的“友好细菌”-此外，这种友好的细菌阻止了患者感染一种可能导致脑膜炎的相关细菌。这种“细菌疗法”的概念作为一种治疗细菌感染的方法正在迅速获得信任-例如，我们现在用来自捐赠者粪便的细菌治疗艰难梭菌腹泻，效果非常好。我们已经发现了一种方法，可以用来自各种生物的基因对内酰胺奈瑟菌进行遗传转化，这意味着我们有可能开发出一系列含有基因的细菌药物，这些基因可以在接受者中发挥特定的预期作用。例如，我们可以制造一种细菌药物，这种药物制造的物质可以杀死有害的细菌或病毒，或者只是在竞争中击败它们。我们的想法的一个问题是，当我们给学生接种内酰胺奈瑟菌时，我们发现65%的学生被定植，但如果我们将研究限制在非吸烟者中，这只有35%。这不是一种非常可靠的细菌疗法，如果这种方法有任何用处，我们需要增加定殖的可能性。因此，在拟议的研究中，我们将使用我们的技术来制造一种内酰胺奈瑟菌菌株，这种菌株可以制造两种蛋白质，这两种蛋白质通常被其他细菌用来粘附细胞。为此，我们将使用两种蛋白质，它们通常由相关的脑膜炎细菌脑膜炎奈瑟氏球菌（Neisseria meningitidis）制造，当它在人类中定居时，它们会粘附在鼻子的内表面。我们将证明新的转基因菌株具有我们预期的所有特征，包括在实验室中更好地粘附细胞的能力，并且释放到社区中是安全的（因为它对免疫系统或抗生素没有更强的抵抗力，并且没有增加逐渐变成更危险的能力）。然后，我们将向适当的监管机构申请许可，在人类志愿者中重复我们的研究，看看我们产生的转基因菌株是否比它所来源的野生型细菌更好地定植。这将是后续研究的主题-如果成功，我们设计的这种策略将成为未来与涉及鼻咽定殖的任何疾病过程相关的治疗方法，例如肺炎、慢性支气管炎、鼻窦炎、耳部感染、脑膜炎或MRSA定殖和疾病。

项目成果

Genomes of Escherichia coli bacteraemia isolates originating from urinary tract foci contain more virulence-associated genes than those from non-urinary foci and neutropaenic hosts.

• DOI: 10.1016/j.jinf.2018.10.011
• 发表时间: 2018-12
• 期刊: The Journal of infection
• 作者: Dale AP;Pandey AK;Hesp RJ;Belogiannis K;Laver JR;Shone CC;Read RC
• 通讯作者: Read RC

Neisseria lactamica Controlled Human Infection Model.

• DOI: 10.1007/978-1-0716-1900-1_21
• 发表时间: 2022-01-01
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Dale, Adam P;Gbesemete, Diane F;Laver, Jay R
• 通讯作者: Laver, Jay R

Effect of colonisation with Neisseria lactamica on cross-reactive anti-meningococcal B-cell responses: a randomised, controlled, human infection trial.

• DOI: 10.1016/s2666-5247(22)00283-x
• 发表时间: 2022-12
• 期刊: The Lancet. Microbe
• 作者: Dale AP;Theodosiou AA;Gbesemete DF;Guy JM;Jones EF;Hill AR;Ibrahim MM;de Graaf H;Ahmed M;Faust SN;Gorringe AR;Polak ME;Laver JR;Read RC
• 通讯作者: Read RC

Public attitudes to a human challenge study with SARS-CoV-2: a mixed-methods study.

公众对SARS-COV-2：混合方法研究的人类挑战研究的态度。

• DOI: 10.12688/wellcomeopenres.17516.1
• 发表时间: 2022
• 期刊: Wellcome open research
• 作者: Barker C;Collet K;Gbesemete D;Piggin M;Watson D;Pristerà P;Lawerence W;Smith E;Bahrami-Hessari M;Johnson H;Baker K;Qavi A;McGrath C;Chiu C;Read RC;Ward H
• 通讯作者: Ward H

Investigating Bordetella pertussis colonisation and immunity: protocol for an inpatient controlled human infection model.

• DOI: 10.1136/bmjopen-2017-018594
• 发表时间: 2017-10-11
• 期刊: BMJ open
• 影响因子: 2.9
• 作者: de Graaf H;Gbesemete D;Gorringe AR;Diavatopoulos DA;Kester KE;Faust SN;Read RC
• 通讯作者: Read RC