Targeting airborne bacterial infection: Studies on patient- and laboratory-generated mycobacterium tuberculosis aerosols.

针对空气传播的细菌感染：对患者和实验室产生的结核分枝杆菌气溶胶的研究。

• 批准号: MR/P023061/1
• 负责人: Michael Barer
• 金额: $ 57.94万
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP023061%2F1
• 关键词: Targeting; airborne; bacterial; infection; Studies

Globally, tuberculosis (TB) is the single most important cause of death and disease due to a bacterial agent. Like many other bacterial infections affecting the lungs, TB is transmitted by aerosols (tiny droplets expelled by coughing and other respiratory efforts) generated by infected individuals. Together TB and other airborne bacterial infections cause approximately 4 million deaths worldwide every year and remain a significant problem in the UK. In spite of the importance of aerosols in transmitting infection we have very little information on the biological properties that bacteria need to be transmitted by this route. Our previous research suggests both that the properties of bacteria expelled by TB cases are distinctive and that they are likely to change further during transit. We recently established methods for capturing aerosols produced by TB patients and to determine the pattern of genes expressed by its bacterial cause, Mycobacterium tuberculosis (Mtb). These methods are built on the patient Cough Aerosol Sampling System (CASS) which has revealed that the risk of infection in household contacts of a TB can be predicted by the number bacteria the patient produces in a standard CASS sample. Our use of the CASS system here will enable us to relate our results to the infectiousness of the individual patients we sample.Here we will characterise the CASS and a laboratory aerosol generation and sampling system, and use both to answer four questions: 1) is the TB aerosol more than just a simple sample of the mucus secretions (sputum) patients cough-up (sputum analysis has traditionally been used to assess infectiousness); 2) how does survival and gene expression of Mtb change with time and ambient conditions in laboratory aerosols; 3) which of Mtb's genes make important contributions to the bacterium's survival and transfer in aerosol; and 4) are the numbers of Mtb bacilli in aerosols underrepresented by standard agar culture methods? By defining the Mtb genes and gene expression patterns important for aerosol transmission we aim to uncover new methods to control infection; these could include targeting critical Mtb gene products in patients to render them less infectious, altering ambient conditions to make them unfavourable for survival and transmission of Mtb and preventing the establishment of new infections. Reducing infectiousness could be particularly important in managing the increasing problem of drug resistant TB, where it may take a long time to render patients non-infectious. Simple alterations to ambient conditions could be valuable in the management of healthcare facilities, a particular problem in resource-limited settings. Finally, the potential for Mtb to change its properties in response to aerosol transfer raises the likelihood that we do not know what features the bacterium expresses when it is breathed in by a new potential victim and which of these features is essential to establishing infection. By identifying the way Mtb adapts to aerosol transfer, our work has clear potential to identify new Mtb targets for prophylactic therapy in recently exposed individuals and for vaccines that might prevent infection, a particularly weak feature of the current BCG vaccine and vaccine candidates in development.Our study involves collaborations between clinicians (Pretoria), bacteriologists (Leicester), and specialists in the biology (Porton) and physics (Leeds) of aerosols. We will use exceptional facilities in South Africa, Leicester and Public Health England (Porton) to deliver the work. The Leeds group will develop computer models of our sampling systems to better define how completely the results reflect the aerosols sampled. These and our biological results will be used to develop new quantitative models of patient infectiousness. We believe that understanding the TB aerosol will create new opportunities to control Mtb and provide important lessons applicable to other airborne infections.

在全球范围内，结核病（TB）是由细菌引起的死亡和疾病的唯一最重要原因。像许多其他影响肺部的细菌感染一样，结核病通过受感染个体产生的气溶胶（咳嗽和其他呼吸努力排出的微小液滴）传播。结核病和其他空气传播的细菌感染每年在全世界造成约400万人死亡，在英国仍然是一个严重的问题。尽管气溶胶在传播传染病方面很重要，但我们对细菌通过这一途径传播所需的生物学特性知之甚少。我们以前的研究表明，结核病病例排出的细菌的特性是独特的，并且它们可能在运输过程中进一步改变。我们最近建立了捕获结核病患者产生的气溶胶的方法，并确定了其细菌病因结核分枝杆菌（Mtb）表达的基因模式。这些方法建立在患者咳嗽气溶胶采样系统（卡斯）的基础上，该系统揭示了结核病家庭接触者的感染风险可以通过患者在标准卡斯样本中产生的细菌数量来预测。我们将使用卡斯系统和实验室气溶胶发生和采样系统来回答以下四个问题：1）肺结核气溶胶是否不仅仅是患者咳出的粘液分泌物（痰液）的简单样本（痰液分析传统上用于评估传染性）; 2）在实验室气溶胶中，结核分枝杆菌的存活和基因表达如何随时间和环境条件而变化; 3）结核分枝杆菌的哪些基因对细菌在气溶胶中的存活和转移做出重要贡献;和4）标准琼脂培养方法是否不能充分代表气溶胶中的结核分枝杆菌数量？通过定义对气溶胶传播重要的Mtb基因和基因表达模式，我们的目标是发现控制感染的新方法;这些方法可能包括靶向患者中的关键Mtb基因产物，使其感染性降低，改变环境条件，使其不利于Mtb的生存和传播，并防止新感染的建立。减少传染性在管理日益严重的耐药结核病问题方面可能特别重要，因为可能需要很长时间才能使患者不具有传染性。对环境条件的简单改变在医疗设施的管理中可能是有价值的，这在资源有限的环境中是一个特别的问题。最后，结核分枝杆菌改变其特性以响应气溶胶转移的可能性增加了我们不知道细菌在被新的潜在受害者吸入时表达什么特征以及这些特征中的哪一个对于建立感染至关重要的可能性。通过确定结核分枝杆菌适应气溶胶转移的方式，我们的工作具有明确的潜力，可以确定新的结核分枝杆菌靶点，用于最近暴露的个体的预防性治疗和可能预防感染的疫苗，这是当前BCG疫苗和正在开发的候选疫苗的一个特别薄弱的特征。（比勒陀利亚）、细菌学家（莱斯特）以及气溶胶的生物学（波顿）和物理学（利兹）专家。我们将利用南非、莱斯特和英国公共卫生部（波顿）的特殊设施来开展工作。利兹小组将开发我们采样系统的计算机模型，以更好地定义结果如何完全反映采样的气溶胶。这些和我们的生物学结果将用于开发新的患者传染性定量模型。我们相信，了解结核病气溶胶将创造新的机会，以控制结核病，并提供适用于其他空气传播感染的重要教训。

项目成果

Exhaled SARS-CoV-2 RNA viral load kinetics measured by facemask sampling associates with household transmission.

• DOI: 10.1016/j.cmi.2022.07.005
• 发表时间: 2023-03
• 期刊: CLINICAL MICROBIOLOGY AND INFECTION
• 影响因子: 14.2
• 作者: Pan, Daniel;Williams, Caroline M.;Decker, Jonathan;Fletcher, Eve;Sze, Shirley;Assadi, Sara;Haigh, Richard;Saleem, Baber;Nazareth, Joshua;Garton, Natalie J.;Pareek, Manish;Barer, Michael R.
• 通讯作者: Barer, Michael R.

Exhaled SARS-CoV-2 quantified by face-mask sampling in hospitalised patients with COVID-19.

• DOI: 10.1016/j.jinf.2021.03.018
• 发表时间: 2021-06
• 期刊: The Journal of infection
• 作者: Williams CM;Pan D;Decker J;Wisniewska A;Fletcher E;Sze S;Assadi S;Haigh R;Abdulwhhab M;Bird P;Holmes CW;Al-Taie A;Saleem B;Pan J;Garton NJ;Pareek M;Barer MR
• 通讯作者: Barer MR

Exhaled Mycobacterium tuberculosis Predicts Incident Infection in Household Contacts.

• DOI: 10.1093/cid/ciac455
• 发表时间: 2023-02-08
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

A Persistent Tuberculosis Outbreak in the UK Is Characterized by Hydrophobic fadB4-Deficient Mycobacterium tuberculosis That Replicates Rapidly in Macrophages.

• DOI: 10.1128/mbio.02656-22
• 发表时间: 2022-12-20
• 期刊: mBio
• 影响因子: 6.4
• 作者: Farzand R;Haigh RD;Monk P;Haldar P;Patel H;Pareek M;Verma R;Barer MR;Woltmann G;Ahyow L;Jagatia H;Decker J;Mukamolova GV;Cooper AM;Garton NJ;O'Hare HM
• 通讯作者: O'Hare HM

COVID-19 symptoms are reduced by targeted hydration of the nose, larynx and trachea.

• DOI: 10.1038/s41598-022-08609-y
• 发表时间: 2022-03-29
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: George CE;Scheuch G;Seifart U;Inbaraj LR;Chandrasingh S;Nair IK;Hickey AJ;Barer MR;Fletcher E;Field RD;Salzman J;Moelis N;Ausiello D;Edwards DA
• 通讯作者: Edwards DA