The typhoid toxin of Salmonella Typhi - a new disease mechanism and a strategy for combatting drug-resistant typhoid and chronic carriage in humans

伤寒沙门氏菌的伤寒毒素——一种新的疾病机制和对抗人类耐药伤寒和慢性携带的策略

基本信息

批准号：
MR/S034390/1
负责人：
Daniel Humphreys
金额：
$ 119.24万
依托单位：
University of Sheffield
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FS034390%2F1
关键词：
typhoid toxin Salmonella Typhi new

项目摘要

Antimicrobial resistance (AMR) is a defining problem facing society. This is epitomised by epidemics of typhoid fever caused by AMR lineages of the bacterial pathogen Salmonella Typhi that underlies 21 million typhoid cases and 168,000 deaths each year. For example, in Malawi, only 7% of typhoid cases were resistant to multiple drugs before 2010. By 2015, 97% of typhoid cases resisted multi-drug treatments. Thus, global organisations who lead the fight against S.Typhi, such as the Typhoid Vaccine Acceleration Consortium (TyVAC), aim to eradicate typhoid. However, there's a second problem: S.Typhi also causes chronic infections in humans without obvious clinical symptoms. These so-called 'chronic carriers' retain and transmit S.Typhi in the population. We know remarkably little about chronic carriage, which impedes global efforts to eradicate typhoid. To combat S.Typhi and develop pathogen eradication strategies, we must resolve the decisive mechanisms responsible for typhoid fever and chronic carriage.Remarkably, the mortal symptoms of typhoid and chronic carriage are facilitated through a single S.Typhi virulence factor called the typhoid toxin, which causes damage to DNA in our cells and activates the cellular DNA damage response (DDR). How the toxin manipulates the DDR and how this mediates typhoid fever and chronic carriage is not understood.My laboratory has made two major discoveries that have the potential to unlock the toxin mechanism and provide a new way to combat typhoid fever and chronic carriage. We discovered that:(i) The toxin drives infections by triggering senescence in human cells. The senescent cells released factors that induced senescence in neighbouring cells creating a domino-like effect throughout the population. To our surprise, the senescent cells have increased susceptibility to intracellular Salmonella infections, which reveals a new role for the toxin - inducing cellular senescence to drive infection.(ii) The toxin induces senescence via a unique DDR Response Induced by a bacterial Genotoxin (RING). The RING phenotype signifies a new virulence mechanism driven by toxin-induced damage at sites of DNA replication, which underpins cell division. The novelty and importance are clear. If the toxin facilitates typhoid fever symptoms and chronic carriage through the DDR, then we need to (i) resolve the DNA damage mechanisms underpinning the RING phenotype, and (ii) understand how senescence facilitates Salmonella infections in cells and animal models (Aims of the 4-year plan). By achieving the 4-year plan objectives, I will unveil the identity of cellular factors that are crucial to the toxin mechanism and reveal potential biomarkers that will help me address the problem of typhoid and chronic carriage in humans via my 7-year plan. This will be achieved by investigating the toxin mechanism in humans using clinical samples to reveal potential biomarkers that will help diagnosis and disease surveillance, and by screening for novel therapeutics, which counteract the toxin underlying typhoid and chronic carriage.To maximise project impact and my leadership potential, I have designed a Fellow Development Plan that integrates with the research aims and builds towards the translational goals of the 7-year plan. The Development Plan includes: (i) experience in typhoid clinical trials and eradication programmes with TyVAC in the USA, (ii) field research on AMR S.Typhi in Vietnam, (iii) leading a typhoid-focussed research meeting in the UK, (iv) 'Take on Typhoid' public engagement experience, and (v) engaging with current leaders in the field who advise the UK government and the World Health Organisation on policy regarding typhoid.The proposed UKRI FLF aims to contribute to global efforts against AMR S.Typhi by revealing how the toxin drives typhoid and chronic disease, which has the potential to improve human health by impacting typhoid control strategies and eradication programmes

抗菌抗性（AMR）是社会面临的定义问题。这是由细菌病原体鼠伤寒谱系引起的伤寒流行病的缩影，每年有2100万个伤寒病例和168,000例死亡。例如，在马拉维，只有7％的伤寒病例在2010年之前对多种药物有抵抗力。到2015年，伤寒病例中有97％抵抗了多药治疗。因此，领导与S.Typhi斗争的全球组织，例如伤寒疫苗加速联盟（TYVAC），旨在消除伤寒。但是，还有第二个问题：S. typhi还会引起人类的慢性感染，而没有明显的临床症状。这些所谓的“慢性携带者”保留并在人群中传播s.typhi。我们对慢性马运输的了解一无所知，这阻碍了全球消除伤寒的努力。为了对抗S. typhi并制定病原体消除策略，我们必须解决负责伤寒和慢性运输的决定性机制。可疑，伤寒和慢性托架的致命症状是通过称为单一的S. typhi毒力因子来促进的。这会导致我们的细胞中DNA损伤，并激活细胞DNA损伤反应（DDR）。毒素如何操纵DDR，以及如何介导伤寒和慢性载体。我的实验室已经做出了两个主要发现，具有解锁毒素机制的潜力，并提供了一种与伤寒发烧和慢性发烧的新方法。我们发现：（i）毒素通过触发人类细胞衰老而驱动感染。衰老细胞释放了诱导邻近细胞衰老的因素，在整个人群中产生了多米诺骨样效应。令我们惊讶的是，衰老细胞具有增加对细胞内沙门氏菌感染的敏感性，这揭示了毒素的新作用 - 诱导细胞衰老引起感染。）。环表型表示由DNA复制位点造成的损伤驱动的一种新的毒力机制，该机制是细胞分裂的基础。新颖性和重要性很明显。如果毒素促进了伤寒症状和通过DDR慢性运输，则我们需要（i）解决基于环表型的DNA损伤机制，以及（ii）了解衰老如何促进细胞和动物模型中的沙门氏菌感染（目标4年计划）。通过实现4年计划目标，我将揭示对毒素机制至关重要的细胞因素的身份，并揭示潜在的生物标志物，这将帮助我通过我的7年计划解决人类中的伤寒和慢性运输问题。这将通过使用临床样品调查人类中的毒素机制来揭示潜在的生物标志物，从而有助于诊断和疾病监测，并筛选新的治疗剂，这些治疗剂抵消了基础的伤寒和慢性运输的毒素。潜力，我设计了一项与研究的旨在集成的发展计划，并朝着7年计划的转化目标建立。该开发计划包括：（i）美国Tyvac在美国的伤寒临床试验和根除计划的经验，（ii）越南AMR S.Typhi的现场研究，（iii）在英国领导了一场以伤寒为重点的研究会议，（（ iv）“接受伤寒”的公众参与经验，以及（v）与该领域的现任领导人互动，这些领域就伤寒建议英国政府和世界卫生组织政策。 .typhi通过揭示毒素如何驱动伤寒和慢性病，这有可能通过影响伤寒控制策略和消除计划来改善人类健康