Acute senescence: a novel host defence counteracting typhoidal Salmonella

急性衰老：对抗伤寒沙门氏菌的新型宿主防御

• 批准号: MR/X02329X/1
• 负责人: Daniel Humphreys
• 金额: $ 75.82万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX02329X%2F1
• 关键词: Acute; senescence; novel; host; defence

Typhoid fever is an infectious disease caused by Salmonella Typhi resulting in 14 million cases, 140,000 deaths and 8 million daily-adjusted life years lost to ill health per annum. The problem is exacerbated by antimicrobial-resistance and poor diagnostics due to a lack of suitable biomarkers. We must advance understanding of typhoid to accelerate development of therapeutic interventions, which represent priorities for the WHO and UN Sustainable Development Goals.S.Typhi lives inside our gut cells before infecting the bloodstream (bacteraemia) and spreading to different organs in the body resulting in typhoid fever. My UKRI FLF was awarded upon our discovery that S.Typhi causes premature ageing in human cells by releasing a toxin. The typhoid toxin causes DNA damage in our cells, in much the same way as UV light, and this elicits an ageing-like process in cells called acute senescence. Ageing comes with increased susceptibility to infection. Thus, we initially hypothesised that the toxin causes senescence to make human cells more vulnerable to infection. To our surprise, discoveries during my FLF indicate the opposite may be true and that acute senescence is a novel immune defence pathway, which can attack S.Typhi through antimicrobial activities and help prevent typhoid. This is unexpected yet, in early life, acute senescence is known to prevent cancer, thus, we hypothesise that acute senescence may have co-evolved to counteract infectious diseases such as typhoid. The FLF renewal aims to lead a new area of research investigating Acute Senescence Antimicrobial Responses (ASAR).Our experiments with cultured cells and clinical samples indicate that when typhoid toxin causes DNA damage, cells signal their distress by(i) entering into a senescent state through the human gene p21, and by(ii) secreting antimicrobial proteins into the extracellular environment.In cancerous cells, p21 stops the cells from growing into tumours and secrete proteins that attracts immune cells to destroy the cancer cells. Thus, we will determine whether p21 launches ASAR: (i) by suppressing the growth of S.Typhi living inside senescent cells, and (ii) by suppressing the growth of extracellular S.Typhi via secretion of antimicrobials and immune cell attractants. This is how we will investigate ASAR:Objective 1: Advance discovery of antimicrobials secreted in human participants with typhoid.A clinical study revealed that the duration of bacteraemia in human participants with typhoid was shorter with wild-type (WT) S.Typhi carrying typhoid toxin than toxin-negative (TN) S.Typhi (WT 48 hours; TN 96 hours). This indicates that unknown factors are attacking WT but not TN S.Typhi. Thus, we will determine whether clinical samples from participants infected with WT contain antimicrobial biomarkers released in response to typhoid toxin.Objective 2: Determine whether antimicrobial responses are regulated by senescence. We will validate whether antimicrobial biomarkers identified through objective 1 rely upon p21-mediated senescence. This will be achieved by examining Salmonella-infected cells undergoing senescence in human tissue culture experiments and infected miceObjective 3: Establish antimicrobial activities of the Acute Senescence Antimicrobial Response We will progress from objective 2 by elucidating whether secreted senescent-associated antimicrobial biomarkers attack extracellular S.Typhi and whether p21 in the infected senescent cells suppress infection by activating intracellular defences against S.Typhi.By revealing ASAR as a novel innate defence suppressing Salmonella infection, my team will discover a new immune pathway that combats typhoid fever, which will be significant during infections by related pathogens of global importance. By leading a new area of research on ASAR, the renewal will facilitate ways to enhance ASAR and discover of translatable antimicrobial biomarkers with diagnostic potential.

伤寒是由沙门氏菌Typhi引起的一种传染病，导致1400万例，每年140,000例死亡和800万例调整的生活年，每年不健康。由于缺乏合适的生物标志物，抗菌抗性和诊断不佳，加剧了问题。我们必须提高对伤寒的理解，以加速治疗干预措施的发展，这代表了WHO和联合国可持续发展目标的优先事项。伤寒。我们的乌克里FLF是在发现S.Typhi通过释放毒素而导致人类细胞过早衰老的情况下授予的。伤寒毒素以与紫外光几乎相同的方式引起我们的细胞中的DNA损伤，这引起了称为急性衰老的细胞中衰老的过程。衰老会增加对感染的敏感性。因此，我们最初假设毒素会导致衰老使人类细胞更容易受到感染的影响。令我们惊讶的是，在我的FLF期间的发现表明恰恰相反，并且急性衰老是一种新型的免疫防御途径，可以通过抗菌活性攻击S. typhi，并有助于防止伤寒。这是意外的，在早期生命中，急性衰老可以预防癌症，因此，我们假设急性衰老可能已经共同发展以抵消诸如伤寒等传染病。 FLF更新旨在领导一项新的研究领域，研究急性衰老抗菌反应（ASAR）。您对培养细胞和临床样品进行的实验表明，当伤寒毒素造成DNA损害时，细胞会通过（I）发出（I）进入鼻鼻状态的痛苦。通过人类基因p21，以及（ii）将抗菌蛋白分泌到细胞外环境中。在癌细胞中，p21阻止细胞生长成肿瘤并分泌吸引免疫细胞破坏癌细胞的蛋白质。因此，我们将确定p21是否发射ASAR：（i）通过抑制居住在衰老细胞内的S. typhi的生长，以及（ii）通过通过分泌抗菌和免疫细胞吸引剂的分泌来抑制细胞外S. typhi的生长。这就是我们将如何调查ASAR：目标1：预先发现在伤寒的人参与者中分泌的抗菌剂。一项临床研究表明，人伤寒参与者的菌血症持续时间较短毒素比毒素阴性（TN）S.typhi（WT 48小时； TN 96小时）。这表明未知因素是攻击WT，而不是Tn s.typhi。因此，我们将确定感染WT参与者的临床样本是否包含对伤寒毒素释放的抗菌生物标志物。目标2：确定抗菌反应是否通过衰老调节。我们将验证通过目标1鉴定的抗菌生物标志物是否依赖于P21介导的衰老。这将通过检查人类组织培养实验中衰老的沙门氏菌感染细胞和感染的小鼠3：建立急性衰老抗菌抗菌反应的抗菌活性来实现这一目标，我们将通过阐明分泌的鼻鼻伴侣抗菌生物标志物攻击外虫生物标志物s.鼠伤寒以及感染衰老细胞中的p21是否通过激活针对s. typhi的细胞内防御能力来抑制感染。通过揭示ASAR作为一种新型的先天防御抑制沙门氏菌感染，我的团队会发现一种新的免疫途径，与Typhoid Fever作战，这将在Typhoid Fever期间进行重大意义，这在相关病原体的感染全球重要性。通过领导有关ASAR的新研究领域，续订将促进具有诊断潜力的可翻译抗菌生物标志物增强ASAR和发现的方法。