Survival and dissemination of enteric pathogens through activation and subsequent inhibition of programmed cell death pathways

通过激活和随后抑制程序性细胞死亡途径来维持和传播肠道病原体

• 批准号: BB/K008005/1
• 负责人: Daniel Wall
• 金额: $ 55.38万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK008005%2F1
• 关键词: Survival; dissemination; enteric; pathogens; through

After being ingested on infected food pathogenic bacteria are taken up by cells in the intestine, entering the cells and attempting to grow. An infected cell recognizing the danger undergoes a tightly controlled form of cell suicide known as apoptosis. Thus the cell removes itself and the danger whilst simultaneously sending out warning signals to the immune system. E. coli and Salmonella are two of the most common food poisoning associated pathogens in the U.K. Based on our knowledge of the body's response to infection we would expect cells to undergo apoptosis when they come into contact with E. coli and Salmonella. In the case of these pathogens however the infected cells survive for some time following infection allowing the bacteria to grow within the infected cell. This extra time for growth is crucial, allowing these pathogens time to multiply and cause a more serious prolonged infection. Through this proposal we aim to understand how these pathogens are prolonging the life of infected cells. This work will have relevance for numerous bacterial pathogens, many of which we now know also attempt to interfere with this process of apoptosis during infection. Our previous work has shed new light on the complex interactions occurring in Salmonella infected cells. During infection the bacteria deliberately target proteins in the cell that respond to the infection by inducing cell suicide. In particular one extremely potent host cell enzyme called caspase-3, or the 'executioner caspase' is targeted. This is the key enzyme in inducing cell suicide, killing the cell quickly but in a controlled fashion. Due to the destructive power of caspase-3 its activation is tightly regulated, making its targeting by bacterial pathogens all the more surprising. However instead of trying to prevent caspase-3 from working these bacteria initially try to harness its activity bypassing the stringent controls put in place to ensure caspase-3 activity is kept in check. We now know Salmonella infection is activating caspase-3 by a unique mechanism and understanding and exploiting this is a key objective for this proposal. Activation of an enzyme as destructive as caspase-3 is a risky strategy for a pathogen that only has a limited time to try to grow within an infected cell. Salmonella and E. coli however have developed a mechanism to control the destructive power of the enzyme. Host cells have a natural recycling system called the proteasome that is used to take old or damaged proteins and break them down and use the building blocks to form new proteins. These bacterial pathogens tap into this recycling system, using their own proteins to mimic proteins from the cell that sort host proteins for recycling. Using this tactic the bacteria divert caspase-3 from its normal role, causing the host cell to inadvertently send it for recycling. This delays cell death meaning the bacteria can now multiply within the cell. This tactic we believe is replicated by numerous other bacterial pathogens during infection, meaning this proposal will have repercussions for the study of numerous microbial infections.

在摄入受感染的食物后，致病菌被肠道中的细胞吸收，进入细胞并试图生长。一个被感染的细胞认识到危险，经历了一种被称为细胞凋亡的严格控制的细胞自杀形式。因此，细胞在消除自身和危险的同时，向免疫系统发出警告信号。E.大肠杆菌和沙门氏菌是英国两种最常见的食物中毒相关病原体。根据我们对机体对感染的反应的了解，我们预期细胞在接触大肠杆菌时会发生凋亡。大肠杆菌和沙门氏菌。然而，在这些病原体的情况下，受感染的细胞在感染后存活一段时间，允许细菌在受感染的细胞内生长。这种额外的生长时间是至关重要的，使这些病原体有时间繁殖并导致更严重的长期感染。通过这项提议，我们的目标是了解这些病原体是如何延长受感染细胞的寿命的。这项工作将与许多细菌病原体有关，我们现在知道其中许多病原体也试图干扰感染期间的细胞凋亡过程。我们以前的工作为沙门氏菌感染细胞中发生的复杂相互作用提供了新的线索。在感染过程中，细菌故意靶向细胞中的蛋白质，这些蛋白质通过诱导细胞自杀对感染作出反应。特别是一种非常有效的宿主细胞酶，称为caspase-3，或“刽子手caspase”。这是诱导细胞自杀的关键酶，快速但受控地杀死细胞。由于caspase-3的破坏力，它的激活受到严格的调控，使其被细菌病原体靶向变得更加令人惊讶。然而，这些细菌最初并没有试图阻止caspase-3发挥作用，而是试图利用其活性，绕过严格的控制措施，以确保caspase-3的活性得到控制。我们现在知道沙门氏菌感染通过一种独特的机制激活caspase-3，理解和利用这一点是这项提案的关键目标。激活像半胱天冬酶-3这样具有破坏性的酶对于病原体来说是一种危险的策略，因为病原体只有有限的时间试图在受感染的细胞内生长。沙门氏菌和然而，大肠杆菌已经开发出一种机制来控制这种酶的破坏力。宿主细胞有一个天然的回收系统，称为蛋白酶体，用于吸收旧的或受损的蛋白质，并将其分解，并使用构建模块形成新的蛋白质。这些细菌病原体利用这种回收系统，使用它们自己的蛋白质来模拟细胞中的蛋白质，这些蛋白质对宿主蛋白质进行分类以进行回收。使用这种策略，细菌将caspase-3从其正常作用中转移，导致宿主细胞无意中将其送去回收。这延迟了细胞死亡，意味着细菌现在可以在细胞内繁殖。我们认为，这种策略在感染过程中被许多其他细菌病原体复制，这意味着这一提议将对许多微生物感染的研究产生影响。

项目成果

Increased S-nitrosylation and proteasomal degradation of caspase-3 during infection contribute to the persistence of adherent invasive Escherichia coli (AIEC) in immune cells.

• DOI: 10.1371/journal.pone.0068386
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Dunne KA;Allam A;McIntosh A;Houston SA;Cerovic V;Goodyear CS;Roe AJ;Beatson SA;Milling SW;Walker D;Wall DM
• 通讯作者: Wall DM

Increasing the bactofection capacity of a mammalian expression vector by removal of the f1 ori.

• DOI: 10.1038/s41417-018-0039-9
• 发表时间: 2019-07
• 期刊: Cancer gene therapy
• 影响因子: 6.4
• 作者: Johnson SA;Ormsby MJ;McIntosh A;Tait SWG;Blyth K;Wall DM
• 通讯作者: Wall DM

Mapping the Influence of the Gut Microbiota on Small Molecules across the Microbiome Gut Brain Axis.

• DOI: 10.1021/jasms.1c00298
• 发表时间: 2022-04-06
• 期刊: JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
• 影响因子: 3.2
• 作者: Hulme, Heather;Meikle, Lynsey M.;Strittmatter, Nicole;Swales, John;Hamm, Gregory;Brown, Sheila L.;Milling, Simon;MacDonald, Andrew S.;Goodwin, Richard J. A.;Burchmore, Richard;Wall, Daniel M.
• 通讯作者: Wall, Daniel M.

SipA Activation of Caspase-3 Is a Decisive Mediator of Host Cell Survival at Early Stages of Salmonella enterica Serovar Typhimurium Infection.

SipA 激活 Caspase-3 是肠沙门氏菌鼠伤寒血清型感染早期宿主细胞存活的决定性介质。

• DOI: 10.1128/iai.00393-17
• 发表时间: 2017-09
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: McIntosh A;Meikle LM;Ormsby MJ;McCormick BA;Christie JM;Brewer JM;Roberts M;Wall DM
• 通讯作者: Wall DM

Monocytes mediate Salmonella Typhimurium-induced tumor growth inhibition in a mouse melanoma model.

• DOI: 10.1002/eji.202048913
• 发表时间: 2021-12
• 期刊: European journal of immunology
• 影响因子: 5.4