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.

在被感染的食物致病细菌摄入后，被肠中的细胞吸收，进入细胞并试图生长。识别危险的感染细胞经历了一种被称为凋亡的细胞自杀形式。因此，该细胞消除了自身和危险，同时向免疫系统发出警告信号。大肠杆菌和沙门氏菌是英国最常见的食物中毒相关病原体中的两种。根据我们对人体对感染的反应的了解，我们期望细胞与大肠杆菌和沙门氏菌接触时会凋亡。但是，在这些病原体的情况下，感染的细胞在感染后存活了一段时间，从而使细菌在感染细胞内生长。这种额外的生长时间至关重要，使这些病原体的时间繁殖并引起更严重的长时间感染。通过这项建议，我们旨在了解这些病原体如何延长感染细胞的寿命。这项工作将与众多细菌病原体具有相关性，我们现在知道其中许多病原体也试图干扰感染过程中的凋亡过程。我们以前的工作为沙门氏菌感染细胞发生的复杂相互作用提供了新的启示。在感染期间，细菌故意靶向细胞中通过诱导细胞自杀反应感染的蛋白质。特别是一种称为caspase-3的极有效的宿主细胞酶，或“ execution子caspase”的目标。这是诱导细胞自杀的关键酶，迅速杀死细胞，但以受控的方式杀死了细胞。由于caspase-3的破坏力，其激活受到严格的调节，这使细菌病原体的靶向更加令人惊讶。但是，与其试图防止Caspase-3起作用，这些细菌最初试图利用其活性，绕过对位置的严格控制，以确保caspase-3活动被检查。我们现在知道沙门氏菌感染正在通过独特的机制激活caspase-3，理解和利用这是该提案的关键目标。对于caspase-3的破坏性酶的激活是一种风险策略，对于病原体而言，该病原体只有有限的时间尝试在感染细胞内生长。然而，沙门氏菌和大肠杆菌开发了一种控制酶破坏力的机制。宿主细胞具有称为蛋白酶体的天然回收系统，该系统用于服用旧或受损的蛋白质，并将其分解并使用构件形成新蛋白质。这些细菌病原体利用自己的蛋白质来模仿细胞中的蛋白质，从而将宿主蛋白质进行回收。使用这种策略，细菌将caspase-3从其正常作用中转移出来，导致宿主细胞无意中发送其回收。这会延迟细胞死亡，这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，这意味着该提案将对许多微生物感染产生影响。

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