Characterizing the role of new host components for the intracellular proliferation and survival of Salmonella enterica

表征新宿主成分对肠沙门氏菌细胞内增殖和存活的作用

• 批准号: RGPIN-2019-07152
• 负责人: Hansmeier, Nicole
• 金额: $ 2.19万
• 依托单位: University of Regina
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=739335
• 关键词: Characterizing; role; new; host; components

Bacterial pathogens dramatically alter host cell function to overcome innate and acquired immune responses and to establish a niche inside host cells. During these complex host-pathogen interactions, pathogens force their hosts to accommodate them in so-called bacterium-containing compartments (BCCs). To form BCCs, bacteria secrete proteins that alter normal cellular functions including signaling pathways or vesicle trafficking control. These subverted host functions then abandon their regular role and support the development of the BCC and promote bacterial growth by providing nutrition and protection. The formation and maturation of these compartments is complex and only parts of the underlying interactions between bacteria and host are understood. Recently, we developed a novel mass spectrometry-based method to tease out the composition of BCCs in Salmonella enterica serovar Typhimurium, a common food-borne pathogen. A key finding of our study was that Salmonella is manipulating more host functions than previously anticipated, including organelles that were believed to be utilized only by other bacterial species. This program intends to build on these insights and will develop and implement methods to reveal the molecular mechanisms underlying the crosstalk between host and microbe. Over the long term we will gain a more complete view of the involved molecular targets, explore hitherto unknown interactions and identify key host mechanisms that may be preferentially targeted by bacteria. These findings are expected to provide mechanistic insights into the co-evolutionary arms race between host and microbes. In the short term, our goals are to investigate the nature of the newly identified interactions between Salmonella and HeLa cells. Knockdown experiments of the novel host components will reveal their importance for the formation and composition of Salmonella BCCs. Proteome analysis of Salmonella isolated from these altered BCCs will indicate whether the bacterium faces different nutritional challenges as a consequence of BCC composition changes. We will further perform interaction studies to identify the bacterial proteins involved in hijacking the novel host components. Together, the work will expand our fundamental understanding of Salmonella-host interactions and provide insights how Salmonella can reside in a variety of host organism and cell types. By understanding those strategies with which Salmonella can adapt to different intracellular conditions it may be possible to develop intervention strategies to prevent infection of livestock and humans and thereby improve food safety.

细菌病原体显著改变宿主细胞功能以克服先天性和获得性免疫应答并在宿主细胞内建立小生境。在这些复杂的宿主-病原体相互作用期间，病原体迫使其宿主将其容纳在所谓的含细菌隔室（BCC）中。为了形成BCC，细菌分泌改变正常细胞功能的蛋白质，包括信号传导途径或囊泡运输控制。这些被破坏的宿主功能然后放弃它们的常规作用，并通过提供营养和保护来支持BCC的发展并促进细菌生长。这些隔室的形成和成熟是复杂的，并且细菌和宿主之间的潜在相互作用仅部分被理解。最近，我们开发了一种新的基于质谱的方法来梳理出肠道沙门氏菌血清型鼠伤寒沙门氏菌，一种常见的食源性病原体的BCC的组成。我们研究的一个关键发现是，沙门氏菌操纵的宿主功能比以前预期的要多，包括被认为只被其他细菌物种利用的细胞器。 该计划旨在建立在这些见解的基础上，并将开发和实施方法，以揭示宿主和微生物之间串扰的分子机制。从长远来看，我们将获得一个更完整的视图所涉及的分子靶标，探索迄今未知的相互作用，并确定可能优先被细菌靶向的关键宿主机制。这些发现有望为宿主和微生物之间的共同进化军备竞赛提供机理上的见解。在短期内，我们的目标是研究新发现的沙门氏菌和HeLa细胞之间相互作用的性质。新宿主成分的敲除实验将揭示它们对沙门氏菌BCC的形成和组成的重要性。从这些改变的BCC中分离的沙门氏菌的蛋白质组分析将表明细菌是否由于BCC组成的变化而面临不同的营养挑战。我们将进一步进行相互作用研究，以确定参与劫持新宿主成分的细菌蛋白质。总之，这项工作将扩大我们对沙门氏菌-宿主相互作用的基本理解，并提供沙门氏菌如何驻留在各种宿主生物和细胞类型中的见解。通过了解沙门氏菌能够适应不同细胞内条件的策略，有可能制定干预策略来预防牲畜和人类的感染，从而提高食品安全性。