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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=683385
• 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.*****

细菌病原体极大地改变宿主细胞的功能，以克服先天和获得性免疫反应，并在宿主细胞内建立一个利基。在这些复杂的宿主-病原体相互作用过程中，病原体迫使宿主将它们安置在所谓的含菌室(BCC)中。为了形成BCC，细菌分泌蛋白质，改变正常的细胞功能，包括信号通路或囊泡运输控制。这些被颠覆的寄主功能然后放弃它们的常规作用，支持BCC的发展，并通过提供营养和保护促进细菌的生长。这些隔室的形成和成熟是复杂的，人们只了解细菌和宿主之间潜在相互作用的一部分。最近，我们开发了一种新的基于质谱学的方法来梳理出一种常见的食源性病原体--鼠伤寒沙门氏菌的BCCs组成。我们研究的一个关键发现是沙门氏菌正在操纵比先前预期更多的宿主功能，包括被认为只被其他细菌物种利用的细胞器。*这个计划打算建立在这些洞察力的基础上，并将开发和实施方法来揭示宿主和微生物之间串扰的分子机制。从长远来看，我们将对相关的分子靶标有一个更完整的了解，探索迄今未知的相互作用，并确定可能优先成为细菌靶标的关键宿主机制。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械性的见解。*短期内，我们的目标是调查新发现的沙门氏菌和HeLa细胞之间相互作用的性质。新宿主成分的击倒实验将揭示它们对沙门氏菌BCCs的形成和组成的重要性。从这些改变的基底细胞中分离出的沙门氏菌的蛋白质组分析将表明，由于基底细胞成分的改变，该细菌是否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居住在各种宿主生物体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那些策略，有可能制定干预策略来预防家畜和人的感染，从而改善食品安全。