Tunneling Nanotubes (TNTs): An Export/Import Strategy for Chlamydia via direct Cell-to-Cell Communication

隧道纳米管 (TNT)：通过直接细胞间通讯的衣原体导出/导入策略

• 批准号: 531660002
• 负责人: Privatdozent Dr. Michael R. Knittler
• 金额: --
• 依托单位: Institut für Immunologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/531660002?language=en
• 关键词: Tunneling; Nanotubes; TNTs; Export; Import

Chlamydiae are obligate intracellular bacteria that can cause sexually transmitted diseases, ocular infections, and atypical pneumonia. These bacteria undergo a unique biphasic developmental cycle within a non-acidified membrane-bound inclusion. Chlamydiae exploit the host cell transport machinery to regulate their survival, physiological maintenance, and export from infected cells. Tunneling nanotubes (TNTs) are cellular connections that facilitate cell-to-cell transport, communication, and other physiological and pathological functions. In a recent study, we discovered that Chlamydia trachomatis-infected host cells use TNTs to export bacteria (as reticulate bodies, RBs) into uninfected neighboring cells, suggesting that these conduits play a critical role in direct cell-to-cell transmission of chlamydia. This transfer requires a functional cytoskeleton and occurs even when extracellular dissemination is impaired. The TNTs involved in the chlamydial transfer are characterized by microtubules and the chlamydial SNARE-like effector protein IncA. Although our studies provide an important insight into the TNT-mediated export of chlamydia from infected to non-infected cells, a more detailed understanding of this newly discovered exit/entry strategy is crucial. We aim to unravel the molecular and cellular processes involved in the biogenesis and acquisition/use of TNTs by Chlamydia. We will employ state-of-the-art cell and molecular biological methods to functionally characterize how chlamydia misuses and manipulates TNT formation to spread infection between neighboring cells. Additionally, we will identify cellular host and pathogen-derived proteins involved in this interaction, explore the impact of oxidative stress and stress adaptors on TNT formation and stability, and assess the involvement of chlamydial IncA protein in TNT-mediated transfer. Our work will also focus on the issues of chlamydial TNT transmission under hypoxia and in persistent cell infections induced by antibiotic treatment, where the expression and function of IncA are maintained. Our studies aim to understand how chlamydiae use intercellular communication mechanisms to export infections directly through cell-to-cell contact.

衣原体是专性细胞内细菌，可引起性传播疾病，眼部感染和非典型肺炎。这些细菌在非酸化的膜结合内含物内经历独特的双相发育周期。衣原体利用宿主细胞的运输机制来调节它们的存活、生理维持和从受感染细胞的输出。Tunneling nanotubes（TNT）是细胞连接，其促进细胞到细胞的运输、通信以及其他生理和病理功能。在最近的一项研究中，我们发现沙眼衣原体感染的宿主细胞使用TNT将细菌（如网状体，RB）输出到未感染的相邻细胞中，这表明这些管道在衣原体的直接细胞间传播中起着关键作用。这种转移需要一个功能性的细胞骨架，即使在细胞外播散受损时也会发生。参与衣原体转移的TNT的特征在于微管和衣原体SNARE样效应蛋白印加。虽然我们的研究提供了一个重要的洞察TNT介导的出口衣原体从感染到未感染的细胞，更详细地了解这种新发现的退出/进入策略是至关重要的。我们的目标是解开的分子和细胞的过程中参与的生物合成和收购/使用的TNT衣原体。我们将采用最先进的细胞和分子生物学方法来功能性地表征衣原体如何滥用和操纵TNT形成以在相邻细胞之间传播感染。此外，我们将确定参与这种相互作用的细胞宿主和病原体衍生蛋白，探索氧化应激和应激衔接子对TNT形成和稳定性的影响，并评估衣原体印加蛋白参与TNT介导的转移。我们的工作还将集中在缺氧和抗生素治疗诱导的持续性细胞感染，其中印加的表达和功能保持衣原体TNT传输的问题。我们的研究旨在了解衣原体如何使用细胞间通讯机制，直接通过细胞间接触输出感染。