Living with uninvited guests - comparing plant and animal responses to endocytic invasions

沙门氏菌是一种革兰氏阴性细菌病原体，能够感染多种宿主，包括人类、猪、牛、鸡甚至植物。鼠伤寒沙门菌是各种人类和动物疾病的病原体，从肠炎到伤寒。根据世界卫生组织的数据，沙门氏菌病是最常见的食源性疾病，全球每年约有15亿人感染。虽然卫生条件有了很大改善，但沙门氏菌感染的数量在过去十年中由于抗菌素耐药性和沙门氏菌隐藏在宿主细胞内的能力而增加。需要采用新的方法来解决这一全球健康问题。沙门氏菌在宿主细胞内的膜结合室中复制，并依赖于宿主细胞的耐受性和资源。因此，为了确保存活和繁殖，沙门氏菌利用III型分泌系统将蛋白质分泌到宿主细胞质中。这些蛋白的一些作用开始被揭示，特别是在调节关键的宿主信号转导途径方面。然而，为了充分掌握宿主-病原体反应的机制，我们需要采取全系统的观点，确定沙门氏菌蛋白与宿主蛋白相互作用的整个网络。这种深刻的见解将产生针对病原体的新方法。近年来，转录组学和蛋白质组学等高通量技术的发展加快了对蛋白质相互作用全球网络的识别。在这里，我们建议确定蛋白质-蛋白质相互作用和途径作为了解植物，动物或人类宿主与沙门氏菌之间的串扰的手段。通过研究不同的宿主，我们将解决以下问题：不同的细胞如何应对细菌入侵？宿主细胞暴露于细菌基因产物的哪个子集？沙门氏菌在动物和植物细胞中是否都有宿主的“弱点”？我们提出的想法是，解决这些基本的生物学问题对于不同的宿主，如植物和动物，可以帮助我们阐明宿主和病原体之间的相互作用在机制水平上的工作方式。分析不同宿主对入侵的反应，并利用系统生物学方法整合这些结果，将揭示宿主反应的优缺点。这将通过开发整合数据分析、建模和实验的工具来推进该领域的发展。实际上，这些信息可用于药物开发、诊断、疾病预测、预防和控制。我们的工作假设是，植物和动物对病原体入侵的反应基本上是相似的，物种特异性是由一般主题的细微差别赋予的。这意味着，原则上，类似的方法应该适用于设计检测和对抗沙门氏菌感染的策略，而不管宿主是什么。我们将通过计算和实验方法的综合循环来检验这一假设。其结果要么是针对一般宿主反应的统一模型，要么是针对每个宿主的单独模型。因此，证明或反驳假设都同样有价值。

Salmonella are Gram-negative bacterial pathogens capable of infecting a wide range of hosts, including humans, pigs, cows, chicken and even plants. Salmonella typhimurium is the causative agent of various human and animal diseases, reaching from enteritis to typhoid fever. According to the World Health Organisation, Salmonellosis is the most frequent food-borne disease with around 1,5 billion infections world-wide yearly. Although hygiene conditions have improved considerably, the number of Salmonella infections has increased over the last decade due to antimicrobial resistance and the ability of Salmonella to hide inside host cells. Novel approaches are needed to address this global health problem. Salmonella replicates within host cells in a membrane-bound compartment and is dependent on tolerance and resources of the host cell. To ensure survival and propagation, Salmonella therefore secretes proteins into the host cytoplasm using a type III secretion system. Some of the roles of these proteins are beginning to be revealed, in particular in modulating key host signal transduction pathways. However, to fully grasp the mechanisms of host-pathogen response, we need to take a system-wide view and determining the whole network of interactions between Salmonella proteins and the host proteins. Such deep insight will yield new approaches to target the pathogens. The identification of global networks of protein-protein interactions has been accelerated in recent years by the development of high-throughput technologies such as transcriptomics and proteomics. Here, we propose to identify protein-protein interactions and pathways as a means to understand the crosstalk between plant, animal or human hosts and Salmonella. By studying diverse hosts, we will address the following questions: How do different cells respond to bacterial invasion? To which subset of bacterial gene products are host cells exposed? Are there host 'weak points' that Salmonella exploits in animals and plant cells alike? We propose the idea that addressing these basic biological questions for divergent hosts such as plants and animals can help us elucidate the way the interaction between the host and the pathogen works at the mechanistic level. Analyzing the responses of different hosts to invasion, and integrating these results using a systems biology approach will expose the weaknesses and strengths in host responses. This will advance the field through the development of tools for the integration of data analysis, modelling and experimentation. In practical terms, this information can be exploited for drug development, diagnosis, disease forecasting, prevention and control. Our working hypothesis is that plants and animals respond to pathogen invasion in fundamentally similar ways, and that species-specificity is conferred by nuances on general themes. This means, that in principle, similar approaches should be applicable to design strategies to detect and fight Salmonella infections irrespective of host. We will test this hypothesis through an integrative cycle of computational and experimental approaches. The outcome will be either a unified model for the general host response, or separate models, one for each host. Thus, both, proving or disproving the hypothesis will be equally valuable.