Targeting Pathogens at the Site of Cellular Entry

针对细胞进入部位的病原体

• 批准号: 183639-2012
• 负责人: Morales, Carlos
• 金额: $ 2.48万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=545935
• 关键词: Targeting; Pathogens; Site; Cellular; Entry

The long term objective of this research is to develop a novel therapeutic approach that will revolutionize the way transmissible diseases are treated, by offering an alternative therapy to antiviral drugs, antibiotics and vaccines. Brucellosis and tuberculosis, for which there are no cures or treatments, are major infectious agents in wild and domestic species. Furthermore, animals are major sources of infectious diseases to other animals and humans. Brucellosis is a zoonosis transmitted by direct animal-to-human contact. Other zoonoses include Leihsmania donovani, H5N1 avian influenza virus and HIV virus. Cross-species viral and bacterial infections are a constant preoccupation with respect to iatrogenic enhancement due to cross-species transmission and antibiotic resistance. It is well known that the majority of pathogens invade the cell via endocytosis, by attaching to existing cell surface receptors. Inside the cell, the pathogens trick the endosomes and lysosomes and preferentially divide within them. In eukaryotic cells the delivery of newly synthesized proteins to endosomes and lysosomes is dependent on the Golgi apparatus, i.e. the organelle that sorts and targets proteins to these destinations. Proteins delivered to endosomes and lysosomes include enzymes and activator proteins. They are directed therein via special sorting receptors. Recently, we identified a region in the lysosomal protein prosaposin that contains a motif required for its binding to the sorting receptors sortilin and consequently for its transport to endosomes and lysosomes. In this proposal we will test the hypothesis that fusion proteins linked to this motiff can be transported to the endo/lysosomal compartment via sortilin, and that this sequence may be useful for the targeting of anti-pathogenic proteins. Our study will permit to establish a proof of concept of a new strategy for the targeting of antimicrobial proteins to the endo/lysosomal compartment. The outcome of our research will be relevant for the treatment of infectious diseases in wild, endangered, and domestic animal species, as well as in humans, and will open innumerable avenues to examine the delivery and effects of antipathogenic peptides in viral, bacterial and protozoal infections.

这项研究的长期目标是开发一种新颖的治疗方法，通过提供抗病毒药物、抗生素和疫苗的替代疗法，彻底改变传染性疾病的治疗方式。布鲁氏菌病和结核病无法治愈或治疗，是野生和家养物种的主要传染源。此外，动物是其他动物和人类传染病的主要来源。布鲁氏菌病是一种人畜共患病，通过动物与人类的直接接触传播。其他人畜共患病包括杜氏利赫曼原虫、H5N1 禽流感病毒和艾滋病病毒。由于跨物种传播和抗生素耐药性，跨物种病毒和细菌感染一直是医源性增强的关注焦点。 众所周知，大多数病原体通过附着于现有的细胞表面受体，通过内吞作用侵入细胞。在细胞内部，病原体欺骗内体和溶酶体并优先在它们内分裂。在真核细胞中，新合成的蛋白质向内体和溶酶体的递送依赖于高尔基体，即对蛋白质进行分类和靶向这些目的地的细胞器。递送至内体和溶酶体的蛋白质包括酶和激活蛋白。它们通过特殊的分选受体被引导至其中。最近，我们在溶酶体蛋白 prosaposin 中发现了一个区域，该区域包含其与分选受体 sortilin 结合所需的基序，从而将其转运至内体和溶酶体。在本提案中，我们将测试以下假设：与该基序连接的融合蛋白可以通过分拣蛋白转运至内切/溶酶体区室，并且该序列可用于靶向抗病原蛋白。我们的研究将允许建立一种新策略的概念证明，用于将抗菌蛋白靶向内/溶酶体区室。我们的研究成果将与野生、濒危和家养动物以及人类传染病的治疗相关，并将开辟无数途径来检查抗病原体肽在病毒、细菌和原生动物中的传递和作用。感染。