Targeting Pathogens at the Site of Cellular Entry

这项研究的长期目标是开发一种新的治疗方法，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是野生和家养物种的主要传染源，目前尚无治愈或治疗方法。此外，动物是其他动物和人类传染病的主要来源。布鲁氏菌病是一种通过动物与人直接接触传播的人畜共患病。其他人畜共患病包括杜氏利什曼原虫、H5 N1禽流感病毒和艾滋病毒。由于跨物种传播和抗生素耐药性，跨物种病毒和细菌感染是医源性增强的持续关注。 众所周知，大多数病原体通过附着于现有的细胞表面受体而经由内吞作用侵入细胞。在细胞内，病原体欺骗了内体和溶酶体，并优先在其中分裂。在真核细胞中，将新合成的蛋白质递送到内体和溶酶体依赖于高尔基体，即将蛋白质分类并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到其中。最近，我们确定了一个地区的溶酶体蛋白saposin，含有一个基序，其结合所需的分选受体分拣蛋白，因此其运输到内体和溶酶体。在这个建议中，我们将测试的假设，连接到这个motiff的融合蛋白可以通过分拣蛋白运输到内/溶酶体隔室，这个序列可能是有用的抗病原蛋白的靶向。我们的研究将允许建立一个新的策略，抗菌蛋白质的靶向内/溶酶体室的概念证明。我们的研究结果将与野生，濒危和家养动物物种以及人类的传染病治疗相关，并将开辟无数途径来检查病毒，细菌和原生动物感染中抗病原体肽的递送和作用。

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.