Deciphering the role of secreted proteins at the host-parasite interface during chronic Toxoplasma gondii infection

刚地弓形虫是一种非常普遍的寄生虫，感染了大约三分之一的人口，以及任何温血动物。它造成长期慢性感染，主要在肌肉和大脑。如果免疫系统被削弱，例如在艾滋病患者或癌症治疗期间，这些寄生虫可以重新激活并引起疾病。慢性寄生虫目前是无法治疗的，我们对它们如何建立长期感染以及这对大脑和精神健康有什么影响知之甚少。在感染早期，寄生虫侵入细胞并在细胞内迅速生长。为了做到这一点，它们分泌大量的蛋白质来控制细胞，例如，通过阻止细胞杀死它们。为了引起慢性感染，寄生虫会转变成一种缓慢生长的形式，并建立一个保护壁，形成一个“囊肿”。这种囊肿存在于大脑的神经元中，但目前尚不清楚这种慢性形式如何控制宿主细胞并保护自己免受免疫系统的攻击。这项研究将探讨慢性寄生虫如何形成囊肿并自我防御以允许长期感染。为了更多地了解寄生虫是如何操纵被感染细胞的，我将确定哪些分泌的蛋白质在慢性感染中是重要的。我将使用一种强大的方法来产生突变的寄生虫，每个寄生虫都有不同的基因被破坏。通过使用寄生虫突变体池并确定哪些寄生虫能够存活，我们可以确定一个基因是否重要。我将用这种方法来确定寄生虫形成慢性囊肿需要哪些基因。我将研究这些基因的产物-蛋白质-研究它们对慢性感染的重要性，例如，它们是否需要形成保护性囊肿壁，或者它们是否有助于保护囊肿免受宿主的侵害。通过观察这些蛋白质的定位，以及它们与哪些宿主蛋白质相互作用，我将确定寄生虫需要控制的途径，以建立长期感染。这将揭示慢性寄生虫的需求和脆弱性，确定针对寄生虫的新方法，并进一步加深我们对慢性感染的理解。

Toxoplasma gondii is a highly prevalent parasite that infects around 1/3 of the human population, as well as any warm-blooded animal. It establishes long-term chronic infection, predominantly in the muscles and the brain. If the immune system is weakened, for example in AIDs patients or during cancer treatment, these parasites can reactivate and cause disease. The chronic stage parasites are currently untreatable, and we understand little of how they establish long-term infection and what impact this has on the brain and mental health.Early in infection, the parasite invades cells and grows rapidly inside them. To do so, they secrete numerous proteins to take control of the cell, for example, by preventing that cell from killing them. To set up a chronic infection, the parasite converts to a slow-growing form and builds a protective wall forming a 'cyst'. This cyst lives within neurons in the brain, but it is not clear how this chronic form takes control of the host cell and protects itself against attack from the immune system. This research will investigate how the chronic stage parasite forms the cyst and defends itself to allow long-term infection.To understand more about how the parasite is manipulating the infected cell, I will determine which secreted proteins are important in chronic infection. I will use a powerful approach to generate pools of parasite mutants, where each parasite has a different gene disrupted. By using pools of parasite mutants and determining which parasites are able to survive, we can identify whether a gene is important or not. I will use this method to determine which genes are required for the parasite to form the chronic cyst. I will investigate the products of these genes - the proteins - investigating how they are important for chronic infection, for example, whether they are required to form the protective cyst wall, or if they help defend the cyst from the host. By looking at where these proteins localise, and what host proteins they interact with, I will identify pathways that the parasite needs to control to set up long-term infection. This will uncover the requirements and vulnerabilities of the chronic parasite, identifying new ways to target the parasite, and furthering our understanding of chronic infections.