Understanding cell-to-cell heterogeneity in African trypanosomes field isolates

细胞间异质性是病原体建立成功感染能力的关键。它可以使耐药性，允许免疫逃避，或触发分化到能够在不同宿主中存活的生命周期阶段。细胞间异质性的一个最好的研究例子是抗原变异-生物体周期性改变向宿主免疫系统展示的蛋白质身份的能力。尽管在感染期间病原体群体内细胞间异质性的重要性，但研究长期以来一直集中在适应细胞培养条件的病原体分离株上，这些病原体分离株通常表现出比其在该领域中的亲属少得多的异质性。因此，它一直难以阐明的机制，有助于细胞variation. Trypanosoma布氏锥虫，昏睡病在人类和动物非洲锥虫病在牲畜的病原体，包含最大的家庭的变异表面抗原的描述日期，并具有许多属性，使其成为最重要的模型之一，研究抗原变异。大T。布鲁氏菌表面抗原是变异的表面糖蛋白（VSG），虽然寄生虫的基因组编码超过2,000个VSG，但在任何一个时间只有一个以互斥的方式表达。VSG同种型表达的周期性转换允许寄生虫逃避宿主免疫应答并建立慢性感染。然而，大多数T。为了解决这个问题，本文提出的研究的中心目标是揭示导致T细胞培养适应期间细胞间异质性降低的遗传或分子事件。布鲁氏菌田间分离株。更具体地说，我们打算合并单细胞组学方法与实地研究，研究锥虫细胞培养适应过程中发生的事件。本文将重点关注寄生虫表面抗原表达的异质性，更好地理解影响病原体群体异质性水平的机制，将使我们能够更好地预测病原体如何适应环境挑战，包括其哺乳动物宿主的免疫反应。

Cell-to-cell heterogeneity is key to the ability of pathogens to establish successful infections. It can enable drug resistance, allow immune evasion, or trigger differentiation to life cycle stages capable of surviving in different hosts. One of the best studied examples of cell-to-cell heterogeneity is antigenic variation – the ability of an organism to periodically change the identity of the proteins displayed to the host immune system. Despite the importance of cell-to-cell heterogeneity within pathogen populations during infections, research has long focused on pathogen isolates adapted to cell-culture conditions that typically exhibit much less heterogeneity than its relatives in the field. As a consequence, it has been difficult to elucidate the mechanism contributing to cellular variation.The protozoan parasite Trypanosoma brucei, the causative agent of sleeping sickness in humans and animal African trypanosomiasis in livestock, contains the largest family of variant surface antigens described to date and possesses many attributes that have made it one of the most important models to study antigenic variation. The major T. brucei surface antigen is the variant surface glycoprotein (VSG), and whilst the parasite’s genome encodes for more than 2,000 VSGs, only one is expressed in a mutually exclusive manner at any one time. Periodic switching in VSG isoform expression allows the parasite to evade the host immune response and to establish chronic infections. Yet, most T. brucei research uses isolates adapted to cell culture that switch at much lower frequency and are more homogenous in morphology than recent field isolates.To address this problem, the central goal of the research proposed here is to uncover the genetic or molecular events that lead to a decrease in cell-to-cell heterogeneity during cell-culture adaption of T. brucei field isolates. More specifically, we intend to merge single-cell omics approaches with field research to study the events occurring during cell-culture adaptation of trypanosomes. A specific focus will be placed on the heterogeneity in expression of the parasite’s surface antigens.A better understanding of the mechanisms affecting the level of heterogeneity within a pathogen population will enable us to better predict how pathogens adapt to environmental challenges, including the immune response of their mammalian hosts.