Mapping the antibody response to Trypanosoma brucei variant surface glycoprotein

绘制布氏锥虫变异表面糖蛋白的抗体反应

• 批准号: 10527979
• 负责人: Monica Mugnier
• 金额: $ 20.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-03 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527979
• 关键词: Africa South of the Sahara; African Trypanosomiasis; Animal Diseases; Animals; Antibodies; Antibody Response; Antigenic Variation; Antigens; B-Lymphocytes; Bacteriophages; Binding; Blood; Cell surface; Chronic; Clone Cells; Collection; Data; Data Analyses; Detection; Diagnosis; Disease; Drug resistance; Economic Development; Epitope Mapping; Epitopes; Exposure to; Future; Genes; Genomics; High-Throughput Nucleotide Sequencing; Human; Immune; Immune Evasion; Immune response; Immune system; Immunity; Infection; Investigation; Libraries; Liquid substance; Maps; Measures; Membrane Glycoproteins; Methods; Molecular Conformation; Monoclonal Antibodies; Mus; Parasitemia; Parasites; Patients; Peptides; Phage Display; Phage ImmunoPrecipitation Sequencing; Play; Population; Positioning Attribute; Prevention; Process; Proteins; Proteome; Public Health; Resolution; Role; Sampling; Serum; Shapes; Specificity; Study models; Time; Tissues; Trypanosoma; Trypanosoma brucei brucei; Trypanosomiasis; Vaccines; Variant; Work; chronic infection; disorder prevention; extracellular; high throughput technology; immunogenic; insight; interest; mouse model; neglect; neglected tropical diseases; pathogen; response; tool

PROJECT SUMMARY Trypanosoma brucei is a causative agent of human and animal African trypanosomiasis, devastating diseases that endanger public health and present a major barrier to economic development in sub-Saharan Africa. The extracellular parasite manages to sustain an infection in the blood and tissues of its mammalian host by periodically “switching” its dense variant surface glycoprotein (VSG) coat. Drawing from a genomic repertoire of ~2000 VSG-encoding genes, the parasite changes its expressed VSG coat throughout infection. Before the host antibody response can clear a population expressing one VSG, the parasite switches expression to a new VSG, rendering it invisible to host antibody for a time. This process occurs continually and allows the parasite to maintain a chronic infection. The interaction between antibody and VSG, therefore, represents a critical interface in this infection. Despite its importance, the principles governing antibody recognition of VSG remain poorly understood. Here we propose to investigate the antibody-VSG interface during infection in high resolution using a high-throughput epitope mapping approach called phage immunoprecipitation sequencing (PhIP-seq). Using a phage display library containing peptides from every VSG ever annotated, we will measure antibody responses to VSG during chronic infections, while simultaneously using a high-throughput sequencing method developed by our lab to track the VSGs expressed during infection. In the first aim, we will characterize the dynamics and targets of anti-VSG antibody during chronic experimental infections. In the second aim, we will use PhIP-seq to map VSG epitopes in natural human infections. The proposed study will further our understanding of anti-VSG antibody responses while establishing T. brucei as a tractable model for the study of antibody responses to antigenically variable pathogens. Long term, this work could inform strategies for diagnosis or prevention of an important neglected tropical disease.

项目概要 布氏锥虫是人类和动物非洲锥虫病的病原体，这是一种毁灭性的疾病 危害公众健康，并成为撒哈拉以南非洲经济发展的主要障碍。 细胞外寄生虫通过以下方式设法维持哺乳动物宿主的血液和组织中的感染 定期“转换”其致密变异表面糖蛋白（VSG）外壳，取自基因组库。 大约 2000 个 VSG 编码基因，寄生虫在感染之前改变其表达的 VSG 外壳。 宿主抗体反应可以清除表达一种 VSG 的群体，寄生虫将表达切换为新的 VSG，使其在一段时间内对宿主抗体不可见。这个过程持续发生，并允许寄生虫。 因此，抗体和 VSG 之间的相互作用对于维持慢性感染至关重要。 尽管 VSG 的抗体识别原理很重要，但其识别原则仍然存在。 在此我们建议研究高感染期间的抗体-VSG 界面。 使用称为噬菌体免疫沉淀测序的高通量表位作图方法进行分辨率 (PhIP-seq)，我们将使用包含来自每个已注释的 VSG 的肽的噬菌体展示库进行测量。 慢性感染期间抗体对 VSG 的反应，同时使用高通量 我们实验室开发的测序方法用于追踪感染过程中表达的 VSG。 表征慢性实验感染期间抗 VSG 抗体的动态和靶标。 第二个目标是，我们将使用 PhIP-seq 绘制人类自然感染中的 VSG 表位图谱。 进一步我们对抗 VSG 抗体反应的理解，同时将布氏锥虫建立为易于处理的模型 从长远来看，这项工作可以为抗原变异病原体的抗体反应研究提供信息。 诊断或预防重要的被忽视的热带病的策略。