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.

项目总结