Antibodies, B cells and resistance to human cryptococcosis

抗体、B 细胞和对人类隐球菌病的抵抗力

• 批准号: 10440391
• 负责人: Liise-anne Pirofski
• 金额: $ 17.75万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-25 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440391
• 关键词: Address; Africa; Anti-Retroviral Agents; Antibodies; Antibody Repertoire; Antibody-mediated protection; Antifungal Therapy; Antigens; Architecture; Area; Asia; B cell repertoire; B-Lymphocyte Subsets; B-Lymphocytes; Bacteria; Binding; Biological Markers; Biological Products; Biology; Brain; Carbohydrates; Cell Wall; Cells; Cessation of life; Clinical; Complication; Cryptococcal Meningitis; Cryptococcosis; Cryptococcus; Cryptococcus neoformans; Data; Development; Diagnosis; Disease; Effector Cell; Encapsulated; Exposure to; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Glioblastoma; Glucans; Goals; Growth; HIV; Human; Human immunodeficiency virus test; Immune; Immunity; Immunoglobulin G; Immunoglobulin M; Immunosuppression; Immunotherapy; In Vitro; Incidence; Inflammatory; Knowledge; Link; Lung; Machine Learning; Measurement; Measures; Mediating; Memory; Memory B-Lymphocyte; Meningitis; Modeling; Monoclonal Antibodies; Morphology; Mouse Strains; Mus; Organ Transplantation; Pathogenesis; Pathway interactions; Patient Care; Patients; Peripheral Blood Mononuclear Cell; Persons; Phagocytosis; Phenotype; Plasma; Play; Polysaccharides; Prevention; Principal Investigator; Prognosis; Public Health; Recurrence; Resistance; Resource-limited setting; Resources; Risk; Role; Serology; Serum; Solid; South Africa; Specificity; Statistical Models; Syndrome; T-Lymphocyte; Testing; Vaccines; Virulence; antigen test; antiretroviral therapy; beta-Glucans; differential expression; fungus; global health; glucuronoxylomannan; high risk; human monoclonal antibodies; immune reconstitution; improved; inhibiting antibody; insight; interest; laminaran; microbial; mind control; mortality; mouse model; natural antibodies; organ transplant recipient; predictive modeling; programs; random forest; response; stem; tool; uptake; vaccine development

HIV-associated immunosuppression portends high risk for cryptococcal meningitis (CM). Despite progress that has increased HIV testing and anti-retroviral therapy (ART) availability in resource-limited settings, the incidence and mortality of CM remain very high. In addition, ART can elicit immune reconstitution inflammatory syndrome (C-IRIS), and CM also occurs in HIV- persons, including recipients of solid organ transplants and biologics. There are no host biomarkers to predict which HIV-infected (HIV+) patients will develop CM or C- IRIS. We are interested in the role antibody (Ab) immunity may play in resistance to CM, which is rare in people with intact immunity. We have contributed significant knowledge in this area, including recent data showing lower natural Laminarin (a β-glucan)-binding Ab levels in HIV+ patients with C-IRIS and positive serum cryptococcal antigen tests. Studies of HIV+ and HIV- patients revealed perturbations in Ab repertoires of patients with CM and C-IRIS, and lower IgM memory B cell levels in patients with CM. In mice, IgM memory homologs, B-1 cells and/or naïve IgM enhanced resistance to CM. These cells make Abs that bind microbial carbohydrates, e.g. the β-glucans on the Cn cell wall. The goal of this project is to probe the link between natural Ab and B cell responses to Cn and resistance to CM. We hypothesize CM risk will associate with deficiency of specific Cn- and/or β-glucan-binding Abs, stemming from B cell repertoire pertubations. Our aims are 1] To characterize Cn- and β-glucan-binding Abs of patients with and at risk for CM and C-IRIS, isolate monoclonal antibodies (huMabs) from normal persons and test their efficacy in mouse models. 2] To determine the ability of huMabs and GXM- and β-glucan-binding Abs to 1] exert direct effects on Cn viability and biology, and/or 2] mediate human effector cell Cn phagocytosis and/or killing. 3] To analyze B cell subsets, VH/VL repertoires, and transcriptional pathways of patients with and at risk for CM and C-IRIS, and controls, and use statistical modeling to identify signatures of CM risk. Knowledge gained from this project will inform tools to predict CM and C-IRIS risk, overcome roadblocks to diagnosis and therapy, provide new insight into the pathogenesis of CM, and inform development of immunotherapy and vaccines.

hiv相关的免疫抑制预示着隐球菌脑膜炎（CM）的高风险。尽管取得了进展