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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

基本信息

批准号：
10656327
负责人：
Liise-anne Pirofski
金额：
$ 54.71万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
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/10656327
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 Biological Response Modifier Therapy 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 Homologous Gene Human Human immunodeficiency virus test Immune Immunity Immunoglobulin G Immunoglobulin M Immunosuppression Immunotherapy In Vitro Incidence Inflammatory Iris 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 feature selection 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 risk prediction stem tool transplantation therapy uptake vaccine development

项目摘要

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相关免疫抑制预示隐球菌脑膜炎（CM）的高风险。尽管取得了进展，在资源有限的情况下，艾滋病毒检测和抗逆转录病毒疗法（ART）的可用性增加， CM发病率和死亡率仍然很高。此外，ART可引起免疫重建炎症反应，综合征（C-IRIS），CM也发生在HIV-人群中，包括实体器官移植的接受者，生物制品没有宿主生物标志物来预测哪些HIV感染（HIV+）患者将发展为CM或C- 爱瑞丝我们感兴趣的是抗体（Ab）免疫可能在抵抗CM中发挥的作用，这在临床上是罕见的。免疫力完好的人我们在这方面贡献了大量知识，包括最近的数据。显示C-IRIS和阳性血清的HIV+患者中天然海带多糖（β-葡聚糖）结合Ab水平较低隐球菌抗原检测对HIV+和HIV-患者的研究显示， CM和C-IRIS患者中IgM记忆B细胞水平较低。在小鼠中，IgM记忆同源物、B-1细胞和/或幼稚IgM增强对CM的抗性。这些细胞产生抗体，在一些实施方案中，细胞壁上的β-葡聚糖是碳水化合物，例如Cn细胞壁上的β-葡聚糖。这个项目的目标是探索天然Ab和B细胞对Cn的应答和对CM的抗性。我们假设CM风险与以下因素相关：源自B细胞库扰动的特异性Cn和/或β-葡聚糖结合Ab的缺乏。我们的目标为了表征CM和C-IRIS患者和有CM和C-IRIS风险的患者的Cn和β-葡聚糖结合Ab，分离使用来自正常人的单克隆抗体（huMab），并在小鼠模型中测试它们的功效。2]到确定huMab和GXM-和β-葡聚糖结合Ab 1]对Cn活力产生直接影响的能力和生物学，和/或2]介导人效应细胞Cn吞噬作用和/或杀伤。3]为了分析B细胞亚群，具有CM和C-IRIS和处于CM和C-IRIS风险中的患者以及对照的VH/VL库和转录途径，并使用统计建模来识别CM风险的特征。从该项目中获得的知识将为预测CM和C-IRIS风险的工具，克服诊断和治疗的障碍， CM的发病机制，并为免疫治疗和疫苗的发展提供信息。