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: 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
• 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

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.

尽管取得了进展，但与 HIV 相关的免疫抑制预示着隐球菌性脑膜炎 (CM) 的高风险。 增加了资源有限地区的艾滋病毒检测和抗逆转录病毒治疗 (ART) 的可用性， CM 的发病率和死亡率仍然很高，此外，ART 还可引发免疫重建炎症。 综合征 (C-IRIS)，CM 也发生在 HIV 感染者中，包括接受实体器官移植和 没有宿主生物标志物可以预测哪些 HIV 感染者 (HIV+) 会发展为 CM 或 C- IRIS。我们对抗体 (Ab) 免疫在 CM 抵抗中可能发挥的作用感兴趣，这在 CM 中很少见。 我们在这一领域贡献了重要的知识，包括最近的数据。 显示 C-IRIS 和血清阳性的 HIV+ 患者中天然昆布多糖（一种 β-葡聚糖）结合抗体水平较低 对 HIV+ 和 HIV- 患者的隐球菌抗原测试揭示了抗体库的扰动。 CM 和 C-IRIS 患者的 IgM 记忆 B 细胞水平较低，而 CM 患者的 IgM 记忆 B 细胞水平较低。 同系物、B-1 细胞和/或初始 IgM 增强了对 CM 的抵抗力。 碳水化合物，例如 Cn 细胞壁上的 β-葡聚糖。 天然 Ab 和 B 细胞对 Cn 的反应和对 CM 的抵抗力将与 CM 风险相关。 由于 B 细胞谱系紊乱而导致的特定 Cn 和/或 β-葡聚糖结合抗体的缺乏。 是 1] 为了表征患有 CM 和 C-IRIS 且有风险的患者的 Cn- 和 β-葡聚糖结合抗体，分离 来自正常人的单克隆抗体 (huMab) 并在小鼠模型中测试其功效 2] To。 确定 huMab 以及 GXM 和 β-葡聚糖结合抗体的能力 1] 对 Cn 活力产生直接影响 和生物学，和/或 2] 介导人效应细胞 Cn 吞噬作用和/或杀伤作用 3] 分析 B 细胞亚群， 患有 CM 和 C-IRIS 的患者和有患 CM 和 C-IRIS 风险的患者和对照的 VH/VL 库和转录途径， 并使用统计模型来识别 CM 风险的特征。从该项目中获得的知识将提供信息。 预测 CM 和 C-IRIS 风险、克服诊断和治疗障碍、提供新见解的工具 CM 的发病机制，并为免疫疗法和疫苗的开发提供信息。

项目成果

Cryptococcus neoformans-Specific and Non-Cryptococcus neoformans-Specific Antibody Profiles in Organ Transplant Recipients With and Without Cryptococcosis.

新型隐球菌 - 患有和不患有隐球菌病的器官移植受者中新型隐球菌特异性和非新型隐球菌特异性抗体谱。

• 发表时间: 2022-07
• 影响因子: 4.2
• 作者: Yoon, Hyunah;Nakouzi, Antonio;Pappas, Peter G;Hemmige, Vagish S;Pirofski, Liise Anne
• 通讯作者: Pirofski, Liise Anne

Association of Antibody Immunity With Cryptococcal Antigenemia and Mortality in a South African Cohort With Advanced Human Immunodeficiency Virus Disease.

南非晚期人类免疫缺陷病毒病队列中抗体免疫与隐球菌抗原血症和死亡率的关联。

• 发表时间: 2023-02-18
• 作者: Yoon, Hyunah;Wake, Rachel M;Nakouzi, Antonio S;Wang, Tao;Agalliu, Ilir;Tiemessen, Caroline T;Govender, Nelesh P;Jarvis, Joseph N;Harrison, Thomas S;Pirofski, Liise
• 通讯作者: Pirofski, Liise