Antibodies, B cells and resistance to human cryptococcosis

HIV相关的免疫抑制预示着隐球菌性脑膜炎(CM)的高风险。尽管取得了进展， 在资源有限的情况下增加了艾滋病毒检测和抗逆转录病毒疗法(ART)的可用性， CM的发病率和死亡率仍然很高。此外，ART还可以诱导免疫重建炎症反应。 综合征(C-IRIS)和CM也发生在艾滋病毒感染者中，包括实体器官移植的接受者和 生物制品。目前还没有宿主生物标志物来预测哪些艾滋病毒感染者会患上CM或C- 爱瑞丝。我们感兴趣的是抗体(Ab)免疫在CM耐药中可能发挥的作用，这在 拥有完整免疫力的人。我们在这一领域贡献了大量知识，包括最近的数据 C-IRIS阳性的HIV患者血清中天然海带多糖(a-β-葡聚糖)结合抗体水平较低 隐球菌抗原检测。对HIV和HIV患者的研究显示，抗体谱系中存在扰动 CM和C-IRIS患者，CM患者的IgM Memory B细胞水平较低。在小鼠中，IgM记忆 同系物、B-1细胞和/或幼稚的IgM增强了对CM的耐药性。这些细胞产生与微生物结合的抗体 碳水化合物，如CN细胞壁上的β-葡聚糖。这个项目的目标是探索 天然抗体和B细胞对CN的反应和对CM的抵抗。我们假设CM风险将与 缺乏特异性CN和/或β葡聚糖结合抗体，源于B细胞谱系紊乱。我们的目标 [目的]鉴定CM和C-IRIS患者的CN-和β-葡聚糖结合抗体，分离 从正常人体内提取单抗(HuMabs)，并在小鼠模型中检测其效力。2]至 确定HuMAbs和GxM-和β-葡聚糖结合抗体对CN活性产生直接影响的能力 和生物学，和/或2]介导人效应细胞CN吞噬和/或杀伤。3]为了分析B细胞亚群， VH/VL谱系，CM和C-IRIS患者及风险患者的转录途径，以及对照， 并使用统计建模来识别CM风险的特征。从这个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，提供对 CM的发病机制，并为免疫治疗和疫苗的发展提供信息。

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.