Biological and Clinical Impact of Cryptococcal Extralcellular Vesicles

隐球菌细胞外囊泡的生物学和临床影响

• 批准号: 8958486
• 负责人: Arturo Casadevall
• 金额: $ 1.57万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8958486
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Africa; Antibodies; Antibody Response; Antigens; Asthma; Binding; Biological; Carrier Proteins; Cells; Chronic Disease; Clinical; Clinical Research; Cryptococcus neoformans; Development; Disease; Epitopes; Funding; HIV Infections; Host Defense; Human; Humoral Immunities; Immune system; Immunity; Immunization; Immunosuppressive Agents; Immunotherapy; In Vitro; Individual; Infection; Inflammatory Response; Instruction; Lead; Life; Mediating; Metabolism; Microbial Biofilms; Molecular; Molecular Analysis; Molecular Structure; Monoclonal Antibodies; Nature; Organ Transplantation; Patients; Polysaccharides; Prevention therapy; Proteins; Regimen; Research; Role; Structure; Vaccines; Vesicle; Virulence Factors; Yeasts; capsule; disorder prevention; fungus; galactoxylomannan; glucuronoxylomannan; in vivo; interest; latent infection; mannoproteins; pathogen; prevent; programs; protective efficacy

Cryptococcus neoformans is a major fungal pathogen for individuals with impaired immunity, including those with advanced HIV infection, organ transplants, and on immunosuppressive regimens. Furthermore, there is increasing evidence that this fungus can establish latent infection in humans that could have profound consequences for the development of other chronic diseases, including possibly asthma. C, neoformans has several well-characterized virulence factors, among which a polysaccharide capsule is considered to be the most important. The capsule is composed of at least three components known as Glucuronoxylomannan (GXM), galactoxylomannan (GalXM) and highly mannosylated proteins known as mannoproteins. Antibody responses to the capsular GXM elicit protective and non-protedive antibodies. Given the seriousness of cryptococcal infections there has been great interest in harnessing humoral immunity for therapy and prevention of disease. A monoclonal antibody (mAb) has completed preliminary clinical studies and continues in development. Immunization with GXM conjugated to protein carriers elicits protective antibodies. The mechanism of antibody action Is multifactorial and includes opsonization, modulation ofthe inflammatory response, and abrogation of GXM release from yeast cells. Remari^ably, protective and non- protective mAbs can be distinguished by their ability to affect GXM release and block biofilm formation in vitro. Although much is now known about the mechanism of antibody action in vivo, and in vitro, the molecular nature ofthe GXM epitopes recognized by protective and non-protective mAbs is unknown. Furthermore, the mechanisms of action of antibodies at the level of the yeast cell that abrogate polysaccharide release are not understood. This application proposes to continue the study ofthe interaction of antibodies with the capsule of C. neofomnans. In contrast to the prior funding cycles when the effort was focused on molecular analysis of the antibody molecule, this proposal refocuses the research program on the polysaccharide antigen and the capsule. In addition to continuing to study antibodies to GXM this application proposes to explore the role of GalXM in capsule structure. Three specific Aims are proposed: 1) To define the polysaccharide molecular structure(s) that bind protective and non-protective mAbs; 2) To determine the mechanism and consequences of antibody-mediated changes in C. neoformans metabolism: 3) To determine the protective efficacy of GalXM-congugate vaccines and GatXM-binding antibodies in host defense. RELEVANCE (See instructions): The research program is focused on a fungal pathogen known as Cryptococcus neoformans that is a major problem for patients with AIDS. Over a million people woridwide suffer life-threatening infections with this fungus and as many as 600,000 die each year in Africa alone. This fungus has a capsule that allows it to cause disease. Hence, understanding this structure is important for knowing how the fungus protects itself against the immune system. We hope that this information will lead to new immune therapies and vaccines.

对于有免疫力受损的个体（包括那些） 具有晚期HIV感染，器官移植和免疫抑制方案。此外，还有 越来越多的证据表明这种真菌可以在人类中建立潜在感染，这些感染可能具有深远 其他慢性疾病的发展，包括哮喘。 C，Neoformans具有 几种特征良好的毒力因子，其中多糖胶囊被认为是 最重要的。胶囊由至少三个称为葡萄糖量氧基瘤的成分组成 （GXM），半氧化物氧基瘤（GALXM）和高度甘露糖基化的蛋白称为甘露蛋白。抗体 对囊膜GXM的反应会引起保护性和非保护性抗体。考虑到严重 隐球菌感染对利用体液免疫的治疗和 预防疾病。单克隆抗体（MAB）已完成初步临床研究和 继续发展。与蛋白质载体共轭的GXM免疫引起了保护 抗体。抗体作用的机制是多因素的，包括调整，调制 炎症反应和从酵母细胞中释放GXM的炎症。明显，保护性和非 - 保护性mab可以通过其影响GXM释放并阻止生物膜形成的能力来区分 体外。尽管现在已经了解了体内抗体作用的机理，并且在体外，但 通过保护性和非保护mAb识别的GXM表位的分子性质尚不清楚。 此外，抗体在废除酵母细胞水平上的作用机理 多糖释放尚不清楚。该申请建议继续研究相互作用 抗体与梭状芽胞杆菌的胶囊的抗体。与先前的资金周期相反， 该提案重点介绍了抗体分子的分子分析，将研究计划重新调整 多糖抗原和胶囊。除了继续研究与GXM的抗体 应用建议探索Galxm在胶囊结构中的作用。提出了三个具体目标：1） 定义结合保护性和非保护mAb的多糖分子结构； 2）到 确定抗体介导的新代谢中抗体介导的变化的机制和后果： 3）确定宿主中Galxm-Congugate疫苗和GATXM结合抗体的保护性功效 防御。 相关性（请参阅说明）： 该研究计划的重点是一种被称为加密赛车的真菌病原体，该病原体是主要的 艾滋病患者的问题。超过一百万的人遭受了威胁生命的感染 真菌，仅在非洲，每年多达60万人死亡。该真菌具有一个胶囊，可以 引起疾病。因此，了解这种结构对于了解真菌如何保护自己很重要 反对免疫系统。我们希望这些信息将导致新的免疫疗法和疫苗。