Biological and Clinical Impact of Cryptococcal Extralcellular Vesicles

新生隐球菌是免疫力受损的人的主要真菌病原体，包括 晚期艾滋病毒感染、器官移植和免疫抑制疗法。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伏感染，这种感染可能会对 对可能包括哮喘在内的其他慢性病的发展造成的后果。C，新形式主义者有 几个表征良好的毒力因子，其中多糖胶囊被认为是 最重要的是。该胶囊由至少三种被称为葡醛酸氧甘露聚糖的成分组成 甘露糖(GXM)、半乳甘露聚糖(GalXM)和被称为甘露糖蛋白的高度甘露糖化蛋白。抗体 对囊膜GXM的反应可诱导保护性抗体和非蛋白抗体。鉴于……的严重性 利用体液免疫治疗和治疗隐球菌感染一直很有兴趣。 预防疾病。一种单抗(MAb)已完成初步临床研究和 继续发展。蛋白载体偶联GXM的免疫保护作用 抗体。抗体的作用机制是多因素的，包括调理、调节 炎症反应，以及酵母细胞释放GXM的减少。更重要的是，保护性的和非 保护性单抗可以通过影响GXM的释放和阻止生物被膜的形成来区分 体外培养。虽然现在对抗体在体内和体外的作用机制已经有了很多了解，但 保护性和非保护性单抗识别的GXM表位的分子性质尚不清楚。 此外，抗体在酵母细胞水平上的作用机制 多糖类的释放还不清楚。这项申请建议继续研究相互作用 新单胞菌衣壳中的抗体。与之前的资金周期相比，当时的努力是 把重点放在抗体分子的分子分析上，这项建议将研究计划的重点重新放在 多糖抗原和胶囊。除了继续研究GXM的抗体外，这 应用提示探索GalXM在胶囊结构中的作用。提出了三个具体目标：1) 确定结合保护性和非保护性单抗的多糖分子结构(S)；2) 确定抗体介导的新生葡萄球菌代谢变化的机制和后果： 3)检测GalXM结合疫苗和GatXM结合抗体在宿主体内的保护效果 防守。 相关性(请参阅说明)： 该研究项目的重点是一种名为新生隐球菌的真菌病原体，它是一种主要的 对艾滋病患者来说是个问题。全世界有100多万人因此而遭受危及生命的感染 仅在非洲，每年就有多达60万人死于真菌。这种真菌有一种胶囊，可以让它 引发疾病。因此，了解这种结构对于了解真菌如何保护自己很重要。 对抗免疫系统。我们希望这些信息将导致新的免疫疗法和疫苗。

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.