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Modulation of host immune defense by Pneumocystis beta-glucans

肺孢子虫β-葡聚糖对宿主免疫防御的调节

基本信息

批准号：
9285821
负责人：
Eva Maria Carmona Porquera
金额：
$ 16.55万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9285821
关键词：
Adaptive Immune System Adjuvant Affect Animal Model Antibiotic Prophylaxis Antibiotics Antibody Formation Antigens Area Autoimmune Diseases B-Cell Activation B-Lymphocytes Bacterial Vaccines Biology CD4 Lymphocyte Count CD4 Positive T Lymphocytes Carbohydrates Cell Wall Cell membrane Cells Cessation of life Chronic Clinic Complement Consensus Data Dendritic Cells Development Development Plans Disease Drug Hypersensitivity Environment Failure Fright Fungal Components Fungal Vaccines Future Goals Guidelines HIV Hematologic Neoplasms Host Defense Human Immune Immune response Immune system Immunity Immunocompromised Host Immunology Immunosuppression Immunotherapeutic agent Impairment Individual Infection Infection prevention Institutes Investigation Knowledge Lung Malignant Neoplasms Mediating Membrane Microdomains Mentors Modeling Molecular Morbidity - disease rate Mus Mycoses Organism Patients Peripheral Pharmaceutical Preparations Pharmacotherapy Phenotype Pneumocystis Pneumocystis Infections Pneumocystis carinii Pneumonia Pneumonia Populations at Risk Preparation Prevention Preventive Preventive treatment Process Property Prophylactic treatment Publishing Recombinants Research Research Personnel Risk Role Signal Pathway Technology Testing Training Translating Transplantation Vaccination Vaccine Adjuvant Vaccine Therapy Vaccines Viral Vaccines base beta-Glucans career career development compliance behavior cytokine expectation experimental study fighting fungus immunogenic immunoregulation insight mortality mouse model new therapeutic target next generation sequencing pathogen prevent public health relevance research and development response skills therapy development therapy duration tool treatment duration

项目摘要

DESCRIPTION (provided by applicant): Modulation of host immune defense by Pneumocystis beta-glucans Pneumocystis are fungal organisms associated with the development of pneumonia in immunocompromised hosts. When Pneumocystis pneumonia (PcP) develops it carries great morbidity and mortality even upon administration of appropriate treatment. In the immunosuppressed patient, PcP can only be prevented with antibiotic prophylaxis. Unfortunately, most of the cases occur in patients in which prophylaxis was never instituted. The main reason for this lies in the lack of consensus guidelines regarding when to initiate prophylaxis in patients at risk. Specifically, the duration of therapy, fear of secondary effects from the preventive drugs, drug allergies and patient compliance have all contributed to the failure of adequate prophylactic treatments. A vaccine that can be administered early to patients at risk of PcP is therefore desperately needed. Beta-glucans (BG) are carbohydrates found in the cell wall of fungi (including Pneumocystis) which modulate both the innate and adaptive immune systems and are potentially excellent agents to use as vaccine adjuvants. Vaccine adjuvants with good immunogenic properties are essential for effective vaccine therapies especially when using recombinant antigens which are generally poorly immunogenic. As part of their innate activation BG induce stimulation of dendritic cell (DCs) and subsequent CD4 differentiation. BG have been additionally shown to modulate B cell responses independent of CD4 cells. All these properties make BG an excellent tool for the manipulation of CD4-dependent and CD4-independent immune responses. The ability of modulating immune responses in the absence of CD4 cells is of particular importance. Specifically as PcP mostly affects patients with low CD4 counts such as with HIV, individuals with autoimmune diseases and hematological malignancies as a result of the diseases themselves or the treatments received. Hence, understanding how Pneumocystis-derived BG (PCBG) modulate the immune responses will allow us to develop tools to manipulate the innate and adaptive host immune response to better fight this and potentially other fungal infections. Therefore, the objectives of this application are to 1. dissect the mechanism(s) by which PCBG activate B cells and the participation of DC in this process, to better understand CD4-independent mechanism of immune response against fungal components and 2. evaluate the effect of PCBG as a vaccine adjuvant together with Pneumocystis antigens in a CD4-replete and CD4-depleted murine models of Pneumocystis infection. We anticipate that the results of these investigations will enhance the understanding of PCBG activation of CD4-independent mechanisms of fungal protection and result in the identification of new targets for therapeutic exploitation in the treatment and prevention of PcP. In addition, we expect to develop a mouse model of Pneumocystis vaccination that could potentially be translated to human use. If PCBG proves it potential role as a potent vaccine adjuvant it could also be applied to other fungal, bacterial and viral vaccines, to enhance protection. The career development plan proposed here will help me gain the knowledge and expertise in B cell responses to PCBG to complement my prior training on human peripheral DC. Additionally, I will gain expertise in mouse model manipulation to achieve the objectives of this application. The future experiments outlined here will also enable me to move into the field of plasma membrane microdomains and initiate an investigation into individualized responses to vaccination through the latest high throughput next generation sequencing technologies. Ultimately, the career development and research plans outlined here will provide me with the skills needed to achieve my long term career goal which is to become an independent investigator with expertise in host defense against fungal infection particularly in the fields of non-CD4 responses and cell- mediated immunotherapeutics.

描述(由申请人提供)：肺孢子虫β-葡聚糖对宿主免疫防御的调节肺孢子虫是与免疫受损宿主肺炎的发展有关的真菌生物。当肺孢子虫肺炎(PCP)发展时，即使进行适当的治疗，它也会带来很高的发病率和死亡率。对于免疫抑制的患者，PCP只能通过抗生素预防来预防。不幸的是，大多数病例发生在从未采取预防措施的患者身上。其主要原因在于缺乏关于何时开始对有风险的患者进行预防的共识指南。具体地说，治疗的持续时间、对预防药物的副作用的恐惧、药物过敏和患者的依从性都是导致适当的预防治疗失败的原因。因此，迫切需要一种能够及早给有PCP风险的患者接种的疫苗。β-葡聚糖(BG)是在真菌(包括肺孢子虫)细胞壁中发现的碳水化合物，可以调节天然免疫系统和获得性免疫系统，是潜在的用作疫苗佐剂的极佳制剂。具有良好免疫原性的疫苗佐剂对于有效的疫苗治疗是必不可少的，特别是当使用通常免疫原性较差的重组抗原时。作为其先天激活的一部分，BG可诱导树突状细胞(DC)的刺激和随后的CD4分化。此外，BG还被证明可以独立于CD4细胞调节B细胞的反应。所有这些特性使BG成为操纵依赖和非依赖免疫反应的极佳工具。在没有CD4细胞的情况下，调节免疫反应的能力尤为重要。具体地说，因为PCP主要影响CD4细胞计数较低的患者，如艾滋病毒携带者、自身免疫性疾病患者和因疾病本身或接受治疗而患上恶性血液病的人。因此，了解肺孢子虫来源的BG(PCBG)是如何调节免疫反应的将使我们能够开发工具来操纵固有的和适应性的宿主免疫反应，以更好地对抗这种和潜在的其他真菌感染。因此，其目标是本研究旨在1.剖析PCBG激活B细胞的机制(S)及DC在这一过程中的作用，以更好地了解CD4非依赖的抗真菌免疫反应机制；2.评价PCBG与肺孢子虫抗原联合作为疫苗佐剂在肺孢子虫感染模型中的作用。我们期望这些研究的结果将加强对PCBG激活的CD4非依赖的真菌保护机制的理解，并导致识别用于治疗和预防PCP的新靶点。此外，我们希望开发一种肺孢子虫疫苗接种的小鼠模型，这种模型可能会被转化为人类使用。如果PCBG证明其作为一种有效的疫苗佐剂的潜在作用，它也可以应用于其他真菌、细菌和病毒疫苗，以加强保护。这里提出的职业发展计划将帮助我获得B细胞应对PCBG的知识和专业知识，以补充我之前关于人类外周DC的培训。此外，我还将获得鼠标模型操作方面的专业知识，以实现此应用程序的目标。这里概述的未来实验还将使我能够进入质膜微域领域，并通过最新的高通量下一代测序技术启动对疫苗接种的个性化反应的研究。最终，这里概述的职业发展和研究计划将为我提供所需的技能，以实现我的长期职业目标，即成为一名独立调查员，具有抵抗真菌感染的专业知识，特别是在非CD_4应答和细胞免疫治疗领域。