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

• 批准号: 8502999
• 负责人: Eva Maria Carmona Porquera
• 金额: $ 12.7万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 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/8502999
• 关键词: 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; 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; Process; Property; Prophylactic treatment; Publishing; Recombinants; Research; Research Personnel; Risk; Role; Signal Pathway; Technology; Testing; Therapeutic; Training; Translating; Transplantation; Vaccination; Vaccine Adjuvant; Vaccine Therapy; Vaccines; Viral Vaccines; base; beta-Glucans; career; career development; compliance behavior; cytokine; expectation; fighting; fungus; immunogenic; immunoregulation; insight; mortality; mouse model; new therapeutic target; next generation sequencing; pathogen; prevent; public health relevance; research and development; research study; response; skills; therapy development; therapy duration; tool; treatment duration

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（由申请方提供）：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功能低下宿主的肺炎发展相关的真菌微生物。当肺孢子虫肺炎（PcP）发展时，即使给予适当的治疗，它也具有很高的发病率和死亡率。在免疫抑制患者中，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中。其主要原因在于缺乏关于风险患者何时开始预防的共识指南。具体而言，治疗的持续时间、对预防性药物的副作用的恐惧、药物过敏和患者依从性都导致了充分预防性治疗的失败。因此，迫切需要一种可以早期给予有PcP风险的患者的疫苗。β-葡聚糖（BG）是在真菌（包括肺孢子虫）的细胞壁中发现的碳水化合物，其调节先天性和适应性免疫系统，并且是用作疫苗佐剂的潜在优秀试剂。具有良好免疫原性的疫苗佐剂对于有效的疫苗疗法是必不可少的，特别是当使用通常免疫原性差的重组抗原时。作为其先天活化的一部分，BG诱导树突状细胞（DC）的刺激和随后的CD 4分化。另外，BG还显示可独立于CD 4细胞调节B细胞应答。所有这些特性使BG成为操纵CD 4依赖性和CD 4非依赖性免疫应答的极好工具。在不存在CD 4细胞的情况下调节免疫应答的能力是特别重要的。具体而言，由于PcP主要影响具有低CD 4计数的患者，例如HIV患者，由于疾病本身或接受的治疗而患有自身免疫性疾病和血液恶性肿瘤的个体。因此，了解肺孢子虫衍生的BG（PCBG）如何调节免疫反应将使我们能够开发工具来操纵先天和适应性宿主免疫反应，以更好地对抗这种和潜在的其他真菌感染。因此， 此应用程序是1.剖析PCBG激活B细胞的机制以及DC在该过程中的参与，以更好地理解针对真菌组分的免疫应答的CD 4非依赖性机制;评价PCBG作为疫苗佐剂与肺孢子虫抗原一起在肺孢子虫感染的CD 4-充满和CD 4-耗尽小鼠模型中的作用。我们预计，这些调查的结果将提高对PCBG激活的CD 4-非依赖性真菌保护机制的理解，并导致在治疗和预防PcP的治疗开发的新目标的识别。此外，我们希望开发一种肺孢子虫疫苗接种的小鼠模型，该模型可能被转化为人类使用。如果PCBG证明它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，细菌和真菌。 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细胞对PCBG反应的知识和专业知识，以补充我之前在人外周DC方面的培训。此外，我将获得鼠标模型操作的专业知识，以实现此应用程序的目标。这里概述的未来实验也将使我能够进入质膜微区领域，并通过最新的高通量下一代测序技术开始对疫苗接种的个体化反应进行调查。最终，这里概述的职业发展和研究计划将为我提供实现我的长期职业目标所需的技能，即成为一名独立的研究人员，在宿主防御真菌感染方面具有专业知识，特别是在 非CD 4应答和细胞介导的免疫治疗领域。