Mechanisms of vaccine protection against AIDS-associated Cryptococcus infection

疫苗预防艾滋病相关隐球菌感染的机制

基本信息

批准号：
10097978
负责人：
Amariliz Rivera
金额：
$ 74.98万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-05 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10097978
关键词：
Acquired Immunodeficiency Syndrome Affect Antifungal Agents Attenuated Biological Response Modifiers CD4 Positive T Lymphocytes CD8B1 gene Cell surface Cells Cessation of life Clinical Complex Cryptococcal Meningitis Cryptococcosis Cryptococcus Cryptococcus gattii Cryptococcus neoformans Cryptococcus neoformans infection Development Disease F-Box Proteins Fungal Meningitis Future Gene Targeting Genetic Goals HIV Hybrids Immune Immune response Immune system Immunity Immunotherapy Inactivated Vaccines Infection Infection Control Interferon Type II Life Link Lung Lung infections Masks Mediating Mediator of activation protein Medical Modeling Molecular Mouse Strains Mus Mycoses Neutrophil Infiltration Opportunistic Infections Outcome Pathway interactions Patients Phenotype Population Preparation Preventative vaccination Production Proteins Publishing Reporter Role Safety Series Shapes Siblings Source T cell response T-Lymphocyte Testing Ubiquitin Vaccination Vaccine Design Vaccines Virulence Virulence Factors Virulent Work adaptive immune response base cellular targeting cost follow-up gain of function immunogenic immunogenicity immunoregulation improved in vivo inhibitor/antagonist insight loss of function monocyte mutant neutrophil novel novel therapeutic intervention novel vaccines pathogen pathogenic fungus patient population protein degradation recruit response success transdifferentiation ubiquitin-protein ligase vaccination strategy vaccine candidate vaccine-induced immunity

项目摘要

Abstract Cryptococcosis is an AIDS-defining illness and the most common fungal disease in HIV-infected patients. Most cases of fungal meningitis in AIDS patients are due to infections with the globally distributed fungal pathogen Cryptococcus neoformans. Recent estimates indicate that C.neoformans causes > 180,000 deaths annually and is responsible for 15% of AIDS-related deaths. Thus, there is a significant, unmet medical need to develop new treatments against this life-threatening fungal infection. A better understanding of host and pathogen factors that shape immunity against Cryptococcus can inform the development of much needed preventative vaccination strategies and immune-based therapies. In recently published studies, we have uncovered that F-box protein 1 (Fbp1) acts as a regulator of C. neoformans immunogenicity. Fbp1 is a subunit of the SCFFbp1 E3 ligase complex, a key component of the ubiquitin-mediated proteolytic pathway that targets specific proteins for degradation. The C. neoformans mutant strain lacking Fbp1 (fbp1D) is hypovirulent in vivo without affecting the expression of known virulence factors, indicating that Fbp1 likely regulates a novel virulence determinant. Pulmonary infection with fbp1D induced the robust recruitment of CCR2+ monocytes and the activation of enhanced CD8+ and CD4+ T cell responses. We uncovered that these enhanced innate and adaptive immune responses cooperate to control C. neoformans infection in the lung and are both required for the long-term survival of the host. Moreover, heat-killed preparations of the fbp1D mutant (HK-fbp1D) acted as an effective vaccine and protected mice of two different genetic backgrounds against infection with the parental, highly virulent strain H99. In this application, we propose a series of collaborative studies to decipher how Fbp1 regulates the activation of anti-Cryptococcus immunity and to further exploit the potential of fbp1D as a novel vaccine strain against cryptococcosis. The central hypothesis of our work is that Fbp1 regulates the abundance of specific target proteins, which in turn shape the immunogenicity of C. neoformans. Our overarching goal is to systematically decipher the immune mechanisms of vaccine-induced protection and to identify and validate specific Fbp1-regulated targets that shape the immunogenicity of C. neoformans. We will utilize our combined expertise to test our hypothesis in three independent, but closely related Specific Aims: 1) Decipher the distinct contributions of innate immune cell populations to protection from infection with fbp1D and to HK-fbp1D vaccine-induced protection, 2) Uncover the molecular mechanisms of IFN-g-mediated vaccine protection, and 3) Identify and validate Fbp1- regulated targets that influence host immunity. In aggregate, these studies will advance our understanding of host-pathogen interactions involved in the immune regulation by Cryptococcus and may guide the design of vaccines and inhibitors of specific C. neoformans factors to enhance host-mediated control of infection.

抽象的隐球菌病是一种艾滋病定义的疾病，也是艾滋病毒感染者中最常见的真菌病患者。艾滋病患者中的大多数真菌性脑膜炎病例是由于感染了全球分布的真菌而引起的。真菌病原体新型隐球菌。最近的估计表明，C.neoformans 导致 > 180,000 每年都有人死亡，占艾滋病相关死亡的 15%。因此，存在一个重要的、未满足的医学上需要开发新的治疗方法来对抗这种危及生命的真菌感染。更好地理解形成针对隐球菌免疫力的宿主和病原体因素可以为许多疾病的发展提供信息需要预防性疫苗接种策略和基于免疫的疗法。在最近发表的研究中，我们发现 F-box 蛋白 1 (Fbp1) 作为新型隐球菌免疫原性的调节因子。 Fbp1 是 SCFFbp1 E3 连接酶复合物的亚基，泛素介导的蛋白水解途径的关键组成部分针对特定蛋白质进行降解。缺乏 Fbp1 (fbp1D) 的新型隐球菌突变株是体内低毒力而不影响已知毒力因子的表达，表明 Fbp1 可能调节新的毒力决定因素。 fbp1D 的肺部感染诱导了 CCR2+ 单核细胞和增强的 CD8+ 和 CD4+ T 细胞反应的激活。我们发现这些增强的先天性和适应性免疫反应共同控制新型隐球菌感染肺，两者都是宿主长期生存所必需的。此外，热灭活制剂 fbp1D突变体（HK-fbp1D）作为有效的疫苗并保护两种不同基因的小鼠抗亲代高毒力菌株 H99 感染的背景。在这个应用中，我们提出了一个一系列合作研究来破译Fbp1如何调节抗隐球菌免疫的激活并进一步开发 fbp1D 作为新型隐球菌疫苗株的潜力。中央我们的工作假设是 Fbp1 调节特定靶蛋白的丰度，进而塑造新型隐球菌的免疫原性。我们的首要目标是系统地破译免疫疫苗诱导的保护机制，并识别和验证特定的 Fbp1 调节靶标塑造新型隐球菌的免疫原性。我们将利用我们的综合专业知识来检验我们的假设三个独立但密切相关的具体目标：1）破译先天免疫的独特贡献细胞群免受 fbp1D 感染和 HK-fbp1D 疫苗诱导的保护，2) 揭示 IFN-g 介导的疫苗保护的分子机制，以及 3) 识别和验证 Fbp1- 影响宿主免疫的调节目标。总的来说，这些研究将增进我们对宿主-病原体相互作用涉及隐球菌的免疫调节，并可能指导设计特定新型隐球菌因子的疫苗和抑制剂可增强宿主介导的感染控制。