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

• 批准号: 10542652
• 负责人: Amariliz Rivera
• 金额: $ 7.14万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-05 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542652
• 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; cross immunity; follow-up; gain of function; immunogenic; immunogenicity; immunoregulation; improved; in vivo; inhibitor; 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

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 隐球菌病是一种定义艾滋病的疾病，是HIV感染的最常见的真菌疾病 患者。艾滋病患者中大多数真菌性脑膜炎的病例是由于全球分布的感染 真菌病原体新生虫。最近的估计表明，C.neoformans导致> 180,000 每年死亡，造成15％与艾滋病有关的死亡。因此，有一个重要的，未得到的 医疗需要开发针对这种威胁生命的真菌感染的新疗法。更好地理解 塑造免疫力对隐球菌免疫力的宿主和病原体因素可以告知很多 需要预防性疫苗接种策略和免疫疗法。在最近发表的研究中，我们 发现F-box蛋白1（FBP1）充当新生梭菌免疫原性的调节剂。 FBP1是一个 SCFFBP1 E3连接酶复合物的亚基，这是泛素介导的蛋白水解途径的关键成分 这靶向特定的蛋白质降解。缺乏FBP1（FBP1D）的Neofans突变菌株为 在体内过量性不足而不会影响已知毒力因子的表达，表明FBP1可能 调节一种新型的毒力决定因素。 FBP1D肺部感染诱导了强大的募集 CCR2+单核细胞以及增强的CD8+和CD4+ T细胞反应的激活。我们发现了这一点 这些增强了先天和适应性免疫反应，以控制新的新生孢菌感染 肺，都是宿主长期生存所必需的。此外， FBP1D突变体（HK-FBP1D）充当有效的疫苗和受保护的小鼠的两种不同遗传的小鼠 与亲本，高毒性菌株H99感染的背景。在此应用程序中，我们建议 一系列协作研究，以解释FBP1如何调节抗晶体免疫的激活 并进一步利用FBP1D作为一种新型疫苗菌株的潜力，以针对隐球菌病。中央 我们工作的假设是FBP1调节了特定靶蛋白的丰度 新生梭菌的免疫原性。我们的总体目标是系统地破译免疫力 疫苗诱导的保护机制，并识别和验证特定的FBP1调节靶标的机制 塑造梭菌C. Neoformans的免疫原性。我们将利用我们的联合专业知识来检验我们的假设 三个独立但密切相关的特定目的：1）解释先天免疫的独特贡献 细胞群体以防止FBP1D感染和HK-FBP1D疫苗诱导的保护，2） 发现IFN-G介导的疫苗保护的分子机制，3）识别和验证FBP1- 影响宿主免疫力的监管靶标。总体而言，这些研究将提高我们对 加密赛中涉及免疫调节的宿主病原体相互作用，可能指导 特异性梭菌因子因子的疫苗和抑制剂增强了宿主介导的感染控制。