Induction of Protection Against Cryptococcus neoformans in Immune Deficient Hosts

在免疫缺陷宿主中诱导针对新型隐球菌的保护

• 批准号: 8414616
• 负责人: Floyd L. Wormley
• 金额: $ 22.05万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8414616
• 关键词: Acquired Immunodeficiency Syndrome; Adoptive Transfer; Alveolar Macrophages; Antifungal Agents; Antigens; B-Lymphocytes; Biological Response Modifiers; Bone Marrow; Cell physiology; Cells; Cellular Immunity; Cellular Infiltration; Cessation of life; Chimera organism; Clinical; Cryptococcal Meningitis; Cryptococcus neoformans; Cryptococcus neoformans infection; Cytoprotection; Dendritic Cells; Development; Effector Cell; Exhibits; Exposure to; Goals; Host Defense; ITGAX gene; Immune; Immune response; Immunity; Immunocompromised Host; Immunosuppression; Individual; Infection; Interferons; Lead; Life; Lung; Mediating; Mediator of activation protein; Memory; Modeling; Morbidity - disease rate; Mus; Mycoses; Natural Immunity; Nitrogen; Opportunistic Infections; Oxygen; Patients; Peptides; Population; Role; T-Lymphocyte; Testing; Transgenic Mice; Vaccines; adaptive immunity; antimicrobial; cell mediated immune response; cell type; combat; cytokine; defense response; design; diphtheria toxin receptor; expectation; innovation; mortality; mouse model; pathogen; prevent; prophylactic; response; therapy development

DESCRIPTION (provided by applicant): Cryptococcus neoformans infections are a leading mycological cause of morbidity and mortality among AIDS patients. Global estimates suggest that one million cases of cryptococcal meningitis occur each year resulting in over 620,000 deaths. Clinical and experimental evidence show that cell-mediated immunity (CMI) by CD4+ Th1-type cells constitutes the protective host defense response against C. neoformans infections. Consequently, it may seem counterintuitive to suggest that development of an effective anti-cryptococcal vaccine that 1) confers protection in the presence or absence of intact immunity and 2) induces protection that endures during the subsequent development of immune suppression is feasible. However, studies presented herein show that B cell deficient mice immunized with an IFN-?-producing C. neoformans strain, denoted H99?, and subsequently depleted of T cells were capable of mounting protective immune responses against an otherwise lethal pulmonary challenge with wild-type (WT) C. neoformans. These findings suggest that an innate population of immune cells can be induced to mount protective anti-cryptococcal immune responses in the absence of classical adaptive immunity. These results challenge our traditional model of adaptive and innate immunity in that innate cells are not considered to undergo rapid expansion to mediate enhanced effector cell function and protection in the absence of antigen-specific T and/or B cells. Identifying the innate cell population/s and mechanism by which protective anti-cryptococcal immune responses occurs in the absence of T and/or B CMI will mark a paradigm change from the classical dichotomy of adaptive versus innate immunity. We therefore hypothesize that "innate immunity can be primed to provide protection against C. neoformans infection that endures during the absence of T and B cell-mediated adaptive immune responses". We plan to test our hypothesis by pursuing the following Specific Aims: (1) to identify the innate cell population(s) that confers protection against C. neoformans in the absence of classical adaptive immunity, and (2) to determine the mediators of anti-cryptococcal activity of innate cells isolated from immunized, T and B cell deficient mice. PUBLIC HEALTH RELEVANCE: Cryptococcus neoformans is an opportunistic fungal pathogen that causes life-threatening infections in immune compromised individuals. The studies proposed in this application are designed to determine a mechanism for inducing protective immunity against C. neoformans in immune suppressed patients. My expectation is that these studies will lead to the development of therapies and/or vaccines to treat or prevent fungal infections.

描述（由申请人提供）：新型隐球菌感染是艾滋病患者发病和死亡的主要真菌原因。全球估计表明，每年发生100万例隐球菌脑膜炎，导致62万多人死亡。临床和实验证据表明，由CD 4 + Th 1型细胞介导的细胞免疫（CMI）构成了针对C.新型感染。因此，似乎违反直觉的是，建议开发一种有效的抗隐球菌疫苗，1）在存在或不存在完整免疫的情况下提供保护，2）诱导在随后的免疫抑制发展过程中持续的保护是可行的。然而，本文中呈现的研究表明，用IFN-γ免疫的B细胞缺陷型小鼠，产生C.新型菌株，命名为H99？，随后耗尽的T细胞能够产生保护性免疫应答，以对抗野生型（WT）C的致命肺攻击。新人类这些发现表明，在缺乏经典适应性免疫的情况下，可以诱导先天免疫细胞群体产生保护性抗隐球菌免疫反应。这些结果挑战了我们的适应性和先天免疫的传统模型，因为先天细胞不被认为在缺乏抗原特异性T和/或B细胞的情况下经历快速扩增以介导增强的效应细胞功能和保护。鉴定先天性细胞群体和在T和/或B CMI不存在下发生保护性抗隐球菌免疫应答的机制将标志着适应性免疫与先天性免疫的经典二分法的范式变化。因此，我们假设“先天免疫可以启动以提供对C的保护。在缺乏T和B细胞介导的适应性免疫反应的情况下持续存在的新型病毒感染”。我们计划通过追求以下具体目标来验证我们的假设：（1）鉴定赋予针对C的保护的先天细胞群体。在缺乏经典的适应性免疫的情况下，测定新生隐球菌的抗隐球菌活性，和（2）测定从免疫的T和B细胞缺陷小鼠分离的先天性细胞的抗隐球菌活性的介质。 公共卫生关系：新型隐球菌是一种机会性真菌病原体，可导致免疫功能低下个体发生危及生命的感染。本申请中提出的研究旨在确定诱导针对C.免疫抑制患者中的新生儿。我的期望是，这些研究将导致治疗或预防真菌感染的疗法和/或疫苗的开发。