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(申请人提供)：新生隐球菌感染是导致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100万例隐球菌性脑膜炎，导致620,000多人死亡。临床和实验证据表明，由CD4+Th1型细胞介导的细胞免疫(CMI)构成了对新生葡萄球菌感染的保护性宿主防御反应。因此，建议开发一种有效的抗隐球菌疫苗是可行的，这种疫苗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，这似乎是违反直觉的。然而，本文提出的研究表明，用产生干扰素的新生芽孢杆菌H99菌株免疫并随后耗尽T细胞的B细胞缺陷小鼠能够建立保护性免疫反应，以抵御野生型(WT)新生芽孢杆菌对其他致命的肺部攻击。这些发现表明，在缺乏经典的适应性免疫的情况下，可以诱导天然的免疫细胞群产生保护性的抗隐球菌免疫反应。这些结果挑战了我们传统的适应性和先天免疫模式，因为在缺乏抗原特异性T和/或B细胞的情况下，先天细胞不被认为经历了快速扩增来介导增强的效应细胞功能和保护。确定天然细胞群/S以及在缺乏T和/或B CMI的情况下发生保护性抗隐球菌免疫反应的机制将标志着从经典的适应性免疫和天然免疫的二分法的范式转变。因此，我们假设“先天免疫可以在缺乏T和B细胞介导的适应性免疫反应的情况下，提供对新生葡萄球菌感染的保护”。我们计划通过追求以下特定目标来验证我们的假设：(1)鉴定在缺乏经典获得性免疫的情况下对新生葡萄球菌具有保护作用的天然细胞群(S)，以及(2)确定从免疫的T和B细胞缺陷小鼠分离的天然细胞抗隐球菌活性的介体。 公共卫生相关性：新生隐球菌是一种机会性真菌病原体，在免疫受损的人中会导致危及生命的感染。本申请中提出的研究旨在确定在免疫抑制患者中诱导对新生葡萄球菌的保护性免疫的机制。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。