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）：加密型新媒体感染是艾滋病患者发病和死亡的主要原因。全球估计表明，每年有100万例隐球菌脑膜炎病例导致62万多人死亡。临床和实验证据表明，CD4+ Th1型细胞介导的细胞介导的免疫力（CMI）构成了针对新旋转梭菌感染的保护性宿主防御反应。因此，提出有效的抗晶局疫苗的开发似乎是违反直觉的，即1）在存在或不存在完整免疫力的情况下赋予保护，而2）诱导保护在随后的免疫抑制过程中忍受的保护是可行的。但是，本文介绍的研究表明，用IFN-？ - 产生的Neoformans菌株免疫的B细胞缺陷小鼠，表示H99？？随后耗尽的T细胞能够对野生型（WT）C。Neoformans进行防护性免疫反应，以防止具有致命的肺挑战。这些发现表明，在没有经典的适应性免疫力的情况下，可以诱导先天的免疫细胞种群来纳入保护性的抗癌症免疫反应。这些结果挑战了我们传统的适应性和先天免疫模型，因为在没有抗原特异性T和/或B细胞的情况下，没有认为先天细胞会经历快速扩张，以介导增强的效应细胞功能和保护。识别先天细胞群和机制，在没有T和/或B CMI的情况下，会出现保护性抗癌免疫反应，这标志着自适应与先天免疫的经典二分法的范式变化。因此，我们假设“可以为天生的免疫力提供针对新梭菌感染的保护，该感染在没有T和B细胞介导的适应性免疫反应的情况下忍受了。”我们计划通过追求以下特定目的来检验假设：（1）在没有经典的适应性免疫力的情况下确定对新生梭菌的保护，这些细胞群体缔结了对新生梭菌的保护，（2）以确定与免疫性，T和B细胞抗性小鼠隔离的抗晶体细胞的介体。 公共卫生相关性：加密型新型人体是一种机会性真菌病原体，可导致免疫损害的个体威胁生命的感染。本应用中提出的研究旨在确定一种在免疫抑制患者中诱导针对新生虫的保护性免疫的机制。我的期望是，这些研究将导致疗法和/或疫苗的发展，以治疗或预防真菌感染。