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Immunity against fungal infections

对真菌感染的免疫力

基本信息

批准号：
10330033
负责人：
Somashekarappa Gowda Nanjappa
金额：
$ 45.59万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10330033
关键词：
Ache Adjuvant Adopted Adoptive Transfer Antifungal Agents Antigen-Presenting Cells Apoptosis Bacterial Infections Blastomyces Bone Marrow CD4 Positive T Lymphocytes CD43 molecule CD8-Positive T-Lymphocytes CRISPR/Cas technology Cells Chimera organism Coupled Cross Presentation Cryptococcus Dendritic Cells Dendritic cell activation Development Diagnosis Differentiation Antigens E-Selectin Elements Fungal Vaccines Genes Genetic Crosses Goals Granulocyte-Macrophage Colony-Stimulating Factor Histoplasma Homeostasis Immune Immunity Immunocompromised Host Individual Interferon Type II Interleukin-17 Interleukin-2 Knockout Mice Lung Lymphopenia Marker Vaccines Mediating Memory Monoclonal Antibodies Morbidity - disease rate Mus Mutant Strains Mice Mycoses Nature PPBP gene Pathology Pneumocystis Population Populations at Risk Preventive measure Reporter Resistance Risk Role Seminal Signal Transduction Subunit Vaccines Surface Surface Antigens T cell response T memory cell T-Lymphocyte TC1 Cell TNF gene Techniques Toxic effect Vaccination Vaccines Virus Diseases Work base congenic cytokine design experimental study fungal pneumonia fungus immunopathology in vivo interleukin-22 metabolic fitness mortality mouse model mutant novel novel vaccines phenotypic biomarker recruit response vaccine access vaccine efficacy vaccine evaluation vaccine platform vaccine response vaccinology

项目摘要

PROJECT SUMMARY Despite the global rise in fungal infections, including those by endemic sp ., there is no licensed fungal vaccine available. This is mainly due to poor understanding of mechanisms of vaccine immunity, and lack of a functional phenotypic marker associated with vaccine efficacy. Opportunistic fungal infections, including those caused by dimorphic fungi, Histoplasma, Coccidiodes and Blastomyces, are rising at an alarming rate in such at-risk individuals. A major limitation in the development of tailored fungal vaccines for the at-risk population is poor understanding of requisite elements of CD8+ T cell responses to mediate vaccine-immunity. Recent advances in the understanding of immune correlates against fungal infections has helped in advancing vaccinology in parallel. T-cell derived IL-17A, IFNγ, GM-CSF, IL-22, and TNFα are primarily involved in protection against fungi. Identification of potential targets on host cells can provide novel efficacious vaccine platforms, including for immunocompromised. We have established a mouse model of CD4+ T cell lymphopenia, where CD8+ T cells can be stimulated to produce protective cytokines IL-17A (Tc17) and IFNγ (Tc1) to execute a sterilizing immunity against lethal pulmonary fungal infection. We have shown that vaccine-elicited antifungal CD8+ T cells persisted as long-term functional memory. In this proposal, we present seminal findings: 1. GM-CSF+ Tc17 cells bolster vaccine-immunity without pathology; 2. Anti-fungal CD8+ T cells preferentially express O-glycosylated Sialophorin; and 3. Sialophorin is required for differentiation and expansion of CD8+ T cells. Therefore, our central hypotheses are that (1) Sialophorin acts as a co-stimulator for CD8+ T cell responses, (2) retention of Sialophorin is essential for memory CD8+ T-cell homeostasis and recall responses, (3) Sialophorin signaling potentiates cross-presentation to augment CD8+ T cell responses. Our specific aims are to: 1. Determine and dissect the role of Sialophorin for CD8+ T-cell fungal vaccine responses. We will decipher and delineate the cell- intrinsic role of Sialophorin for vaccine-induced Tc17 and Tc1 cell responses using adoptive transfer and bone- marrow chimera experiments, and using TCRα KO, congenic and crosses of Sialophorin KO mice. 2. Elucidate the role of Sialophorin for memory T cell homeostasis and recall responses during fungal pneumonia. We will define the role of Sialophorin for vaccine-induced memory CD8+ T-cell homeostasis, recall responses, and vaccine-immunity. We will use bone marrow chimera, adoptive transfers, CRISPR-Cas9 gene-editing, in vivo stimulation, and E-selectin blocking to delineate the role of Sialophorin on memory CD8+ T-cell responses. 3. Dissect the role of Sialophorin on dendritic cells for CD8+ T-cell fungal vaccine responses. We will identify the role of CD43 on antigen-presenting cells for activation of CD8+ T cells following vaccination . Our findings will uncover the functional role of Sialophorin for fungal CD8+ T-cell responses and immunity to guide in the design of novel vaccine platforms and test the efficacy of vaccines.

项目概要尽管全球真菌感染呈上升趋势，包括地方性病菌 ., 没有获得许可的真菌疫苗可用的。这主要是由于对疫苗免疫机制了解不够，缺乏认识。功能性的相关表型标记疫苗功效。机会性真菌感染，包括由以下原因引起的感染：二相性真菌、组织胞浆菌、球孢子菌和芽生菌在此类高危环境中正以惊人的速度增长个人。为高危人群开发定制真菌疫苗的一个主要限制是效果不佳的理解 CD8+ T 细胞反应介导疫苗免疫的必要元素。最近的进展对真菌感染免疫相关性的了解也有助于同时推动疫苗学的发展。 T 细胞来源的 IL-17A、IFNγ、GM-CSF、IL-22 和 TNFα 主要参与针对真菌的保护。宿主细胞上潜在靶标的鉴定可以提供新型有效的疫苗平台，包括免疫功能低下。我们建立了CD4+T细胞淋巴细胞减少症的小鼠模型，其中CD8+T细胞可被刺激产生保护性细胞因子 IL-17A (Tc17) 和 IFNγ (Tc1) 以执行灭菌免疫对抗致命的肺部真菌感染。我们已经证明疫苗诱导的抗真菌 CD8+ T 细胞持续存在作为长期功能记忆。在此提案中，我们提出了开创性的发现： 1. GM-CSF+ Tc17 细胞支持无病理学的疫苗免疫； 2. 抗真菌CD8+ T细胞优先表达O-糖基化唾液酸蛋白； 3. CD8+ T 细胞的分化和扩增需要唾液酸蛋白。因此，我们的中心假设是 (1) 唾液酸蛋白作为 CD8+ T 细胞反应的共刺激剂，(2) 保留唾液酸蛋白对于记忆 CD8+ T 细胞稳态和回忆反应至关重要，(3) 唾液酸蛋白信号传导增强交叉呈递以增强 CD8+ T 细胞反应。我们的具体目标是： 1. 确定并剖析唾液酸蛋白在 CD8+ T 细胞真菌疫苗反应中的作用。我们将破译并描绘细胞- 唾液酸蛋白在疫苗诱导的 Tc17 和 Tc1 细胞反应中的内在作用骨髓嵌合体实验，并使用TCRα KO、Sialophorin KO小鼠的同系和杂交。 2. 阐明唾液酸蛋白在真菌性肺炎期间记忆 T 细胞稳态和回忆反应中的作用。我们将定义唾液酸蛋白在疫苗诱导的记忆 CD8+ T 细胞稳态、回忆反应和疫苗-免疫。我们将使用骨髓嵌合体、过继移植、CRISPR-Cas9 体内基因编辑刺激和 E-选择素阻断来描述唾液酸蛋白对记忆 CD8+ T 细胞反应的作用。 3. 剖析唾液酸蛋白对 CD8+ T 细胞真菌疫苗反应的树突状细胞的作用。我们将确定 CD43 对抗原呈递细胞在疫苗接种后激活 CD8+ T 细胞中的作用。我们的研究结果将揭示唾液酸蛋白对真菌 CD8+ T 细胞反应和免疫的功能作用，以指导设计新型疫苗平台并测试疫苗的功效。