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.

项目摘要尽管真菌感染的全球增长，但包括内在SP的那些。，没有许可的真菌疫苗可用的。这主要是由于对疫苗免疫机制的理解不足，缺乏功能与表型标记有关疫苗效率。机会性真菌感染，包括二态真菌，组织流质，球虫和爆炸性在这种危险中以惊人的速度上升个人。为高危人群开发量身定制的真菌疫苗的主要局限性理解 CD8+ T细胞对中介疫苗免疫的必要元素。最近的进步对免疫感染的理解与真菌感染相关，有助于并行推进疫苗学。 T细胞衍生的IL-17A，IFNγ，GM-CSF，IL-22和TNFα主要参与对真菌的保护。识别宿主细胞上潜在靶标的可以提供新型有效的疫苗平台，包括免疫功能低下。我们已经建立了CD4+ T细胞淋巴细胞减少的小鼠模型，其中CD8+ T细胞可以刺激以产生受保护的细胞因子IL-17A（TC17）和IFNγ（TC1）进行灭菌免疫针对致命的肺真菌感染。我们已经表明，疫苗吸收的抗真菌CD8+ T细胞持续存在作为长期功能记忆。在此提案中，我们提出了第二个发现：1。GM-CSF+ TC17细胞增强没有病理的疫苗免疫性； 2。抗真菌CD8+ T细胞优先表达O-糖基化唾液磷脂；和3。唾液磷酸蛋白是CD8+ T细胞的分化和扩展所必需的。因此，我们的中心假设是（1）唾液磷脂充当CD8+ T细胞反应的共刺激剂，（2）保留 Sialophorin对于记忆CD8+ T细胞稳态和回忆反应至关重电势交叉呈递，以增强CD8+ T细胞反应。我们的具体目的是：1。确定和剖析唾液酸蛋白在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，使用自适应转移和骨 - 骨髓嵌合体实验，并使用TCRαKO，先天性和唾液酸蛋白KO小鼠的杂交。 2。阐明在真菌肺炎期间，唾液磷脂在记忆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，自适应转移，CRISPR-CAS9基因编辑，体内刺激和E-选择素阻断，以描绘唾液酸蛋白在记忆CD8+ T细胞反应中的作用。 3。剖析唾液酸蛋白在CD8+ T细胞真菌疫苗反应中的树突状细胞上的作用。我们将确定疫苗接种后，CD43在抗原呈递细胞中激活CD8+ T细胞的作用。我们的发现会揭示唾液磷脂在真菌CD8+ T细胞反应中的功能作用和免疫力指导设计新型疫苗平台并测试疫苗的效率。