The Function of Host-derived Extracellular Vesicles in Trafficking of Bacterial Antigens to Stimulate the Antibacterial Immune Response

宿主来源的细胞外囊泡在细菌抗原运输中刺激抗菌免疫反应的功能

• 批准号: 10443148
• 负责人: Mariola Jadwiga Ferraro
• 金额: $ 54.33万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-12 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443148
• 关键词: Address; Advanced Development; Affect; Animals; Anti-Bacterial Agents; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; Autophagocytosis; Bacteria; Bacterial Antigens; Bacterial Infections; Bone Marrow; CD4 Positive T Lymphocytes; Cell Communication; Cell physiology; Cells; Cellular Immunity; Cessation of life; Data; Dendritic Cells; Development; Feces; Food Contamination; Future; Gastroenteritis; Genus Mycobacterium; Goals; Host Defense; Human; Humoral Immunities; ITGAM gene; Immune; Immune response; Immune signaling; Immune system; Immunity; Infection; Infiltration; Intranasal Administration; Knowledge; Lead; Life; Mediating; Mission; Mucous Membrane; Mus; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Natural Immunity; Outcome; Pathogenicity; Pathway interactions; Pharmaceutical Preparations; Phenotype; Preventive measure; Process; Production; Proteins; Public Health; Publishing; RNA; Research; Role; Salmonella; Salmonella enterica; Salmonella infections; Salmonella typhimurium; Septicemia; Subunit Vaccines; T-Cell Activation; T-Lymphocyte; Th1 Cells; Therapeutic; Vaccine Design; Vaccines; Vesicle; Water consumption; acid fast bacteria; adaptive immune response; adaptive immunity; base; cytokine; design; exosome; extracellular vesicles; innovation; intercellular communication; lymph nodes; macrophage; migration; mouse model; nanoscale; novel; pathogen; recruit; response; trafficking

There is no licensed vaccine for humans against potentially life-threatening paratyphoid and nontyphoidal septicemia caused by the Salmonella enterica. This intracellular pathogen evades sophisticated host immune defenses. The host immune system is controlled by regulatory mechanisms, such as intercellular communication between infected and uninfected cells, which can also be accomplished via small extracellular vesicles (EVs), exosomes. Exosomes are vesicles that originate in the endosomal pathway and transport cargo to other cells. We found that exosomes carry bacterial antigens (Ags) from S. Typhimurium-infected macrophages ( MΦ s) and stimulate naïve antigen-presenting cells involved in T cell recruitment, and an intranasal administration of these exosomes leads to the production of anti-S. Typhimurium antibodies (Abs) and stimulation of Th 1 response critical for engulfing and killing intracellular bacteria. These adaptive responses are Ags-dependent, but the Ags responsible for this humoral response or the mechanisms responsible for Ag trafficking to EVs are unknown. We will address the contribution of exosomes to adaptive immune responses against intracellular pathogens as there is a critical need to determine new mechanisms of protective immune responses, such as exosome-modulated immunity. Our long-term goal is to advance the development of mechanism-based preventative measures for bacterial infections. Our overall objective is to elucidate the mechanisms whereby bacterial Ags are trafficked to exosomes and identify the capability of exosomes to generate protective cellular and humoral immunity against intracellular Salmonella. Our central hypothesis is that Salmonella Ags are trafficked to endosomal compartments of infected MΦs and released via exosomes to stimulate innate responses and Ag-specific Th1 cell responses . The rationale is that determining the mechanisms via which Salmonella Ags are trafficked to exosomes and generate adaptive immunity against Salmonella, we will assign a novel role of EVs in host defense, important for the design of preventative approaches. In Aim 1, we will identify mechanisms whereby Salmonella Ags are trafficked into EVs. In Aim 2, we will determine the mechanisms by which EVs produced by Salmonella-infected determine how EVs MΦ s regulate the activation and function of DCs in mucosal tissues. In Aim 3, we will derived from Salmonella-infected MΦ s drive adaptive immunity. The expected outcomes are that we will have established a mechanism responsible for the trafficking of Ags into EVs, and characterize novel roles of EVs in innate immunity and Th1 adaptive immunity. This study will have a positive impact as it will provide a conceptual framework for the future development of targets for vaccine design and significantly advance knowledge of how Salmonella disrupts host immunity, which is vital for the development of preventative and therapeutic approaches against this pathogen. The innovation lies in addressing the function of EVs produced by host cells in rendering protection against salmonellosis. This study is significant since we will advance knowledge on the function of host exosomes in altering the immune response to Salmonella infection.

目前还没有获得许可的人类疫苗，可预防可能危及生命的副伤寒和非伤寒疫苗 由肠道沙门氏菌引起的败血症，这种细胞内病原体逃避复杂的宿主免疫。 宿主免疫系统由细胞间通讯等调节机制控制。 感染细胞和未感染细胞之间的相互作用，这也可以通过小的细胞外囊泡（EV）来完成， 外泌体是起源于内体途径并将货物转运至其他细胞的囊泡。 我们发现外泌体携带来自鼠伤寒沙门氏菌感染的巨噬细胞的细菌抗原（Ag）（ MΦ 沙 刺激参与 T 细胞募集的初始抗原呈递细胞，并鼻内施用这些细胞 外泌体导致抗鼠伤寒沙门氏菌抗体 (Abs) 的产生并刺激 Th 1 反应。 这些适应性反应对于吞噬和杀死细胞内细菌至关重要。 负责这种体液反应或负责将Ag贩运到EV的机制尚不清楚。 将解决外泌体对针对细胞内病原体的适应性免疫反应的贡献 迫切需要确定保护性免疫反应的新机制，例如外泌体调节 我们的长期目标是推动建立基于机制的预防措施。 我们的总体目标是阐明细菌 Ag 被贩运到的机制。 外泌体并鉴定外泌体产生保护性细胞和体液免疫的能力 我们的中心假设是沙门氏菌 Ag 被转运至内体。 受感染的 MΦ 区室并通过外泌体释放以刺激先天反应和 Ag 特异性 Th1 细胞反应 基本原理是确定沙门氏菌抗原被贩运到的机制 外泌体并产生针对沙门氏菌的适应性免疫，我们将赋予 EV 在宿主中的新作用 防御，对于设计预防方法很重要，因此在目标 1 中，我们将确定机制。 在目标 2 中，沙门氏菌抗原被贩运到电动汽车中，我们将确定沙门氏菌生产电动汽车的机制。 沙门氏菌感染 确定电动汽车如何 MΦ 在目标 3 中，我们将调节粘膜组织中 DC 的激活和功能。 源自沙门氏菌感染 MΦ s 驱动适应性免疫。 我们将建立一个机制，负责将 Ag 贩运到 EV 中，并描述 EV 在先天免疫和 Th1 适应性免疫中的新作用这项研究将产生积极的影响。 为疫苗设计目标的未来发展提供概念框架，并显着 了解沙门氏菌如何发展破坏宿主免疫力，这对于预防性药物的开发至关重要 针对这种病原体的治疗方法的创新在于解决 EV 的功能。 由宿主细胞产生，可​​提供针对沙门氏菌病的保护，这项研究意义重大，因为我们将 关于宿主外泌体在改变沙门氏菌感染免疫反应中的功能的知识。