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: 10609082
• 负责人: Mariola Jadwiga Ferraro
• 金额: $ 45.18万
• 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/10609082
• 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; Communication; Data; Dendritic Cells; Development; Endosomes; Feces; Food Contamination; Future; Gastroenteritis; Goals; Host Defense; Human; Humoral Immunities; ITGAM gene; Immune; Immune response; Immune signaling; Immune system; Immunity; Infection; Infiltration; Intranasal Administration; Knowledge; Lead; Licensing; Life; Macrophage; Mediating; Mission; Modeling; Mucous Membrane; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Natural Immunity; Outcome; Pathogenicity; Pathway interactions; 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; Work; acid fast bacteria; adaptive immune response; adaptive immunity; contaminated water; cytokine; design; exosome; extracellular vesicles; in vivo; innovation; intercellular communication; lymph nodes; migration; mouse model; nanoscale; novel; pathogen; recruit; response; trafficking; transmission process

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.

目前还没有针对可能危及生命的副伤寒和非伤寒的许可疫苗 由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 的防御合作.宿主免疫系统受调节机制控制，如细胞间通讯 感染和未感染的细胞之间，这也可以通过小的细胞外囊泡（EV）来实现， 外来体外泌体是起源于内体途径并将货物运输到其他细胞的囊泡。 我们发现外泌体携带来自S.伤寒沙门氏菌感染的巨噬细胞（ MΦ s）和 刺激参与T细胞募集的幼稚抗原呈递细胞，以及鼻内施用这些抗原呈递细胞。 外泌体导致抗S抗体的产生。鼠伤寒抗体（Abs）和刺激Th 1应答 对吞噬和杀死细胞内细菌至关重要。这些适应性反应是依赖于Ags的，但Ags 负责这种体液反应或负责Ag运输到EV的机制尚不清楚。我们 将解决外泌体对细胞内病原体的适应性免疫反应的贡献， 目前迫切需要确定保护性免疫反应的新机制，例如外泌体调节的 免疫力我们的长期目标是推进基于机制的预防措施的发展， 细菌感染我们的总体目标是阐明细菌抗原被运输到 外泌体，并鉴定外泌体产生保护性细胞和体液免疫的能力， 胞内沙门氏菌我们的中心假设是沙门氏菌抗原被运输到内体， 感染的MΦ的隔室，并通过外泌体释放，以刺激先天性反应和Ag特异性免疫反应。 Th1 细胞应答 .其基本原理是，确定沙门氏菌抗原被贩运到 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，对预防方法的设计很重要。在目标1中，我们将确定 沙门氏菌Ag被贩运到电动汽车中。在目标2中，我们将确定通过以下方式产生EV的机制： 沙门氏菌感染 确定电动汽车如何 MΦ s调节粘膜组织中DC的活化和功能。在目标3中，我们 来源于沙门氏菌感染 MΦ s驱动适应性免疫。预期成果 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，因为它将 为疫苗设计的目标的未来发展提供了一个概念框架， 沙门氏菌如何破坏宿主免疫力的先进知识，这对于预防性药物的开发至关重要。 以及针对这种病原体的治疗方法。创新在于解决电动汽车的功能 由宿主细胞产生以提供对沙门氏菌病的保护。这项研究意义重大，因为我们将 进一步了解宿主外泌体在改变对沙门氏菌感染的免疫反应中的功能。