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.

人类没有持牌疫苗，可抵抗潜在的威胁生命的核心和非细肾脏 由沙门氏菌引起的败血病。这种细胞内病原体逃避了复杂的宿主免疫 防御。宿主免疫系统由调节机制控制，例如细胞间通信 在感染和未感染的细胞之间，这些细胞也可以通过小细胞外蔬菜（EV）来完成 外泌体。外泌体是起源于内体途径并将货物运输到其他细胞的蔬菜。 我们发现，外泌体携带来自伤寒链霉菌感染的巨噬细胞的细菌抗原（AGS）（AGS）（ mφ 沙 刺激参与T细胞募集的抗原呈递细胞，以及这些细胞的鼻内给药 外泌体导致抗S的产生。伤寒抗体（ABS）和Th 1反应的刺激 对于吞噬和杀死细胞内细菌至关重要。这些适应性反应是AGS依赖性的，但是AGS 负责这种体液反应或负责AG贩运电动汽车的机制是未知的。我们 将解决外泌体对在那里针对细胞内病原体的自适应免疫反应的贡献 是确定受保护免疫复杂的新机制的迫切需要，例如外泌体调节 免疫。我们的长期目标是推动开发基于机制的预防措施 细菌感染。我们的总体目标是阐明细菌AG被贩运到的机制 外泌体并确定外泌体能够产生受保护的细胞和体液免疫对抗 细胞内沙门氏菌。我们的中心假设是沙门氏菌AGS被贩运到内体 受感染的Mφ的隔室，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 。理由是确定沙门氏菌AGS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学，我们将分配EV的新作用 防御，对于预防方法的设计很重要。在AIM 1中，我们将确定机制 沙门氏菌AG被贩运到电动汽车中。在AIM 2中，我们将确定电动汽车产生的机制 沙门氏菌感染 确定电动汽车的方式 mφ S调节DC在粘膜组织中的激活和功能。在AIM 3中，我们将 源自感染沙门氏菌的 mφ S驱动自适应免疫。预期的结果 是我们将建立一种负责将AG贩运到电动汽车的机制，并表征 电动汽车在先天免疫和Th1适应性免疫中的新作用。这项研究将产生积极的影响 为未来的疫苗设计目标开发提供了一个概念框架 提前了解沙门氏菌如何破坏宿主免疫，这对于预防性的发展至关重要 和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 由宿主细胞产生的，以防止沙门氏菌病。这项研究很重要，因为我们将 提前了解宿主外泌体在改变对沙门氏菌感染的免疫反应方面的功能。