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人类疫苗的许可。 由肠道沙门氏菌引起的败血症。这种细胞内的病原体逃避复杂的宿主免疫 防御。宿主免疫系统由调节机制控制，如细胞间通讯。 在感染和未感染的细胞之间，这也可以通过细胞外小泡(EVS)来实现， 外显体。外体是起源于内体途径的囊泡，将货物运输到其他细胞。 我们发现，外体携带来自鼠伤寒沙门氏菌感染的巨噬细胞的细菌抗原(AGS)。 MΦ S)和 刺激与T细胞募集有关的幼稚抗原提呈细胞，并对其进行鼻腔给药 外切体导致抗S抗体的产生。小鼠抗体(Abs)与Th1刺激反应 对吞噬和杀灭细胞内细菌至关重要。这些适应性反应依赖于AGS，但AGS 对这种体液反应负责的人或将银贩运到电动汽车的机制尚不清楚。我们 将讨论外体对针对细胞内病原体的适应性免疫反应的贡献，因为 是确定保护性免疫反应的新机制的迫切需要，例如外显体调节 豁免权。我们的长远目标是推进以机制为基础的预防措施的发展 细菌感染。我们的总体目标是阐明细菌抗原被运送到 并鉴定外切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ags被贩卖到内体。 感染M-ΦS并通过外体释放刺激先天反应和抗原特异性的间隔区 Th1 细胞反应 。其基本原理是，确定沙门氏菌AGS被贩运到 并产生针对沙门氏菌的获得性免疫，我们将赋予EVS在宿主中的新角色 防御，对于预防方法的设计很重要。在目标1中，我们将确定各种机制， 沙门氏菌AGS被贩运到电动汽车中。在目标2中，我们将确定由 感染沙门氏菌 确定电动汽车如何 MΦ S调节粘膜组织中树突状细胞的激活和功能。在《目标3》中，我们将 源自受沙门氏菌感染的 MΦ S推动适应性免疫。预期结果 我们将建立一个负责将AGS贩运到电动汽车的机制，并表征 EVS在先天性免疫和Th1获得性免疫中的新作用。这项研究将会产生积极的影响 为疫苗设计目标的未来发展提供一个概念性框架，并显著 关于沙门氏菌如何扰乱宿主免疫的高级知识，这对预防疾病的发展至关重要 以及针对这种病原体的治疗方法。创新之处在于解决了电动汽车的功能问题 由宿主细胞产生，对沙门氏菌病具有保护作用。这项研究具有重要意义，因为我们将 关于宿主外切体在改变沙门氏菌感染免疫反应中的作用的高级知识。