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预防潜在威胁生命的副伤寒和非伤寒的疫苗