Motorized delivery of bacterial antigens to mucosal barriers to enhance immunity against infection

将细菌抗原机动递送至粘膜屏障以增强抗感染免疫力

• 批准号: 10605209
• 负责人: Ronnie H Fang
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-08 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10605209
• 关键词: Address; Affinity; Anti-Bacterial Agents; Antibiotics; Antibodies; Antigens; Authorization documentation; B-Lymphocytes; Bacteria; Bacterial Antigens; Bacterial Infections; Bacterial Toxins; Binding; Biological; Biological Assay; Biomimetics; Cell membrane; Cessation of life; Characteristics; Chitosan; Clostridium Infections; Clostridium difficile; Collaborations; Communicable Diseases; Consumption; Data; Development; Disease; Dose; Enteral; Environment; Evaluation; Formulation; Future; Gastrointestinal tract structure; Goals; Histologic; Hospitals; Immobilization; Immune; Immune response; Immune system; Immunity; In Vitro; Incidence; Infection; Intestines; Long-Term Care; Macrophage; Magnesium; Malignant Neoplasms; Measures; Membrane; Molecular Conformation; Motor; Motor Activity; Mucous Membrane; Mus; Oral; Oral Administration; Pathogenesis; Penetration; Population; Proliferating; Proteins; Public Health; Recording of previous events; Regimen; Research; Research Personnel; Safety; Scheme; Stomach; Technology; Tissue Sample; Toxin; Toxoids; Training; United States; Vaccination; Vaccine Design; Vaccines; Virulence; Virulence Factors; Virus; antitoxin; authority; design; draining lymph node; experience; fabrication; in vivo; mouse model; nanovaccine; novel; oral vaccine; parenteral administration; pathogen; primary endpoint; priority pathogen; prophylactic; response; success; uptake; vaccine development; vaccine distribution; weapons

PROJECT SUMMARY/ABSTRACT Clostridium difficile is a highly threatening pathogen that has risen to prominence as a result of antibiotic overuse and misuse. The bacteria are particularly rampant in long-term care and hospital settings, where it is responsible for a significant number of infections. In response to this challenge, researchers are looking into different ways of managing C. difficile infections. One such strategy that holds significant potential is antivirulence vaccination, where the body is trained to recognize and neutralize the “weapons” employed by bacteria to colonize their hosts and proliferate. Despite their promise, these vaccines oftentimes suffer from a lack of efficacy, and their deployment can also be encumbered by the need for parenteral administration. In this exploratory project, our goal is to develop an entirely new biomimetic micromotor vaccine that can be orally administered to effectively protect against C. difficile infection. The platform consists of two key components: (1) a self-propelled magnesium (Mg)-based micromotor and (2) a macrophage membrane coating that detains bacterial virulence factors. When combined together, we hypothesize that these motor toxoids will be capable of delivering C. difficile toxins to the gut’s immune system, where it can elicit potent antibacterial immune responses that protect against subsequent challenge by the pathogen. By leveraging the natural affinity of toxins for cell membranes, this approach can be used to immobilize multiple antigens in a nonreversible manner. The Mg core enables the motor toxoids to propel upon entry into the intestines, and this will promote the active delivery of the antigenic payloads towards the mucosal barrier, enabling better antigen retention and therefore more efficient immune processing and activation. To achieve our goals, we will first develop a motor toxoid formulation loaded with C. difficile toxins and evaluate its characteristics both in vitro and in vivo (Aim 1). Then, in vivo prophylactic efficacy will be evaluated in a murine model of live C. difficile infection (Aim 2). If successful, this approach for the active delivery of oral vaccines can be readily applied to other high-priority pathogens by modulating the membrane coating and bacterial antigens used for synthesis.

项目摘要/摘要 艰难梭菌是一种高威胁性的病原体，由于过度使用抗生素而引起了突出 和滥用。在长期护理和医院环境中，细菌特别猖ramp 对于大量的感染。为了应对这一挑战，研究人员正在研究不同的方式 管理艰难梭菌感染。具有巨大潜力的这样的策略是抗电力疫苗， 训练身体以识别和中和细菌携带的“武器”以定居宿主的地方 并扩散。尽管有承诺，这些疫苗通常会缺乏效率，他们的 肠胃外管理的需求也可以解决部署。在这个探索性项目中，我们的 目标是开发一种全新的仿生微型疫苗，可以口服以有效地给药 预防艰难梭菌感染。该平台由两个关键组成部分组成：（1）一个自propelled镁 （Mg）基于微噬细胞的微型运动和（2）巨噬细胞膜涂层，它是细菌病毒因子。什么时候 合并在一起，我们假设这些运动毒素将能够将艰难梭菌毒素传递给 肠道的免疫系统，它可以引起有效的抗菌免疫反应，以防止随后的序列 病原体的挑战。通过利用毒素对细胞膜的自然亲和力，这种方法可以是 用于以不可逆的方式固定多种抗原。 MG核使运动型毒素能够推动 进入肠道后，这将促进主动交付抗原有效载荷 粘膜屏障，可以更好地保留抗原，因此可以更有效地免疫加工和激活。 为了实现我们的目标，我们将首先开发带有艰难梭菌毒素的运动毒素配方，并评估 它的体外和体内特征（AIM 1）。然后，将在鼠中评估体内预防效率 艰难梭菌感染的模型（AIM 2）。如果成功，这种主动输送口服疫苗的方法可以 通过调节膜涂层和细菌抗原，容易应用于其他高优先性病原体 用于合成。