Trained immunity in the prevention of viral myocarditis and pancreatitis

训练有素的免疫力预防病毒性心肌炎和胰腺炎

• 批准号: 10515667
• 负责人: Jay Reddy
• 金额: $ 18.07万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515667
• 关键词: 2019-nCoV; Address; Adjuvant; Affect; Animals; Antigens; Antiviral Response; Attention; BCG Live; Bacteria; Biological Assay; COVID-19; Cells; Coxsackie B Viruses; Coxsackie Viruses; Data; Derivation procedure; Development; Dilated Cardiomyopathy; Disease; Disease Outbreaks; Encephalitis; Enterovirus; Enterovirus Infections; Epigenetic Process; Exanthema; Exposure to; Foot Diseases; Foundations; Freund' s Adjuvant; Future; Genus Mycobacterium; Goals; Health; Heart; Histocompatibility Antigens Class II; Histologic; Human; Immune; Immune response; Immunity; Immunization; Immunize; Immunologic Stimulation; Individual; Infant; Infection; Innate Immune Response; Insulin-Dependent Diabetes Mellitus; Lipopolysaccharides; Macrophage; Mediating; Memory; Meningitis; Metabolic; Methods; Mission; Molecular; Molecular Structure; Morbidity - disease rate; Mouth Diseases; Mycobacterium tuberculosis; Myocarditis; Natural Killer Cells; Neutralization Tests; Outcome; Pancreas; Pancreatitis; Paralysed; Parasites; Pathogenicity; Pathway interactions; Patients; Prevention; Property; Public Health; Research; Serotyping; Stimulus; T-Lymphocyte; Testing; Therapeutic Uses; Training; United States; United States National Institutes of Health; Vaccine Adjuvant; Vaccinee; Vaccines; Viral; Viral Proteins; Viral Vaccines; Virus; Virus Diseases; adaptive immune response; beta-Glucans; chromatin immunoprecipitation; cytokine; diabetic cardiomyopathy; gene function; improved; incomplete Freund' s adjuvant; innovation; insulitis; microbial; monocyte; mortality; mycobacterial; neutrophil; novel; prevent; respiratory; response; small molecule; success; tool; unvaccinated; vaccine candidate; vaccine response; vaccine strategy; vaccine trial; viral myocarditis; γδ T cells

PROJECT SUMMARY/ABSTRACT Enteroviruses, such as group B Coxsackieviruses, are common suspects in myocarditis and pancreatitis. However, no vaccines are currently available for these viruses, in part because multiple serotypes of Coxsackieviruses can induce similar diseases. Thus, exploration of alternative strategies to protect against them may have merit. The research team has made an unexpected observation that animals immunized with complete Freund’s adjuvant (CFA) were completely protected from both myocarditis and pancreatitis induced with Coxsackievirus B3 (CVB) pointed to a possibility that trained immunity may be an underlying mechanism of CFA-mediated effects, as demonstrated with the Bacillus Calmette-Guérin (BCG). The long-term goal of this research is to identify adjuvants that induce trained immunity to enhance anti-viral vaccine responses in the prevention of enteroviral infections. The objective of this application is to determine if macrophages primed with CFA mediate trained immunity. The central hypothesis is that the CFA contributes to the induction of anti-viral responses by trained immunity. This hypothesis will be tested by two specific aims: 1) characterize anti-viral responses in animals immunized with CFA and 2) determine the mechanisms of CFA- mediated protection in CVB infection. Methods and tools to be used include multiplex cytokine bead array, virus neutralization test, and major histocompatibility complex class II dextramers to assess antigen-specific immune responses and chromatin immunoprecipitation and metabolite assays to investigate the mechanisms of CFA-induced trained immunity. The project is innovative because it aims to determine whether trained immunity offers protection against CVB infections. The proposed studies are significant because they will: 1) mechanistically investigate whether trained immunity is sufficient to prevent enterovirus infections and 2) identify pathways that contribute to CFA-induced trained immunity. These outcomes may have a significant impact on strategies for preventing and/or treating viral infections using mycobacterial components that are known to possess immune-stimulating properties.

项目摘要/摘要 肠病毒（例如B组Coxsackievieviruses）是心肌炎和胰腺炎的常见嫌疑人。 但是，目前尚无疫苗用于这些病毒，部分原因是多种血清型 Coxsackievivirus可以诱发类似的疾病。探索替代策略以防止 他们可能有价值。研究小组已经意外地观察到动物免疫 完全保护完整的Freund的辅助（CFA）免受心肌炎和胰腺炎诱导 用Coxsackievivirus B3（CVB）指出训练的免疫力可能是一种基本机制 CFA介导的效果，如杆菌Calmette-guérin（BCG）所证明的。长期目标 这项研究是为了确定诱导受过训练的免疫力以增强抗病毒疫苗反应的适应器 预防肠病毒感染。该应用的目的是确定巨噬细胞是否 用CFA介导的受过训练的免疫力。中心假设是CFA有助于 通过受过训练的免疫力诱导抗病毒反应。该假设将通过两个具体目标来检验：1） 表征用CFA免疫的动物中的抗病毒反应，2）确定CFA-的机制 CVB感染中介导的保护。要使用的方法和工具包括多个细胞因子珠阵列， 病毒神经化测试和主要的组织相容性复合物II类葡萄膜，以评估抗原特异性 免疫反应和染色质免疫沉淀和代谢物测定法 CFA诱导的训练有素的免疫力。该项目具有创新性，因为它旨在确定是否训练 免疫提供了防止CVB感染的保护。拟议的研究很重要，因为它们会：1） 机械地研究训练训练的免疫学是否足以防止肠病毒感染和2） 确定有助于CFA诱导的受过训练的免疫力的途径。这些结果可能具有重要的 对使用分枝杆菌成分预防和/或治疗病毒感染的策略的影响 已知具有免疫刺激特性。