A STINGing vaccine for TB

结核病疫苗

基本信息

批准号：
10085403
负责人：
WILLIAM Ramses BISHAI
金额：
$ 84.24万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10085403
关键词：
ATAC-seq Address Adult Aerosols Alveolar Animal Model Anti-Infective Agents Antibacterial Response Antitumor Response Attenuated Autophagocytosis Autopsy BCG Live BCG Vaccine Blood Cause of Death Cavia Cell Line Cells Cellular Immunity ChIP-seq Chromatin Clinical Communicable Diseases Confocal Microscopy Dendritic Cells Development Disease Engineering Epigenetic Process Eragrostis Evaluation Flow Cytometry Genetic Transcription Glycolysis Histologic Histones Human IRF3 gene Immune Immunity Immunotherapy Infant Inflammatory Inflammatory Response Pathway Interferons Intervention Intravenous Knockout Mice Lymphoid Cell Malignant neoplasm of urinary bladder Measures Medicine Modeling Mononuclear Morbidity - disease rate Mus Mycobacterium bovis Mycobacterium tuberculosis Myeloid Cells Nature Phagocytosis Phenotype Population Publishing Pulmonary Tuberculosis Rattus Recombinants Recording of previous events Route STING agonists Safety Sampling Sting Injury Testing Tissues Training Translating Tuberculosis Tuberculosis Vaccines Vaccinated Vaccination Vaccines Virulent base cancer cell cancer immunotherapy cost effective cytokine disorder prevention epigenetic profiling improved in vitro Model in vivo Model intravesical macrophage metabolomics monocyte mortality mouse model non-muscle invasive bladder cancer nonhuman primate nonhuman tissue novel overexpression peripheral blood polarized cell prevent protective efficacy reactivation from latency recruit response single-cell RNA sequencing tool transcriptome sequencing tuberculosis granuloma

项目摘要

PROJECT SUMMARY Tuberculosis (TB) is the leading cause of death from a single infectious disease agent worldwide. Vaccination is the most cost-effective control intervention for any infectious disease. Bacille Calmette–Guérin (BCG) remains the most widely used vaccine in human history, but as currently used it has failed to control TB. Thus, the development of improved vaccines against TB therefore remains a high global priority. Recent studies indicate that BCG, when modified, administered through alternate routes, or used in revaccination, offers improved protection, suggesting that it is well poised to make comeback. We have generated a novel recombinant BCG known as BCG-disA-OE which is engineered to overexpress c-di-AMP, a potent STING agonist Our preliminary studies show that BCG-disA-OE is more effective than BCG-WT (wild type BCG) in prevention of disease (POD) following TB challenge and also as an immunotherapy for non-muscle invasive bladder cancer (NMIBC) where intravesical BCG is currently the first-line therapy. Guinea pigs vaccinated with BCG-disA-OE were significantly better protected against aerosol challenge with virulent M.tb than with BCG-WT, and we found that BCG-disA-OE also showed superior efficacy BCG-WT in rat and mouse models of NMIBC. Compared with BCG-WT, BCG-disA-OE leads to more potent pro-inflammatory cytokine responses in macrophage and bladder cancer cells, a higher degree of proinflammatory epigenetic marks, and greater myeloid cell polarization towards the M1 phenotype—changes that are all consistent with enhanced “trained immunity”, a newly discovered phenomenon characterized by epigenetic and functional reprogramming of innate immune cells. In this application, our central scientific premise is that the addition of STING agonist overexpression to BCG will augment trained immunity changes in macrophages and provide more effective protection against TB. To test these hypotheses, in Aim 1 we will determine the protective efficacy of BCG-disA-OE versus BCG-WT against TB disease in non-human primates (NHPs) and against reactivation of latent tuberculosis in mice. In Aim 2 we will evaluate trained immunity changes induced by the two BCG strains in macrophage cell lines, as well as primary murine, NHP, and human (leukopacs from healthy donors) macrophages. We will include serial sampling of NHP mononuclear cells from blood and BAL of NHPs as well as their post-mortem tissues obtained under Aim 1. In Aim 3, we will characterize polarization of myeloid and lymphoid cell populations in the TB granuloma induced by prior vaccination with BCG-WT versus BCG-disA-OE in mouse and NHP models of TB.

项目概要结核病 (TB) 是全球单一传染病疫苗接种导致死亡的主要原因。对于任何传染病来说，卡介苗（BCG）仍然是最具成本效益的控制干预措施。人类历史上使用最广泛的疫苗，但目前使用的疫苗未能控制结核病。因此，最近的研究表明，开发改进的结核病疫苗仍然是全球的首要任务。卡介苗经过修改、通过替代途径给药或用于重新接种时，可提供改善的效果保护，表明它已做好卷土重来的准备。我们已经生成了一种新型重组 BCG，称为 BCG-disA-OE，经过工程设计可过度表达 c-di-AMP，一种有效的 STING 激动剂我们的初步研究表明，BCG-disA-OE 比 BCG-WT（野生型 BCG）用于预防结核病挑战后的疾病 (POD) 以及作为免疫疗法对于非肌层浸润性膀胱癌 (NMIBC)，膀胱内注射卡介苗目前是一线治疗方法。使用 BCG-disA-OE 治疗的豚鼠肺炎可明显更好地抵御气溶胶攻击与 BCG-WT 相比，BCG-disA-OE 对 M.tb 的毒力更强，并且我们发现 BCG-disA-OE 在大鼠中也表现出优于 BCG-WT 的功效与 NMIBC 小鼠模型相比，BCG-disA-OE 具有更有效的促炎作用。巨噬细胞和膀胱癌细胞中的细胞因子反应，促炎性表观遗传程度较高标记，以及更大的骨髓细胞向 M1 表型极化——这些变化都与增强的“训练有素的免疫力”，一种新发现的现象，其特征是表观遗传和功能先天免疫细胞的重新编程。在此应用中，我们的核心科学前提是添加 STING 激动剂过度表达卡介苗将增强巨噬细胞经过训练的免疫变化，并提供更有效的结核病保护。为了检验这些假设，在目标 1 中，我们将确定 BCG-disA-OE 与 BCG-WT 的保护功效对抗非人类灵长类动物 (NHP) 的结核病和对抗小鼠潜伏结核病的再激活。目标 2 我们将评估两种 BCG 菌株在巨噬细胞系中诱导的经过训练的免疫变化，如以及原代小鼠、NHP 和人类（来自健康供体的白细胞）巨噬细胞，我们将包括系列巨噬细胞。从 NHP 的血液和 BAL 及其死后组织中取样 NHP 单核细胞目标 1。在目标 3 中，我们将描述结核病中骨髓细胞和淋巴细胞群的极化在小鼠和 NHP 结核病模型中，预先接种 BCG-WT 与 BCG-disA-OE 诱导的肉芽肿。