Cytomegalovirus as a risk factor for exacerbation of Mycobacterium tuberculosis infection

巨细胞病毒是结核分枝杆菌感染恶化的危险因素

• 批准号: 10416959
• 负责人: ANGELO A IZZO
• 金额: $ 9.57万
• 依托单位: UNIVERSITY OF SYDNEY
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10416959
• 关键词: Cytomegalovirus; risk; factor; exacerbation; Mycobacterium

SUMMARY Mycobacterium tuberculosis is a worldwide public health problem, and the need to develop new vaccines to prevent further deaths is critical. However, vaccine development is hindered by the difficulty of translating pre- clinical animal model data to human trials. There may be multiple factors associated with the difference in outcomes between pre-clinical and clinical settings. Of significant interest is the role that co-infections play in mediating immunity to M. tuberculosis infection and how these co-infections increase the risk of developing tuberculosis disease. Co-infections, such as with human Cytomegalovirus virus (HCMV), are important drivers of immune activation in HIV, particularly in sub-Saharan Africa. HCMV associated immune activation in the HIV exposed is known to drive CD4+ T cell decline, hasten immuno-senescence and lead to eventual immune exhaustion. There also emerging evidence to support the fact that HCMV plays a significant role in exacerbating tuberculosis disease in immunocompetent individuals, thus it is important to investigate the interaction between these pathogens and how they mediate the immunity. The current proposal is designed to develop an in vivo experimental co-infection in mice with M. tuberculosis and Cytomegalovirus and with M. tuberculosis. Thus the primary focus of this application is to develop a mouse model to investigate the role of co-infection in the immune mechanisms required to kill M. tuberculosis, and once these have been identified can we start to understand better how to make effective TB vaccines. We will focus on cytomegalovirus co-infection during M. tuberculosis infection to determine how it contributes to exacerbation of TB disease using a mouse model. We will develop the model to understand innate and adaptive immune responses during co-infection (Aim 1), test the hypothesis that excessive reactive species contribute to TB disease using a Type I interferon independent mechanism (Aim 2) and determine how infection with each pathogen interacts with neighboring cells and determine if CMV infection of macrophages and dendritic cells skews development of macrophages towards an M2 or suppressive phenotype resulting in poor adaptive immunity to M. tuberculosis in-vitro. (Aim 3). These studies will provide the basis for future model development to identify mechanisms that may interfere with the efficacy of new and existing anti-tuberculosis vaccines.

概括 结核分枝杆菌是全球公共卫生问题，需要开发新的疫苗 防止进一步的死亡至关重要。但是，很难翻译前的疫苗开发 人类试验的临床动物模型数据。可能有多个因素与差异有关 临床前和临床环境之间的结果。感兴趣的是共同感染在 介导对结核分枝杆菌感染的免疫力以及这些共同感染如何增加发展的风险 结核病。共同感染，例如人类巨细胞病毒病毒（HCMV），是重要的驱动因素 艾滋病毒中的免疫激活，特别是在撒哈拉以南非洲。 HCMV相关的HIV中的免疫激活 已知暴露会驱动CD4+ T细胞下降，急速免疫染色并导致最终免疫 精疲力尽。也有新兴的证据支持HCMV在加剧中起重要作用的事实 免疫能力个体的结核病疾病，因此研究 这些病原体及其如何介导免疫。当前的建议旨在开发体内 与结核分枝杆菌和巨细胞病毒以及结核分枝杆菌的小鼠共同感染。因此 该应用的主要重点是开发小鼠模型，以研究共感染在 杀死结核分枝杆菌所需的免疫机制，一旦确定了这些机制，我们可以开始 更好地了解如何制作有效的结核病疫苗。我们将重点关注M的巨细胞病毒共感染。 结核病感染，以确定其如何使用小鼠模型对结核病疾病加剧。我们 将开发模型以了解共同感染期间先天和适应性免疫反应（AIM 1），测试 假设过度反应性物种使用I型干扰素独立于TB疾病 机理（AIM 2），并确定每种病原体感染如何与相邻细胞相互作用，以及 确定巨噬细胞和树突状细胞的CMV感染是否偏向巨噬细胞的发展 M2或抑制表型，导致对结核分枝杆菌的适应性不良。 （目标3）。这些 研究将为未来的模型开发提供基础，以确定可能干扰的机制 新的和现有的抗结核疫苗的功效。