Effects of carbon dioxide on M. tuberculosis growth and gene expression

描述(由申请人提供)： 结核病仍然是一个严重的全球健康问题。该项目的长期目标是更好地了解结核分枝杆菌(Mtb)对宿主相关环境条件的生理反应，以便制定有效的策略来预防和/或治疗Mtb感染。对于寄主环境中的许多细菌病原体来说，二氧化碳是与毒力相关的基本环境信号，但它对结核分枝杆菌的影响尚未得到严格的研究。最近的研究表明，生理水平的二氧化碳完全消除了低氧诱导的结核复合菌生长停滞。这些发现挑战了结核分枝杆菌“缺氧诱导生长停滞”模型的体内意义，因为宿主体内的大多数区域都含有丰富的二氧化碳。这一探索性项目的目标是确定二氧化碳对结核分枝杆菌基因调控和代谢的相关影响，包括那些可能促进结核分枝杆菌向非复制持久性过渡的影响。具体目标包括： 目的1：利用基于蛋白质组和RNA表达的微阵列方法，鉴定二氧化碳对结核分枝杆菌基因表达的相关影响； 目的2：用遗传学和生物化学方法评价二氧化碳对结核分枝杆菌胞内pH和碳途径利用的影响。 这项工作将探索有关可能影响结核分枝杆菌在宿主内代谢状态的条件的新见解，并有可能为结核病疫苗、治疗和/或诊断目的确定新的靶点。结核分枝杆菌对二氧化碳的生理反应的特征将扩大我们对结核杆菌对宿主内将遇到的关键环境条件的反应的理解，并提供关于可能影响结核病感染、持久性和/或疾病建立的因素的信息。 由结核分枝杆菌引起的结核病仍然是一个严重的全球公共卫生问题。结核分枝杆菌对二氧化碳的生理反应的特征将扩大我们对结核杆菌对宿主内将遇到的关键环境条件的反应的理解，并有可能为结核病疫苗、治疗和/或诊断目的确定新的靶点。

DESCRIPTION (provided by applicant): Tuberculosis remains a critical global health problem. The long-term objective of this project is to better understand Mycobacterium tuberculosis' (Mtb) physiological response to host-associated environmental conditions, so that effective strategies can be developed to prevent and/or treat Mtb infection. Carbon dioxide is an essential virulence-associated environmental signal for many bacterial pathogens within their host environments, but its effects on Mtb have not been rigorously examined. Recent studies showed that physiologic levels of carbon dioxide completely abrogate hypoxia-induced growth arrest in TB complex bacteria. These findings challenge the in vivo significance of the Mtb 'hypoxia-induced growth arrest' model, because carbon dioxide is abundant in most areas within the host. The goal of this exploratory project is to identify CO2-associated effects on Mtb gene regulation and metabolism, including those that may facilitate Mtb's transition to non-replicating persistence. Specific aims include: Aim 1: identification of CO2-associated effects on Mtb gene expression, using proteomic and RNA expression-based microarray approaches; Aim 2: evaluation of CO2-associated effects on Mtb's intracellular pH and carbon pathway utilization, using genetic and biochemical approaches. This work will explore new insights regarding conditions that may affect Mtb's metabolic state within the host, with the potential to identify new targets for TB vaccines, therapeutics, and/ or diagnostic purposes. Characterization of Mtb's physiological response to carbon dioxide will broaden our understanding of the tubercle bacillus' response to a critical environmental condition that will be encountered within the host, and provide information on factors that may affect the establishment of tuberculosis infection, persistence and/or disease. Tuberculosis, caused by Mtb, remains a serious global public health problem. Characterization of Mtb's physiological response to carbon dioxide will broaden our understanding of the tubercle bacillus' response to a critical environmental condition that will be encountered within the host, with the potential to identify new targets for TB vaccines, therapeutics, and/ or diagnostic purposes.