Prevention of oxidative stress decreases persistence of drug tolerant M. Tubercu

描述（由申请方提供）：在结核分枝杆菌（Mtb）感染的早期阶段，由于局部肺部炎症而发生不可逆的组织坏死。巨噬细胞和嗜中性粒细胞的杀菌机制，被认为是控制感染，实际上会导致肺组织损伤，从而创造一个有利于结核持续存在的微环境。虽然结核分枝杆菌主要是一种细胞内病原体，但我们和其他人已经表明，耐药杆菌可以在坏死的病变中持续存在于细胞外。我们的长期目标是确定是否恢复抗氧化能力治疗将防止建立持久的，耐药的杆菌，从而使传统的抗结核治疗更有效的动物和人类。我们建议的核心是在豚鼠中使用实验性Mtb感染，其发展与自然发生的结核病的人类相似的原发性病变坏死。我们的假设是，通过治疗恢复由宿主转录因子核氧化还原因子2（Nrf2）在结核分枝杆菌感染的豚鼠中调节的抗氧化防御，常规抗结核药物治疗将更有效地对抗持久性耐药杆菌。我们的初步数据表明，氧化应激存在于人类和豚鼠结核病病变。这些病变具有过度的氧化应激，消耗全身和肺的抗氧化防御。宿主的氧化防御部分由转录因子Nrf2调节。在人类和豚鼠的结核分枝杆菌病变中，Nrf2是有缺陷的，因为它不能从细胞质易位到细胞核。因此，其他下游抗氧化蛋白在病变中不表达。这项资助的目的是：解决Nrf2靶向抗氧化治疗是否会增加抗结核药物的疗效。我们将通过以下方式实现这一目标：（1）进一步确定氧化应激和Nrf2调节的抗氧化防御在病变坏死和结核分枝杆菌持续性发病机制中的作用，（2）确定抗氧化药物是否可以恢复Nrf2调节的内源性抗氧化防御，以及（3），确定Nrf2诱导药物是否可用于通过消除耐药杆菌的持久性来增强当前抗结核药物的有效性。通过更好地了解结核分枝杆菌持久性和耐药性的发病机制，可以为全球控制人类结核病的斗争增加新的治疗策略。公共卫生相关性：当身体对抗导致人类结核病的细菌时，会发生永久性的组织损伤，这使得细菌隐藏起来，避免被抗菌药物杀死。我们的研究旨在防止组织损伤和细菌持续存在，使抗生素更有效，缩短患者治疗所需的时间。

DESCRIPTION (provided by applicant): In the early stages of Mycobacterium tuberculosis (Mtb) infection, irreversible tissue necrosis occurs as the result of localized lung inflammation. The bactericidal mechanism of macrophages and neutrophils, that are supposed to control the infection, in fact cause lung tissue damage and thus create a microenvironment that favors Mtb persistence. While Mtb is primarily an intra- cellular pathogen, we and others have shown that drug-tolerant bacilli can persist extra- cellularly in lesions with necrosis. Our long term goals is to determine whether restoring antioxidant capacity therapeutically will prevent the establishment of persistent, drug-tolerant bacilli thus rendering conventional anti-tuberculosis therapy more effective in animals and humans. Central to our proposal is the use of experimental Mtb infections in guinea pigs which develop primary lesion necrosis similar to humans with naturally occurring tuberculosis. Our hypothesis is that by restoring therapeutically the antioxidant defenses regulated by the host transcription factor nuclear redox factor2 (Nrf2) in Mtb-infected guinea pigs, conventional anti-tuberculosis drug therapy will be more effective against persistent, drug-tolerant bacilli. Our preliminary data shows that oxidative stress exists in human and guinea pig Mtb lesions. These lesions have excessive oxidative stress that depletes systemic and pulmonary antioxidant defenses. Oxidative defenses in the host are regulated, in part, by the transcription factor Nrf2. In human and guinea pig Mtb lesions, Nrf2 is defective since it fails to translocate from the cytoplasm to the nucleus. As a result, other downstream antioxidant proteins are not expressed in lesions. The aim of this grant is to: Resolve whether Nrf2 targeted antioxidant therapy will increase the efficacy of anti-tuberculosis drugs. We will accomplish this aim by (1) further defining the role of oxidative stress and the depletion of Nrf2- regulated antioxidant defenses in the pathogenesis of lesion necrosis and Mtb persistence, (2) determining whether antioxidant drugs can restore Nrf2-regulated endogenous antioxidant defenses and (3), determining whether Nrf2 inducing drugs can be used to enhance the effectiveness of current anti-tuberculosis drugs by eliminating the persistence of drug-tolerant bacilli. By better understanding the pathogenesis of Mtb persistence and drug-tolerance, new treatment strategies can be added to the global fight to control human tuberculosis. PUBLIC HEALTH RELEVANCE: As the body fights the bacterium that causes human tuberculosis, permanent tissue damage occurs, which allows the bacterium to hide and avoid being killed by antimicrobial drugs. Our research is aimed at preventing tissue damage and bacterial persistence so that antibiotics are more effective and the length of time required for patient treatment is reduced.