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

描述（由申请人提供）：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。本应控制感染的巨噬细胞和中性粒细胞的杀菌机制，实际上会导致肺组织损伤，从而创造一个有利于结核分枝杆菌持续存在的微环境。虽然结核分枝杆菌主要是细胞内病原体，但我们和其他人已经表明，耐药杆菌可以在坏死病变的细胞外持续存在。我们的长期目标是确定通过治疗恢复抗氧化能力是否会阻止持久性耐药杆菌的建立，从而使传统的抗结核治疗在动物和人类中更有效。我们建议的核心是在豚鼠中使用实验性结核分枝杆菌感染，这些豚鼠的原发性病变坏死与自然发生的结核病类似。我们的假设是，通过治疗性地恢复mtb感染豚鼠中由宿主转录因子核氧化还原因子2 （Nrf2）调节的抗氧化防御，传统的抗结核药物治疗将对持久性耐药杆菌更有效。我们的初步数据表明，氧化应激存在于人类和豚鼠结核杆菌病变。这些病变有过度的氧化应激，消耗全身和肺部的抗氧化防御。宿主的氧化防御在一定程度上受转录因子Nrf2的调节。在人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转移到细胞核。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：确定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(1)进一步确定氧化应激和Nrf2调控的抗氧化防御在病变坏死和结核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调控的内源性抗氧化防御，以及(3)确定Nrf2诱导药物是否可以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来实现这一目标。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，可以为控制人类结核病的全球斗争增加新的治疗策略。公共卫生相关性：当人体与引起人类结核病的细菌作斗争时，会发生永久性的组织损伤，这使细菌得以隐藏，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的持续存在，使抗生素更有效，减少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.