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

预防氧化应激可降低耐药结核分枝杆菌的持久性

• 批准号: 7897739
• 负责人: Randall J Basaraba
• 金额: $ 18.7万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897739
• 关键词: Address; Adverse effects; Animals; Antibiotics; Antioxidants; Antitubercular Agents; Bacillus (bacterium); Bacteria; Bacterial Infections; Cause of Death; Cavia; Cell Nucleus; Combination Drug Therapy; Complex; Cytoplasm; Data; Development; Drug Combinations; Drug Tolerance; Effectiveness; Epidemic; Extreme drug resistant tuberculosis; Face; Goals; Grant; Host Defense; Human; Immune response; Infection; Infection Control; Length; Lesion; Lung; Lung Inflammation; Mediating; Microscopic; Modeling; Mycobacterium tuberculosis; Necrosis; Necrotic Lesion; Nuclear; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacotherapy; Play; Population; Prevention; Primary Lesion; Proteins; Research; Role; Staging; Structure of parenchyma of lung; Testing; Therapeutic; Time; Tissues; Tuberculosis; antimicrobial drug; antioxidant therapy; bactericide; base; burden of illness; cost; design; fight against; fighting; human tissue; in vivo; killings; macrophage; neutrophil; novel; novel strategies; pathogen; prevent; public health relevance; resistant strain; transcription factor; treatment duration; treatment strategy; tuberculosis drugs; tuberculosis treatment

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.

描述（由申请人提供）：在结核分枝杆菌（MTB）感染的早期，由于局部肺部炎症而发生不可逆的组织坏死。巨噬细胞和中性粒细胞的杀菌机制应该控制感染，实际上会导致肺组织损伤，从而创造出有利于MTB持久性的微环境。虽然MTB主要是细胞内病原体，但我们和其他人表明，耐药杆菌可以在坏死病变中持续持续持续细胞。我们的长期目标是确定在治疗上恢复抗氧化能力是否会阻止建立持续的，耐药的杆菌，从而使常规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MTB感染，这些尼亚猪会出现与天然结核病类似的人类类似的原发性病变坏死。我们的假设是，通过恢复由宿主转录因子核氧化还原因子2（NRF2）在MTB感染的豚鼠中调节的抗氧化剂防御剂，常规抗结核药物疗法将更有效地抵抗持久的药物耐药性细菌。我们的初步数据表明，人和豚鼠MTB病变中存在氧化应激。这些病变具有过多的氧化应激，可消耗全身性和肺抗氧化剂防御能力。转录因子NRF2部分调节宿主中的氧化防御。在人和豚鼠MTB病变中，NRF2有缺陷，因为它无法从细胞质转移到细胞核。结果，其他下游抗氧化剂蛋白在病变中未表达。该赠款的目的是：解决NRF2靶向抗氧化剂治疗是否会增加抗结核药物的功效。我们将通过（1）进一步定义氧化应激的作用以及NRF2调节的抗氧化剂防御的作用在病变坏死和MTB持久性的发病机理中的消耗（2）确定抗氧化剂是否可以恢复NRF2调节的抗氧化药物，并确定NRF2调节的药物是否可以恢复NRF，并确定NRRF，并确定（3），（3）是否可以确定（3）。当前抗结核药物的有效性通过消除耐药杆菌的持久性。通过更好地了解MTB持久性和耐药性的发病机理，可以将新的治疗策略添加到控制人类结核病的全球斗争中。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，会发生永久性组织损害，这使细菌可以隐藏并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久性，以使抗生素更有效，并且患者治疗所需的时间长度会减少。