Mechanisms of anthrax lethal toxin-induced mortality and the novel biological-based targeted therapies

炭疽致死毒素致死机制及新型生物靶向治疗

• 批准号: 10654406
• 负责人: Shihui Liu
• 金额: $ 60.63万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-17 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654406
• 关键词: Acute; Affect; Animals; Anthrax Attack; Anthrax disease; Antibiotics; Antibodies; Bacillus anthracis; Bacterial Infections; Bioenergetics; Biological; Biological Process; Bioterrorism; Cardiac Myocytes; Cardiovascular system; Caring; Cell Proliferation; Cell Survival; Cells; Cessation of life; Clinical; Clinical Management; Communicable Diseases; Complement; Data; Disease; Epidermal Growth Factor; Goals; Host Defense Mechanism; Human; Impairment; Infection; Inhalation; MAP Kinase Gene; MAP2K1 gene; MAPK8 gene; MEKs; Mediating; Medical; Medical Assistance; Metabolism; Metalloproteases; Mitogens; Molecular; Molecular Target; Organ; Pathogenesis; Pathway interactions; Patients; Play; Public Health; Research; Resistance; Role; Septic Toxemia; Stress; Symptoms; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxin; Virulence Factors; anthrax lethal factor; antitoxin; c-myc Genes; cardiovascular collapse; evidence base; expectation; flu; in vivo; lethal factor; mortality; mouse model; novel; p38 Mitogen Activated Protein Kinase; pathogen; prevent; repaired; resistance allele; targeted treatment

Bacillus anthracis, the causative agent of anthrax disease, has remained as a top bioterrorism concern since the 2001 anthrax attack. B. anthracis causes anthrax through a combination of bacterial infection and toxemia. As a major virulence factor, the anthrax lethal toxin (LT) plays an essential role during multiple steps of the disease. Due to the rapid course of anthrax disease, in particular, the early non-specific, flu-like symptoms of inhalational anthrax, patients usually seek medical assistance when the disease is already in the middle/late stages, making the clinical management of anthrax patients an extremely challenging task. Current treatments include antibiotics and anti-toxin antibodies that respectively eliminate the pathogen and neutralize the toxin. However, there is no therapy available to deal with the cellular/tissue damage caused by LT already having reached its molecular targets inside cells. Mortality usually follows when the host fails to repair this damage, the so called “point-of-no- return” for current therapy. Thus, even with intensive medical care, the mortality rate of systemic anthrax is high, reaching > 50%. Therefore, there is an urgent unmet clinical need to develop better targeted therapies to avert anthrax-induced mortality. Our goal in this application is to discover the molecular mechanisms underlying LT- induced lethality and to develop potential targeted therapeutics to treat patients beyond the “point-of-no-return”. Here, we set out to determine the specific roles of disrupting each of the ERK, p38, and JNK pathways in anthrax- induced lethality, discover the underlying molecular mechanisms, and develop the concept of reactivation /mobilization of these pathways as a targeted therapy for anthrax-induced mortality. In Aim 1, we will determine the role of specifically disrupting the ERK pathway in anthrax-induced lethality. Among the three core MAPK pathways targeted by LT, the ERK pathway is fundamental to many biological processes, including cell proliferation and survival. Thus, we hypothesize that disrupting the ERK pathway is the major cause of anthrax- induced lethality. We will generate and use novel mouse models containing MEK alleles that are resistant to LT- cleavage to understand the precise role of ERK pathway inactivation in anthrax pathogenesis. In Aim 2, we will further determine the roles of disrupting the p38 and JNK pathways, the two major stress-activated pathways that hosts activate in order to adapt to a myriad of unfavorable conditions, in anthrax pathogenesis. Based on our strong preliminary data that the LT-disrupted MAPK pathways, in particular the ERK pathway, can be reactivated by the addition of potent mitogens, in Aim 3, we will explore the ERK pathway reactivation as a targeted therapy for anthrax-induced tissue damage. Upon completion of these studies, it is our expectation that we will provide significant conceptual advances in our understanding of the underlying molecular mechanisms of anthrax pathogenesis, and offer an evidence- based framework for developing anthrax-targeted therapies, which will complement the current therapies with antibiotics and anti-toxin antibodies, to prevent anthrax mortality, even at advanced stages of anthrax infection.

炭疽病的病原体炭疽芽孢杆菌一直是最高生物恐怖主义的关注 2001炭疽攻击。 B.炭疽病通过细菌感染和毒血症的结合引起炭疽病。作为 主要病毒因子，炭疽致死毒素（LT）在多个疾病的多个步骤中起着至关重要的作用。 由于炭疽病的迅速过程，尤其是意外的早期非特异性，类似流感的症状 炭疽病，患者通常在疾病已经处于中期/晚期时寻求医疗援助，使 炭疽患者的临床管理是一项极其挑战的任务。当前治疗包括抗生素 分别消除病原体并中和毒素的抗毒素抗体。但是，没有 可用于处理由LT已达到其分子引起的细胞/组织损伤的治疗 细胞内部的目标。当宿主无法修复这种损害时，死亡率通常会遵循，所谓的“无关 当前疗法的回报。 达到> 50％。因此，紧急未满足的临床需要开发出更好的靶向疗法以避免 炭疽引起的死亡率。我们在此应用中的目标是发现LT-的分子机制 诱导致死性并开发潜在的靶向疗法，以治疗“无归因点”以外的患者。 在这里，我们着手确定破坏炭疽中每个ERK，p38和JNK途径的特定作用。 诱导致死性，发现潜在的分子机制并发展重新激活的概念 /将这些途径作为针对炭疽诱导的死亡率的靶向疗法。在AIM 1中，我们将确定 特异性破坏ERK途径在炭疽引起的致死性中的作用。在三个核心MAPK中 LT靶向的途径，ERK途径是许多生物过程的基础，包括细胞 增殖和生存。这是，我们假设破坏ERK途径是炭疽 - 诱导的致死性。我们将生成和使用含有抗LT-的MEK等位基因的新型鼠标模型 裂解以了解ERK途径失活在炭疽发病机理中的精确作用。在AIM 2中，我们将 进一步确定破坏p38和JNK途径的作用，这是两个主要的应力激活途径 该主机在炭疽病的发病机理中占据激活以适应多种不利条件。基于 我们强大的初步数据，即LT破坏的MAPK途径，尤其是ERK途径，可以是 在AIM 3中，通过添加潜在有丝分裂剂重新激活，我们将探索ERK途径重新激活 针对炭疽引起的组织损伤的靶向治疗。 完成这些研究后，我们期望我们在 我们对炭疽发病机理的潜在分子机制的理解，并提供证据 - 基于开发炭疽病靶向疗法的框架，该疗法将完成当前的疗法 即使在炭疽感染的晚期阶段，抗生素和抗毒素抗体，以防止炭疽死亡率。