Boosting Innate Immunity Through HIF to Treat Antibiotic-Resistant Infections

通过 HIF 增强先天免疫力来治疗抗生素耐药性感染

• 批准号: 8638886
• 负责人: RANDALL Scott JOHNSON
• 金额: $ 97.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-05 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638886
• 关键词: Abscess; Address; Agonist; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Apoptosis; Apoptotic; Bacteria; Bacterial Infections; Basic Science; Biotechnology; Cell Death; Cells; Cellular biology; Chlamydophila pneumoniae; Chromatin; Clinical Trials; Collaborations; Companions; Cutaneous; Cytoplasmic Granules; Data; Development; Development Plans; Discipline; Drug Design; Drug Kinetics; Elements; Epithelial; Epithelium; Gene Expression Regulation; Gene Targeting; Generations; Genes; Genetic; Goals; Gold; Healed; Host Defense; Human; Hypoxia; Immune; Immunogenetics; Immunotherapeutic agent; In Vitro; Industry; Infection; Infectious Skin Diseases; Inflammatory; Investigational New Drug Application; Knockout Mice; Knowledge; Laboratories; Lead; Leukocytes; Lipopolysaccharides; Lung; Manuscripts; Mediating; Medicine; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; NIH Program Announcements; National Institute of Allergy and Infectious Disease; Natural Immunity; Necrosis; Nitric Oxide; Pathway interactions; Pattern; Peptide Hydrolases; Phagocytes; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pneumonia; Positioning Attribute; Preparation; Procollagen-Proline Dioxygenase; Production; Program Development; Pseudomonas Infections; Pseudomonas aeruginosa; Publishing; Puncture procedure; Research; Research Personnel; Resistance; Resolution; Role; Safety; Skin; Staphylococcal Infections; Staphylococcus aureus; Systemic Therapy; TNF gene; Therapeutic; Toll-like receptors; Topical agent; Toxic effect; Toxin; Transcriptional Regulation; Translational Research; Vancomycin; Work; Wound Infection; antimicrobial; antimicrobial peptide; bacterial resistance; bactericide; cytokine; drug resistant bacteria; extracellular; healing; hypoxia inducible factor 1; in vivo; in vivo Model; industry partner; inhibitor/antagonist; innate immune function; innovation; keratinocyte; killings; macrophage; mast cell; methicillin resistant Staphylococcus aureus; microbial; microbicide; mouse model; neutrophil; novel; overexpression; pathogen; pre-clinical; product development; promoter; response; subcutaneous; superinfection; synergism; tool; transcription factor; treatment strategy; treatment trial; wound

DESCRIPTION (provided by applicant): Our proposal directly addresses the Program Announcement (RFA-AI-10-003) goals of "development of broad- spectrum (innate immunity) immunotherapeutic that targets NIAID Priority Agents" and establishment of "collaborations between researchers in different disciplines and/or with industry" in a very powerful and unique fashion. Here we will describe our extensive published data revealing the novel function of transcription factor hypoxia inducible factor-1 (HIF-1) as a master regulator of host innate immune function, including proof-of-principle demonstrations that pharmacologic targeting of HIF-1 can augment the bactericidal capacity of phagocytic cells against Gram+ and Gram- bacteria in vitro and in vivo. HIF-1 is induced by bacterial infection, even under normoxia, and regulates the production of key immune effector molecules including granule proteases, antimicrobial peptides, nitric oxide and TNF-a. We then provide exciting new unpublished data that show how potent new-generation prolyl hydroxylase (PHD) inhibitor drugs from Akebia Therapeutics, Inc. boost HIF-1 in human phagocytes and cause them to kill pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) with efficiency comparable to classical antibiotic therapy. Importantly, the same class of agents accelerates wound closing in skin, providing a therapeutic approach for skin and wound infections that promotes healing while simultaneously providing an anti-infective barrier. This innovative antimicrobial treatment strategy, working through the host, is inherently broad spectrum and can be used as an adjunct to classical antibiotic therapy. Rather than designing drugs to target the bacteria, medications that promote HIF-1a activity could be used to boost the bacterial killing ability of white blood cells and promote the resolution of infection through the actions of our natural immune defenses. The research plan will further establish the mechanistic underpinnings for HIF-1 antimicrobial activity by microarray and companion immunogenetic analysis of HIF-1 regulated genes in the context of infection, the role of HIF-1 in protecting against microbial toxin induced phagocyte toxicity and apoptosis, and the involvement of phagocyte extracellular traps in HIF-1 mediated bacterial killing. HIF-1 knockout mice will be used to assess the role of the transcriptional control pathway in control of MRSA and Pseudomonas infections in skin, skin wounds, and pneumonia models of infection. Then, as informed by the results of those studies, treatment trials of HIF-agonist lead compound AKB-4924 against MRSA and P. aeruginosa will be explored in these same models, with topical compared to systemic therapy in the skin and wound models. Through our partnership with Akebia Therapeutics, an extensive preclinical development plan of pharmacokinetic and safety/toxicity analyses will be conducted with the goal of an FDA Investigational New Drug Application for entry into clinical trials of bacterial skin infection, initial as a topical agent. Ultimately, HIF-1 immune boosting therapy could find wide application in the treatment of difficult infections complicated by antibiotic resistance or weakened host defense.

描述(由申请人提供)：我们的建议直接涉及计划公告(RFA-AI-10-003)的目标，即“开发针对NIAID优先药物的广谱(天然免疫)免疫治疗药物”，并以非常强大和独特的方式建立“不同学科的研究人员和/或与行业的合作”。在这里，我们将描述我们发表的大量资料，揭示了转录因子缺氧诱导因子-1(HIF-1)作为宿主先天性免疫功能的主要调节因子的新功能，包括在体外和体内通过药物靶向HIF-1可以增强吞噬细胞对革兰氏阳性菌和革兰氏菌的杀菌能力。HIF-1是由细菌感染诱导的，甚至在常氧条件下也是如此，它调节关键免疫效应分子的产生，包括颗粒蛋白酶、抗菌肽、一氧化氮和肿瘤坏死因子-α。然后，我们提供了令人兴奋的新的未发表的数据，展示了来自木通治疗公司的新一代有效的Pro羟基酶(PhD)抑制剂药物如何促进人类吞噬细胞中的HIF-1，并使它们以与经典抗生素疗法相当的效率杀死病原体，如耐甲氧西林金黄色葡萄球菌(MRSA)。重要的是，同一类药物可以加速皮肤伤口的闭合，为皮肤和伤口感染提供一种治疗方法，在促进愈合的同时提供抗感染屏障。这一创新的抗菌治疗策略通过宿主发挥作用，天生就是广谱的，可以作为经典抗生素治疗的辅助手段。与其设计针对细菌的药物，不如使用促进HIF-1a活性的药物来提高白细胞的杀菌能力，并通过我们自然免疫防御的行动促进感染的解决。该研究计划将通过对感染背景下HIF-1调控基因的微阵列和伴随免疫遗传学分析，进一步建立HIF-1抗微生物活性的机制基础，HIF-1在保护微生物毒素诱导的吞噬细胞毒性和凋亡中的作用，以及吞噬细胞外陷阱参与HIF-1介导的细菌杀灭。HIF-1基因敲除小鼠将被用来评估转录控制途径在皮肤、皮肤伤口和肺炎感染模型中控制MRSA和假单胞菌感染的作用。然后，根据这些研究的结果，将在这些相同的模型中探索HIF激动剂先导化合物AKB-4924对MRSA和铜绿假单胞菌的治疗试验，并在皮肤和伤口模型中进行局部治疗与全身治疗的比较。通过我们与木通治疗公司的合作，将实施广泛的药代动力学和安全性/毒性分析的临床前开发计划，目标是FDA的新药研究申请进入细菌性皮肤感染的临床试验，最初是作为外用药物。最终，HIF-1免疫增强疗法可能会在治疗合并抗生素耐药性或宿主防御减弱的难治性感染中得到广泛应用。