Boosting Innate Immunity Through HIF to Treat Antibiotic-Resistant Infections

描述（由申请人提供）：我们的提案直接涉及计划公告（RFA-AI-10-003）的目标，即“开发针对NIAID优先因子的广谱（先天免疫）免疫系统”，并以非常强大和独特的方式建立“不同学科和/或行业研究人员之间的合作”。在这里，我们将描述我们广泛发表的数据，揭示了新的功能，转录因子缺氧诱导因子-1（HIF-1）作为一个主调节宿主先天免疫功能，包括证明的原则证明，药理学靶向HIF-1可以增强杀菌能力的吞噬细胞对革兰氏阳性菌和革兰氏阴性菌在体外和体内。HIF-1由细菌感染诱导，甚至在常氧下，并调节关键免疫效应分子的产生，包括颗粒蛋白酶、抗微生物肽、一氧化氮和TNF-α。然后，我们提供了令人兴奋的新的未发表的数据，显示如何有效的新一代脯氨酰羟化酶（PHD）抑制剂药物从Akebia治疗公司。增强人类吞噬细胞中的HIF-1，并使它们杀死病原体，如耐甲氧西林金黄色葡萄球菌（MRSA），其效率与经典抗生素治疗相当。重要的是，同一类药物加速皮肤中的伤口闭合，为皮肤和伤口感染提供了一种治疗方法，促进愈合，同时提供抗感染屏障。这种创新的抗菌治疗策略，通过主机工作，本质上是广谱的，可以作为一个辅助经典的抗生素治疗。与其设计针对细菌的药物，不如使用促进HIF-1 a活性的药物来提高白色血细胞的杀菌能力，并通过我们的天然免疫防御作用促进感染的解决。该研究计划将通过微阵列和在感染背景下HIF-1调节基因的伴随免疫遗传学分析，HIF-1在保护免受微生物毒素诱导的吞噬细胞毒性和凋亡中的作用，以及吞噬细胞胞外陷阱参与HIF-1介导的细菌杀伤，进一步建立HIF-1抗微生物活性的机制基础。HIF-1基因敲除小鼠将用于评估转录控制途径在控制皮肤、皮肤伤口和肺炎感染模型中MRSA和假单胞菌感染中的作用。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将局部治疗与全身治疗进行比较。通过我们与Akebia Therapeutics的合作，将进行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研究性新药申请，以进入细菌性皮肤感染的临床试验，最初作为局部药物。最终，HIF-1免疫增强疗法可以广泛应用于治疗抗生素耐药性或宿主防御能力减弱的复杂感染。

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molecules including granule proteases, antimicrobial peptides, nitric oxide and TNF-a. We then provide exciting new unpublished data that show how potent new-generation prolyl hydroxylase (PHD) inhibitor drugs from Akebia Therapeutics, Inc. boost HIF-1 in human phagocytes and cause them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.