Targeting TLR Signaling Pathways to Blunt Pathogen-mediated Acute Lung Injury

靶向 TLR 信号通路以减弱病原体介导的急性肺损伤

基本信息

批准号：
9306674
负责人：
JORGE C BLANCO
金额：
$ 54.71万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-10 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9306674
关键词：
Abate Acute Lung Injury Address Animals Antimicrobial Resistance Antiviral Agents Antiviral Therapy Bacterial Infections Bacterial Pneumonia Binding Cells Cessation of life Clinical Communicable Diseases Cotton Rats Data Development Dimerization Disease Ear Epithelial Cells Experimental Animal Model Family Francisella tularensis Gene Expression Goals HMGB1 gene Human Immune Immune response Immune signaling Immunologics Infection Inflammation Inflammatory Inflammatory Response Influenza Innate Immune Response Interleukin-1 alpha Investigation Klebsiella pneumonia bacterium Lead Ligands Macrophage-1 Antigen Mediating Middle East Respiratory Syndrome Coronavirus Modeling Molecular Mouse Strains Mus Mutation Myeloid Cells Pathologic Pathway interactions Patients Pattern Pattern recognition receptor Permeability Pharmaceutical Preparations Philosophy Predisposition Process Pulmonary Edema Receptor Signaling Research Resistance Rodent Role SARS coronavirus Secondary to Signal Pathway Signal Transduction Staphylococcal Pneumonia Streptococcus pneumoniae Stromal Cells Structure System TLR2 gene TLR4 gene Testing Therapeutic Therapeutic Agents Therapeutic Intervention Tight Junctions Time Tissues Toll-like receptors Translating Treatment Efficacy Vaccines Viral Drug Resistance Virus anti-influenza antimicrobial drug base biothreat cytokine dimer effective therapy experimental study immunogenic infectious disease treatment influenzavirus inhibitor/antagonist insight killings macrophage microbial mortality mouse model novel novel therapeutic intervention novel therapeutics novel vaccines pathogen receptor-mediated signaling relative effectiveness respiratory response targeted treatment tool vaccine development

项目摘要

For decades, a “one bug, one drug” approach has characterized development of vaccines or treatments for specific infectious diseases. We propose a different approach based on the development of novel treatment of infectious diseases by capitalizing on common host innate immune responses that are triggered during infec- tion by influenza and other priority pathogens. Influenza virus infects up to 5 million people yearly worldwide, killing as many as ~500,000. Our strong experimental evidence demonstrates that the potent TLR4 antagonist, Eritoran (Eisai, Inc.), as well as multiple other TLR4 antagonists, significantly decreased both acute lung injury (ALI) and mortality when administered therapeutically to influenza-infected mice. Eritoran not only blocks influ- enza-mediated release of host-derived ”danger-associated molecular patterns” (DAMPs), but also blunted DAMP-mediated TLR4 signaling in macrophages that normally results in a “cytokine storm.” While we have elucidated several novel mechanisms by which influenza mediates ALI and lethality that are counteracted by Eritoran therapy (e.g., release of host-derived DAMPS that signal through TLR4; increased tight-junction per- meability leading to pulmonary edema; a role for IL-1α/β in lethality), our understanding of the overall innate immune signaling pathways that control influenza-induced ALI and Eritoran-mediated protection remains in- complete, necessitating further investigation to develop a highly efficacious host-directed therapy. Therefore, Specific Aim 1 will focus on the identification of innate immune mechanisms that underlie both influenza sensi- tivity and Eritoran-mediated protection. We will take advantage of genetically modified mouse strains to dissect the signaling pathways engaged. Whether TLR4 must be expressed on stromal and/or myeloid cells, the role of virus-induced epithelial cell necroptosis in DAMP release, mechanisms by which non-TLR4 PRRs contribute to influenza resistance/susceptibility, and the possibility that TLR2/TLR4 dimerization is required for the host response to influenza will be evaluated as novel potential mechanisms that can be exploited to enhance thera- peutic efficacy. In Specific Aim 2, the therapeutic benefit of a novel IKKβ inhibitor, E6070 (Eisai, Inc.), against influenza, alone or in the presence of current anti-influenza antiviral therapies, will be tested in cotton rats (CR), a second rodent species that permits analysis of ALI in response to infection by non-adapted human in- fluenza isolates. Aim 2 will also compare Eritoran and E6070 in CR in a model of secondary staphylococcal (MRSA) pneumonia following influenza infection. Lastly, we will assess the relative effectiveness of Eritoran and E6070 for the ability to block ALI caused by other clinically important or biothreat pathogens associated with ALI in humans (e.g., Francisella tularensis, Streptococcus pneumoniae, Klebsiella pneumoniae, SARS- CoV and MERS-CoV), first in mice, and, if effective, in CR. These experiments will challenge the overarching central hypothesis that TLR antagonists represent broad-based, therapeutic agents that mitigate pathologic host responses to multiple ALI-inducing priority pathogens.

几十年来，“一种病菌，一种药物”的方法已成为疫苗或治疗方法的特点。我们根据新疗法的发展提出了不同的方法。通过利用感染过程中触发的常见宿主先天免疫反应来预防传染病流感病毒和其他主要病原体每年感染全世界多达 500 万人，我们强有力的实验证据表明，有效的 TLR4 拮抗剂， Eritoran (Eisai, Inc.) 以及多种其他 TLR4 拮抗剂可显着减少急性肺损伤 (ALI) 和对感染流感的小鼠进行治疗时的死亡率。 enza介导的宿主衍生的“危险相关分子模式”（DAMP）的释放，但也被削弱 DAMP 介导的巨噬细胞中的 TLR4 信号传导通常会导致“细胞因子风暴”。阐明了流感介导 ALI 和致死率的几种新机制，这些机制可被依立托伦疗法（例如，释放通过 TLR4 发出信号的宿主源性 DAMPS；增加紧密连接导致肺水肿的可溶性；IL-1α/β在致死率中的作用），我们对整体先天性的理解控制流感引起的 ALI 的免疫信号通路和 Eritoran 介导的保护仍然存在完整，需要进一步研究以开发高效的宿主导向疗法。具体目标 1 将重点关注流感敏感性基础的先天免疫机制的识别。我们将利用转基因小鼠品系来剖析。 TLR4 是否必须在基质细胞和/或骨髓细胞上表达，以及其作用。病毒诱导的上皮细胞坏死性凋亡在 DAMP 释放中的作用，非 TLR4 PRR 的贡献机制流感抵抗/易感性，以及宿主需要 TLR2/TLR4 二聚化的可能性对流感的反应将被评估为可用于增强治疗的新的潜在机制。在具体目标 2 中，新型 IKKβ 抑制剂 E6070（卫材公司）的治疗益处。流感，单独或与当前的抗流感抗病毒疗法一起使用，将在棉鼠中进行测试（CR），第二种啮齿动物物种，允许分析 ALI 对非适应性人类感染的反应目标 2 还将比较 Eritoran 和 E6070 在继发性葡萄球菌模型中的 CR 效果。 (MRSA) 流感感染后肺炎最后，我们将评估 Eritoran 的相对有效性。 E6070 能够阻止由其他临床重要或生物威胁病原体引起的 ALI 人类 ALI（例如土拉弗朗西斯菌、肺炎链球菌、肺炎克雷伯菌、SARS- 冠状病毒和中东呼吸综合征冠状病毒），首先在小鼠中进行，如果有效的话，将在 CR 中进行这些实验将挑战总体情况。中心假设是 TLR 拮抗剂代表广泛的治疗药物，可减轻病理宿主对多种诱导 ALI 的优先病原体的反应。