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:
  • 金额:
    $ 54.71万
  • 依托单位:
  • 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

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,“一种细菌、一种药物”的方法一直是疫苗或治疗方法发展的特征。 特定的传染病。我们根据新的治疗方法的发展提出了一种不同的方法 通过利用感染过程中触发的常见宿主先天免疫反应来感染传染病- 由流感和其他优先病原体感染。全球每年有多达500万人感染流感病毒, 造成多达50万人死亡。我们强有力的实验证据表明,强大的TLR4拮抗剂, 厄立特里亚(Eisai,Inc.)以及其他多种TLR4拮抗剂显著减轻了两种急性肺损伤 (ALI)和死亡率,当给药治疗流感感染的小鼠。厄立特里亚不仅封锁了影响- Enza介导的宿主衍生的“危险相关分子模式”(DAMPS)的释放,但也钝化 在巨噬细胞中,潮湿介导的TLR4信号通常会导致“细胞因子风暴”。当我们有了 阐明了流感介导ALI和致死率的几种新机制,这些机制被 厄立特里亚疗法(例如,释放通过TLR4发出信号的宿主来源的阻滞剂;增加每- 导致肺水肿的可行性;IL-1α/β在致命性中的作用),我们对整体先天 控制流感诱导的ALI和厄立特里亚介导的保护的免疫信号通路仍处于- 完全的,需要进一步的研究来开发一种高效的宿主导向疗法。因此, 具体目标1将集中在识别两种流感感觉的先天免疫机制上。 活动和厄立特里亚调停的保护。我们将利用转基因小鼠品系来解剖 信号通路接合了。TLR4是否必须在基质细胞和/或髓系细胞上表达,其作用 湿释放中病毒诱导的上皮细胞坏死性下垂的研究,非TLR4PRR的作用机制 与流感耐药性/敏感性有关,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以利用的新的潜在机制,以增强对流感的反应。 灵丹妙药。在特定目标2中,一种新的IKKβ抑制剂E6070(卫材公司)的治疗益处 流感单独或在目前的抗流感抗病毒疗法存在的情况下,将在棉鼠身上进行测试。 (Cr),第二种啮齿动物物种,允许分析ALI对非适应人类免疫系统感染的反应. 流感病毒分离株。AIM 2还将在继发性葡萄球菌模型中比较厄立特里亚和E6070的CR (MRSA)流感感染后的肺炎。最后,我们将评估厄立特里亚的相对效力。 和E6070用于阻断由其他临床重要或生物治疗相关病原体引起的ALI的能力 人类感染ALI(如图拉氏方济氏菌、肺炎链球菌、肺炎克雷伯氏菌、SARS- 冠状病毒和MERS冠状病毒),首先在小鼠身上,如果有效,在CR中。这些实验将挑战最重要的 中心假设TLR拮抗剂代表基础广泛的治疗药物,可减轻病理变化 寄主对多种诱导ALI的优先病原菌的反应。

项目成果

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JORGE C BLANCO其他文献

JORGE C BLANCO的其他文献

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{{ truncateString('JORGE C BLANCO', 18)}}的其他基金

Inducible HMGB1 antagonist for viral-induced acute lung injury.
诱导型 HMGB1 拮抗剂,用于治疗病毒引起的急性肺损伤。
  • 批准号:
    10591804
  • 财政年份:
    2023
  • 资助金额:
    $ 54.71万
  • 项目类别:
RSV-induced M2 macrophage differentiation: role of TLR4/PPARg/RXR signaling axis (80)
RSV 诱导的 M2 巨噬细胞分化:TLR4/PPARg/RXR 信号轴的作用 (80)
  • 批准号:
    10418803
  • 财政年份:
    2021
  • 资助金额:
    $ 54.71万
  • 项目类别:
RSV-induced M2 macrophage differentiation: role of TLR4/PPARg/RXR signaling axis (80)
RSV 诱导的 M2 巨噬细胞分化:TLR4/PPARg/RXR 信号轴的作用 (80)
  • 批准号:
    10287155
  • 财政年份:
    2021
  • 资助金额:
    $ 54.71万
  • 项目类别:
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
  • 批准号:
    10098763
  • 财政年份:
    2017
  • 资助金额:
    $ 54.71万
  • 项目类别:
Development of VLP vaccine for RSV
RSV VLP 疫苗的开发
  • 批准号:
    9897525
  • 财政年份:
    2014
  • 资助金额:
    $ 54.71万
  • 项目类别:
Development of VLP vaccine for RSV
RSV VLP 疫苗的开发
  • 批准号:
    9137089
  • 财政年份:
    2014
  • 资助金额:
    $ 54.71万
  • 项目类别:
Development of VPL Vaccine for RSV
RSV VPL 疫苗的开发
  • 批准号:
    8645890
  • 财政年份:
    2014
  • 资助金额:
    $ 54.71万
  • 项目类别:
Development of VLP vaccine for RSV
RSV VLP 疫苗的开发
  • 批准号:
    9334692
  • 财政年份:
    2014
  • 资助金额:
    $ 54.71万
  • 项目类别:
Eritoran (E5564), a TLR4 antagonist, as a novel therapeutic for influenza
Eritoran (E5564),一种 TLR4 拮抗剂,作为流感的新型治疗剂
  • 批准号:
    8884533
  • 财政年份:
    2013
  • 资助金额:
    $ 54.71万
  • 项目类别:
Eritoran (E5564), a TLR4 antagonist, as a novel therapeutic for influenza
Eritoran (E5564),一种 TLR4 拮抗剂,作为流感的新型治疗剂
  • 批准号:
    8711276
  • 财政年份:
    2013
  • 资助金额:
    $ 54.71万
  • 项目类别:

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Combinatorial cytokine-coated macrophages for targeted immunomodulation in acute lung injury
组合细胞因子包被的巨噬细胞用于急性肺损伤的靶向免疫调节
  • 批准号:
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Inducible HMGB1 antagonist for viral-induced acute lung injury.
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