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Pathogenic Mechanisms of Vascular Dysfunction in Scrub Typhus

恙虫病血管功能障碍的致病机制

基本信息

批准号：
9753929
负责人：
LYNN SOONG
金额：
$ 39.5万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-02 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9753929
关键词：
Acute Address Angiopoietin-2 Animal Model Antibodies Asia Bacteria Bacterial Infections Biological Markers Blood Platelets Blood Vessels Bone Marrow Cell Culture Techniques Cessation of life Color Containment Data Disease Endothelial Cells Endothelium FDA approved Functional disorder Gene Proteins Goals HMGB1 gene Human IL8RB gene Immune Immune response Immunity In Vitro Infection Infection Control Injury Institutes Intervention Kinetics Knockout Mice Knowledge Leukocytes Life Lung Mediating Modality Modeling Molecular Mus Neutrophil Activation Orientia tsutsugamushi Pathogenesis Pathogenicity Pathologic Pathway interactions Pattern Peroxidases Phagocytes Platelet Activation Populations at Risk Prognostic Marker Public Health Recombinants Regulation Regulatory Pathway Research Role Scrub Typhus Sepsis Signal Transduction System TNF gene Testing Therapeutic Thrombocytopenia Time Tissues Umbilical vein Vaccines Validation Vascular Diseases Work base cell injury cohesion cost effective cytokine ethyl pyruvate human disease improved infection risk innovation insight macrophage mortality mouse model neutrophil novel preclinical study preservation protective effect receptor response specific biomarkers synergism therapeutic target tool

项目摘要

Scrub typhus is a life-threatening disease caused by Orientia tsutsugamushi, a LPS-negative bacterium that replicates preferentially in endothelial cells (EC) and phagocytes. While one million people are infected yearly, with about one-third of world population at risk of infection, effective strategies for infection control are lacking. Information on disease pathogenesis and immune dysregulation is limited. To address these challenges, we have developed mouse models that mimic certain key pathological features of human scrub typhus. We found that endogenous damage-associated molecular pattern (DAMP) molecules such as HMGB1 and myeloperoxidase (MPO) are key regulators responsible for molecular dysfunctions involving angiopoietin 2 (Ang2), Tie2, and CD41+ platelets. We also discovered the detrimental effect of sustained neutrophil activation in thrombocytopenia and vascular injury, and the potential of Ang2 and miR-200b as unique biomarkers for vascular dysfunction. The objective of this study is to define pathogenic mechanisms of vascular dysfunction and therapeutic modalities for severe scrub typhus by utilizing the EC-targeting model of O. tsutsugamushi infection. Our central hypothesis is that the infection-triggered release of DAMPs exacerbates O. tsutsugamushi-induced vascular damage by altering neutrophil/platelet activation; interventions aimed at preserving vascular integrity or phagocyte function help to elicit a balanced immunity against acute tissue damage and severe scrub typhus. This hypothesis will be tested in three cohesive Specific Aims. Aim 1 will examine the mechanisms of HMGB1- and TNF-mediated sensitization and exacerbation of human endothelium in Orientia infection. We will use human microvascular endothelial cells (HMEC) to test whether Orientia triggers the release of HMGB1, TNF, Ang2, and miR-200b and their target genes/proteins, and if therapeutics targeting these mechanisms mitigate EC injury. Aim 2 will examine mechanisms by which neutrophils and HMGB1 contribute to vascular and platelet dysfunction during infection in mice. We will set up lethal and sublethal infections in CXCR2-/- or MPO-/- mice at different infection stages. Likewise, the deletion of RAGE (a HMGB1 receptor, RAGE-/- mice) or anti-RAGE antibody will reveal specific roles of HMGB1/RAGE signaling in tissue-infiltrated leukocytes, platelet and vascular function. Aim 3 will test whether anti-Ang2 and statin-based therapeutics promote host survival via modulating vascular function and phagocyte activation in mice. Mice will be treated with anti-Ang2 antibody, recombinant Ang1, or statins (alone or in combination) before or during lethal and sublethal infection. We will examine bacterial dissemination, neutrophil/platelet activation, and the levels of Tie2 and signature cytokines/DAMPs. This mechanism-focused study capitalizes on the synergism among several research teams. Discovery of vascular-specific biomarkers, novel regulatory pathways, and their impact on immune responses to Orientia is timely, innovative and highly significant.

恙虫病是一种危及生命的疾病，由恙虫病东方体（一种 LPS 阴性细菌）引起，优先在内皮细胞 (EC) 和吞噬细胞中复制。虽然每年有一百万人被感染，由于世界上约三分之一的人口面临感染风险，因此缺乏有效的感染控制策略。有关疾病发病机制和免疫失调的信息有限。为了应对这些挑战，我们开发了模仿人类恙虫病某些关键病理特征的小鼠模型。我们发现内源性损伤相关分子模式 (DAMP) 分子，例如 HMGB1 和髓过氧化物酶 (MPO) 是涉及血管生成素 2 的分子功能障碍的关键调节因子 (Ang2)、Tie2 和 CD41+ 血小板。我们还发现持续中性粒细胞激活的有害影响血小板减少症和血管损伤中的作用，以及 Ang2 和 miR-200b 作为独特生物标志物的潜力血管功能障碍。本研究的目的是确定血管功能障碍的致病机制利用恙虫病 EC 靶向模型治疗严重恙虫病的方法和方法感染。我们的中心假设是感染触发的 DAMP 释放加剧了 O. 通过改变中性粒细胞/血小板活化来引起恙虫病引起的血管损伤；干预措施旨在保持血管完整性或吞噬细胞功能有助于引发针对急性组织的平衡免疫力损害和严重的恙虫病。这一假设将在三个有凝聚力的具体目标中得到检验。目标1将研究 HMGB1 和 TNFα 介导的致敏和恶化的机制 Orientia 感染中的内皮细胞。我们将使用人微血管内皮细胞（HMEC）来测试是否 Orientia 触发 HMGB1、TNFα、Ang2 和 miR-200b 及其靶基因/蛋白质的释放，如果针对这些机制的治疗可减轻 EC 损伤。目标 2 将检查机制中性粒细胞和 HMGB1 在小鼠感染期间导致血管和血小板功能障碍。我们将设立 CXCR2-/- 或 MPO-/- 小鼠在不同感染阶段的致死和亚致死感染。同样，删除 RAGE（HMGB1受体，RAGE-/-小鼠）或抗RAGE抗体将揭示HMGB1/RAGE的特定作用组织浸润白细胞、血小板和血管功能中的信号传导。目标 3 将测试是否抗 Ang2 和基于他汀类药物的治疗通过调节血管功能和吞噬细胞激活来促进宿主生存老鼠。小鼠将接受抗 Ang2 抗体、重组 Ang1 或他汀类药物（单独或组合）治疗在致死和亚致死感染之前或期间。我们将检查细菌传播、中性粒细胞/血小板激活，以及 Tie2 和特征细胞因子/DAMP 的水平。这项以机制为重点的研究利用了几个研究团队之间的协同作用。血管特异性生物标志物的发现，新的监管途径，及其对 Orientia 免疫反应的影响是及时的、创新的和非常重要的。