Dysregulated type-1 and Vascular Responses in Scrub typhus Pathogenesis

恙虫病发病机制中 1 型失调和血管反应

• 批准号: 8873311
• 负责人: LYNN SOONG
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8873311
• 关键词: Acute; Address; Angiopoietin-1; Angiopoietin-2; Angiopoietins; Animal Model; Animals; Arts; Asia; Bacteria; Bacteriology; Biological Markers; Blood Vessels; CXCL9 gene; CXCR3 gene; Cells; Cellular Stress; Cessation of life; Clinical; Complex; Data; Disease; Disease Progression; Dose; Endothelial Cells; Evaluation; Event; Extravasation; Flow Cytometry; Functional disorder; Genes; Goals; Hepatocyte; Human; Immune; Immune response; In Vitro; Infection; Inflammatory Response; Injection of therapeutic agent; Interferons; Intervention; Kinetics; Knowledge; Laboratories; Leukocytes; Life; Link; Liver; Lung; Mediating; Messenger RNA; Modeling; Molecular; Mus; Nature; Onset of illness; Organ; Organ failure; Orientia tsutsugamushi; Pathogenesis; Pathology; Phagocytes; Population; Proteins; Public Health; Recombinants; Regulation; Reporter; Research; Risk; Role; Scrub Typhus; Severities; Severity of illness; Shock; Source; Spleen; Staging; Testing; Therapeutic; Tissues; Transcript; Vaccines; Vascular Diseases; Vascular Endothelial Growth Factors; Work; base; biosafety level 3 facility; chemokine; cytokine; design; experience; immunoregulation; improved; in vivo; insight; monocyte; mortality; mouse model; novel; outcome forecast; pathogen; public health relevance; response; tool

 DESCRIPTION (provided by applicant): Scrub typhus is a life-threatening disease caused Orientia tsutsugamushi, a LPS-negative bacterium that replicates preferentially in endothelial cells (EC) and monocytes. Approximately one million people are infected every year; about one third of world population is at risk of infection. There is no effective vaccine for this infection information on disease pathogenesis is limited. To address these challenges, we have developed mouse models that can mimic pathological features of human scrub typhus. We found that lethal infection was linked to excessive type 1, but deficient type 2, immune responses, which correlated with vascular damage in multiple organs. However, the underlying mechanisms are poorly defined. The goal of this study is to examine the molecular basis of such dysregulation by utilizing the EC-targeting model of O. tsutsugamushi Karp strain (OtK) infection, the most prevalent strain for human infections. Our central hypothesis is that type 1-skewed inflammatory responses and dysregulated angiopoietin (Ang) expression are leading causes for lethal OtK infection. Aim 1 will examine the cellular sources of IFN- and dual functions of IFN--related responses in bacterial clearance versus immunopathogenesis during Orientia infection. The innate vs. adaptive cell sources of IFN- and its related CXCR3 chemokines in infected liver, lungs and spleen will be examined by using IFN- reporter mice, as well as mice deficient in RAG2, IFN- or CXCR3 expression. Mice receiving anti-IFN- treatment at different stages of disease will help define in vivo function of IFN- in bacterial clearance vs. immunopathogenesis. Immunological findings from the single-cell and molecular levels will be integrated with those from tissue bacterial load and pathology evaluations. Aim 2 will test the hypothesis that endothelial activation/dysregulation initiated by bacterial infectionis ameliorated by IFN--related cytokines/chemokines. Lethally infected mice will be treated with recombinant Ang 1, alone or together with vascular endothelial growth factor (VEGF) or anti-IFN-, at early and late stages of disease. Similar treatment in IFN--/- or CXCR3-/- mice, as well as EC-focused in vitro studies, will help dissect complex interplays between cytokines and vascular responses. This mechanism-focused study endorses synergy among research teams (each with unique expertise); it utilizes the state-of-art ABSL3/BSL3 facilities at UTMB. The long-term goal of this study is to define the pathogenic mechanisms associated with Orientia infection and to utilize this information for the design of control strategies. Discovery of the onet and nature of initial dysfunction will reveal the critical window for immune intervention, as well s for signature immune profiles for disease prognosis. This timely study will have a broad implication for other intracellular pathogens.

 描述（由申请人提供）：恙虫病是一种由恙虫病东方体（Orientia tsutsugamushi）引起的危及生命的疾病，东方体是一种LPS阴性细菌，优先在内皮细胞（EC）和单核细胞中复制。每年约有一百万人被感染；世界上约三分之一的人口面临感染风险。目前尚无针对这种感染的有效疫苗，有关疾病发病机制的信息有限。为了应对这些挑战，我们开发了可以模拟人类恙虫病病理特征的小鼠模型。我们发现致命感染与过度的 1 型免疫反应和缺乏的 2 型免疫反应有关，这与多个器官的血管损伤相关。然而，根本机制尚不清楚。本研究的目的是通过利用恙虫病卡普菌株 (OtK) 感染（人类感染最常见的菌株）的 EC 靶向模型来检查这种失调的分子基础。我们的中心假设是，1 型偏向炎症反应和血管生成素 (Ang) 表达失调是致命 OtK 感染的主要原因。目标 1 将检查 IFN-γ 的细胞来源以及东方体感染期间 IFN-γ 相关反应在细菌清除与免疫发病机制中的双重功能。将使用 IFN-γ 报告小鼠以及 RAG2、IFN-γ 或 CXCR3 表达缺陷的小鼠来检查受感染的肝脏、肺和脾脏中 IFN-γ 及其相关 CXCR3 趋化因子的先天与适应性细胞来源。在疾病的不同阶段接受抗 IFN-γ 治疗的小鼠将有助于确定 IFN-γ 在细菌清除与免疫发病机制中的体内功能。单细胞和分子水平的免疫学发现将与组织细菌负荷和病理学评估的结果相结合。目标 2 将检验以下假设：细菌感染引发的内皮激活/失调可通过 IFN-γ 相关细胞因子/趋化因子得到改善。在疾病的早期和晚期阶段，致命感染的小鼠将单独使用重组 Ang 1 或与血管内皮生长因子 (VEGF) 或抗 IFN-γ 一起治疗。对 IFN-γ-/- 或 CXCR3-/- 小鼠进行类似的治疗，以及以 EC 为重点的体外研究，将有助于剖析细胞因子和血管反应之间复杂的相互作用。这项以机制为重点的研究支持研究团队之间的协同作用（每个团队都拥有独特的专业知识）；它利用 UTMB 最先进的 ABSL3/BSL3 设施。这项研究的长期目标是确定与 Orientia 感染相关的致病机制，并利用这些信息来设计控制策略。初始功能障碍的本质和性质的发现将揭示免疫干预的关键窗口，以及疾病预后的特征免疫特征。这项及时的研究将对其他细胞内病原体产生广泛的影响。