NONHUMAN PRIMATE MODEL OF MELIODOSIS

非人类灵长类动物鼻根瘤模型

基本信息

批准号：
8358092
负责人：
CHAD J. ROY
金额：
$ 3.72万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8358092
关键词：
Acute Address Adrenal Cortex Adrenal Glands Aerosols Animals Area Australia Autopsy Axilla Bacteria Bacterial Infections Bacterial Pneumonia Biological Biological Products Blood Breathing Bronchial Lymph Node Bronchopneumonia Burkholderia pseudomallei CD8-Positive T-Lymphocytes Cavia Cells Centers for Disease Control and Prevention (U.S.)Clinical Communicable Diseases Coupled Disease Disease model Dose Edema Emerging Communicable Diseases Equus caballus Exhibits Exposure to Functional disorder Funding Genes Goals Grant Hamsters Hemorrhage Histologic Human Immune Immune response Incidence Infection Inflammation Lesion Liver Lung Lymphocyte Depletion Macaca mulatta Mediating Melioidosis Methods Microscopic Modeling Molecular Molecular Genetics Mucous Membrane National Center for Research Resources Necrosis Pathogenesis Pathologic Phase Phenotype Play Pneumonia Primate Diseases Primates Principal Investigator Recrudescences Reporting Research Research Infrastructure Research Personnel Resources Rodent Diseases Rodent Model Role Route Sepsis Sigma Factor Son of Sevenless Proteins Source Southeastern Asia Symptoms Syndrome Time Type III Secretion System Pathway United States National Institutes of Health Vaccines Virulence clinically relevant cost disorder prevention in vivo mutant nonhuman primate particle subcutaneous therapeutic development tool vaccine candidate

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Melioidosis is an infectious disease caused by exposure to Burkholderia pseudomallei, a saprophyte found primarily in Southeast Asia and Northern Australia. Melioidosis is considered an emerging infectious disease and epizoonotic agent. Incidence of B. pseudomallei-associated bacterial sepsis and bronchopneumonia has significantly increased in endemic areas over the past decade. B. pseudomallei is a biological threat agent primarily because of its remarkable infectivity at a low (less than 100 bacterial cells) dose. As a result, the Centers of Disease Control and Prevention (CDC) have identified B. pseudomallei as a select biological agent, with a high potential for misuse against masses. Melioidosis is associated with a severe clinical syndrome which is dependant in part on the route of exposure, dose, and immune status of the host, although much remains unclear about pathogenesis of the disease. Although infection from subcutaneous inoculation is not uncommon, inhalation produces the most severe disease. Presently, in vivo study of melioidosis has been mostly restricted to rodent disease models (e.g., hamster, guinea pig). Molecular genetic studies coupled with rodent disease models have implicated genes encoding Inv/Mxi-Spa-like Type III secretion system bsa, alternate and stationary phase sigma factor R SOS responder recA in mediating virulence and protection from host immune response. No nonrodent model (other than equine) have been identified or characterized to further study this disease. Although intensive vaccine discovery and therapeutic development is ongoing, there has been minimal research into a nonhuman primate disease model to support these studies. As such, a nonhuman primate model would represent a significant tool to further define pathogenesis and study the clinically relevant parameters of the disease. Moreover, the establishment of a nonhuman primate model will also allow researchers to study the phenotype of B. pseudomallei mutants that exhibit loss of virulence in rodent models, in a more appropriate human-like model. It is conceivable that such B. pseudomallei strains carrying multiple lesions will serve as potential vaccine candidates. The goals of this project are to define a nonhuman primate model that emulates the reported pathophysiology of human melioidosis when inhaled, to identify molecular correlates in the bacterium during host-infection and conditions that mimic it; and define immunological parameters associated with the disease. The severe clinical symptom of melioidosis is dependant in part on the route of exposure, dose, and immune status of the host, although much remains unclear about pathogenesis of the disease. To address this gap, we performed a study to develop an aerosol exposure method for induction of melioidosis in rhesus macaques (Macaca mulatta) and characterize the pneumonic form of the disease. Six rhesus macaques were experimentally exposed by small particle aerosol to 10^3 to 10^6 CFU of Burkholderia pseudomallei 1026b. One animal succumbed to disease +7d postinfection; all other animals were euthanized at day 30 (1) or 45 (4). Gross and microscopic lesions, bacterial burden in lungs and blood, and histologic changes were evaluated. Results of aerosol exposure to B. pseudomallei proved lethal (8 days) at the highest inhaled doses (H10^6 CFU); lower doses resulted in a localized pulmonary bacterial infection clinically similar to bacterial pneumonia. Grossly, the one animal succumbing to disease +7d PI was characterized as a severe pneumonia with focal necrotizing lesions in the tracheal mucosa, adrenal and bronchial lymph nodes. Histologically, there was severe subacute fibrinopurulent inflammation, edema, hemorrhage, and necrosis in the lung. Milder acute congestion was observed in the liver, with mild to moderate necrosis in the tracheal mucosa, adrenal cortex, axillary, and bronchial lymph nodes. The other animals showed minimal histologic changes at the time of necropsy. An attempt to initiate bacterial recrudescence in convalescent animals via CD8+ lymphocyte depletion failed, suggesting that CD8+ lymphocytes play a minimal role in controlling B. pseudomallei infection. Pathologic findings in rhesus macaques after aerosol exposure to B. pseudomallei show a dose-related gradient for infection and are comparable to clinical cases of the pneumonic form of the disease in humans.

该副本是利用资源的众多研究子项目之一由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持而且，副投影的主要研究员可能是其他来源提供的包括其他NIH来源。列出的总费用可能代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 Melioidosis是一种由暴露于Burkholderia pseudomallei引起的传染病，这是一种主要在东南亚和澳大利亚北部发现的腐生症。 Melioidosis被认为是一种新兴的传染病和epizoonotic剂。在过去的十年中，假叶芽孢杆菌相关的细菌败血症和支气管性败血症的发生率显着增加。假子杆菌是一种生物威胁剂，主要是因为其在低（小于100个细菌细胞）剂量下的显着感染性。结果，疾病控制和预防的中心（CDC）已将假单胞菌芽孢杆菌视为精选的生物学剂，具有滥用质量的很高潜力。 Melioidosis与严重的临床综合征有关，该综合症部分取决于宿主的暴露途径，剂量和免疫状态，尽管对疾病的发病机理尚不清楚。尽管皮下接种引起的感染并不少见，但吸入会产生最严重的疾病。目前，在体内研究混蛋式病的研究主要仅限于啮齿动物疾病模型（例如仓鼠，豚鼠）。结合啮齿动物疾病模型的分子遗传研究牵涉到编码INV/MXI-SPA样型III型分泌系统BSA，替代和固定期Sigma因子R SOS RESSONDER RECA中的基因，从而介导毒力和保护免受宿主免疫反应。尚未确定或表征非生产模型（除马以外）以进一步研究这种疾病。尽管正在进行密集的疫苗发现和治疗发育，但对非人类灵长类动物疾病模型的研究很少，以支持这些研究。因此，非人类灵长类动物模型将代表进一步定义发病机理并研究疾病临床相关参数的重要工具。此外，建立非人类灵长类动物模型还将允许研究人员研究在更合适的人类模型中，在啮齿动物模型中表现出毒力丧失的假单胞菌突变体的表型。可以想象的是，携带多种病变的假芽孢杆菌菌株将作为潜在的候选疫苗。该项目的目标是定义一个非人类的灵长类动物模型，该模型在吸入时模拟了人类混蛋病的病理生理学，以鉴定在宿主感染和模拟IT的宿主感染和疾病期间细菌中的分子相关性。并定义与该疾病相关的免疫学参数。黑梅利病的严重临床症状部分取决于宿主的暴露途径，剂量和免疫状态，尽管对疾病的发病机理仍不清楚。为了解决这一差距，我们进行了一项研究，以开发一种气溶胶暴露方法，以诱导鼠尾草猕猴（Macaca Mulatta）诱导梅洛尼亚病，并表征了该疾病的肺炎形式。通过小粒子气溶胶实验暴露于burkholderia pseudomallei 1026b的10^3至10^6 Cfu，实验暴露于10^3至10^6 Cfu。一只动物屈服于疾病 +7D感染后；所有其他动物在第30（1）或45（4）天进行了安乐死。评估了总体和微观病变，肺和血液中的细菌负担，并评估了组织学变化。气溶胶暴露于假单胞菌的结果证明是致命的（8天），最高吸入剂量（H10^6 CFU）；较低剂量导致局部肺部细菌感染在临床上与细菌性肺炎相似。总体而言，一种屈服于疾病 +7D PI的动物被描述为严重的肺炎，在气管粘膜，肾上腺和支气管淋巴结中具有局灶性坏死病变。从组织学上讲，肺部有严重的亚急性纤维纤维纤维纤维纤维炎，水肿，出血和坏死。在肝脏中观察到较轻的急性充血，气管粘膜，肾上腺皮质，腋窝和支气管淋巴结中有轻度至中度坏死。其他动物在尸检时显示出最小的组织学变化。试图通过CD8+淋巴细胞耗竭在康复动物中引发细菌繁殖的尝试失败，这表明CD8+淋巴细胞在控制假子芽孢杆菌感染中起着最小的作用。气溶胶暴露于假单胞菌的恒河猴猕猴中的病理发现显示与剂量相关的感染梯度，并且与人类疾病的肺炎形式的临床病例相当。