Genomic Correlates with Differential Virulence in Melioidosis Animal Models

类鼻疽动物模型中基因组与差异毒力的相关性

• 批准号: 8260261
• 负责人: Paul Stephen Keim
• 金额: $ 34.6万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260261
• 关键词: Animal Model; Animals; Australia; Burkholderia pseudomallei; Clinic; Clinical Research; Collection; Data; Dermal; Differential Mortality; Disease; Emerging Communicable Diseases; Frequencies; Gene Expression; Genome; Genomic Islands; Genomics; Genotype; Human; Inbred Mouse; Incidence; Infection; Infectious Diseases Research; Intervention; Knowledge; Lesion; Lung; Melioidosis; Modeling; Mouse Strains; Mus; Near Drowning; Outcome; Pattern; Phenotype; Population; Proteomics; Rattus; Research; Resolution; Route; Surveys; Thailand; Virulence; Virulence Factors; biodefense; health care quality; human disease; knockout gene; mortality; nonhuman primate; pathogen; prospective; skin abscess

Burkholderia pseudomallei, are commonly observed in Thailand and Australia (but also other equatorial regions), where mortality rates are 40% and 14%, respectively. The difference in these mortality rates has been attributed to healthcare quality (28), but our data demonstrate that pathogen populations also differ between these regions (145). In addition, prospective clinical studies in Australia are under way with promising preliminary associations between strain types and outcomes (Currie, Tuanyok, Wagner, Keim, et al., unpublished data). It is well established that B. pseudomallei contains an "open" genome (90) that recombines at a high frequency, leading to great diversity within and among pathogen populations. We believe differential virulence among pathogen populations (strains) contributes to differential mortality rates around the globe. Our primary hypothesis is that highly diverse B. pseudomallei strains have different virulence levels, and that these virulence differences will depend on the strain genomic composition (e.g., genomic islands). Multiple infection routes have been documented. Melioidosis infection routes are frequently hard to determine in the clinic, but inhalational and percutaneous routes both occur. Melioidosis incidence increases following tropical storms and near-drowning (30, 31), consistent with a pulmonary route. However, most melioidosis cases probably result from percutaneous inoculation (39), which is consistent with the presence of skin abscesses and dermal lesions (28). Virulence varies according to the infective route in animals and depends on the particular strain (see CK#3 and (11,146)). Animal models are important. Because human studies can be problematic, animal models are a common and powerful research approach to understand pathogen virulence. The mouse is the least expensive model, yet a very powerful one, but a single model may not always accurately represent diseases in other animals, including humans. Developing additional animal models (e.g., multiple mouse strains, rat, nonhuman primates) can support initial studies in the mouse and make our disease understanding more generalized and representative for human disease intervention. Knowledge and understanding of animal models is critical to infectious disease research.

Burkholderia pseudomallei通常在泰国和澳大利亚（以及其他赤道）观察到 区域），死亡率分别为40％和14％。这些死亡率的差异是 归因于医疗保健质量（28），但我们的数据表明，病原体种群也有所不同 这些地区（145）。此外，澳大利亚的前瞻性临床研究正在进行中 应变类型和结果之间的初步关联（Currie，Tuanyok，Wagner，Keim等，等等 未发表的数据）。 B. pseudomallei含有一个“开放”基因组（90），重新组合 在高频率下，导致病原体种群内部和中间的多样性。我们相信差异 病原体种群（菌株）之间的毒力有助于全球的差异死亡率。 我们的主要假设是，高度多样的假疟原虫菌株具有不同的毒力水平，并且 这些毒力差异将取决于菌株基因组组成（例如基因组岛）。 已记录了多个感染路线。 Melioidosis感染途径通常很难 在诊所确定，但都会出现吸入和经皮路线。 Melioidisois发病率增加 在热带风暴和几乎陷入困境之后（30，31），与肺部路线一致。但是，大多数 Melioidosis病例可能是由经皮接种引起的（39），这与存在 皮肤脓肿和皮肤病变（28）。毒力根据动物的感染途径而变化， 取决于特定的菌株（请参阅CK＃3和（11,146））。 动物模型很重要。因为人类研究可能是有问题的，所以动物模型是 常见且强大的研究方法来理解病原体毒力。鼠标是最便宜的 模型，但非常有力的模型，但是单个模型可能并不总是准确地代表其他模型 包括人类在内的动物。开发其他动物模型（例如，多种小鼠菌株，大鼠，非人类 灵长类动物）可以支持小鼠中的初始研究，并使我们的疾病了解更多 人类疾病干预的广义和代表。对动物的知识和理解 模型对于传染病研究至关重要。