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way with promising preliminary associations between strain types and outcomes (Currie, Tuanyok, Wagner, Keim, et al., unpublished data).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.

类鼻疽伯克霍尔德氏菌，通常在泰国和澳大利亚观察到（但也在其他赤道地区观察到）。 地区），死亡率分别为40%和14%。这些死亡率的差异 归因于医疗质量（28），但我们的数据表明，病原体种群之间也存在差异 这些地区（145）。此外，澳大利亚的前瞻性临床研究正在进行中， 菌株类型和结果之间的初步关联（Currie，Tuanyok，瓦格纳，Keim等， 未公布的数据）。众所周知，B。类鼻疽包含一个“开放”基因组（90）， 高频率，导致病原体种群内部和之间的巨大多样性。我们认为， 病原体种群（菌株）之间的毒力导致了地球仪各地不同的死亡率。 我们的主要假设是高度多样化的B。类鼻疽菌株具有不同的毒力水平， 这些毒力差异将取决于菌株基因组组成（例如，基因组岛）。 已记录了多种感染途径。类鼻疽感染途径通常很难 在临床上确定，但吸入和经皮途径都发生。类鼻疽发病率增加 热带风暴和溺水（30，31），符合肺部途径。但大多数 类鼻疽病例可能是由经皮接种引起的（39），这与 皮肤脓肿和真皮病变（28）。毒力根据动物的感染途径而变化， 取决于特定菌株（见CK#3和（11，146））。 动物模型很重要。由于人类研究可能存在问题，动物模型是一种 共同和强大的研究方法来了解病原体的毒力。鼠标最便宜 模型，但一个非常强大的模型，但一个单一的模型可能并不总是准确地代表疾病在其他 动物，包括人类。开发额外的动物模型（例如，多种小鼠品系、大鼠、非人 灵长类动物）可以支持小鼠的初步研究， 对人类疾病干预具有普遍性和代表性。对动物的认识和理解 模型对传染病研究至关重要。