Genetics of Coxiella burnetii

伯内氏柯克斯体的遗传学

• 批准号: 6987135
• 负责人: robert a heinzen
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6987135
• 关键词: Coxiella burnetii; Q fever; bacteria infection mechanism; bacterial genetics; bioterrorism /chemical warfare; confocal scanning microscopy; disease /disorder classification; functional /structural genomics; genetic polymorphism; genetic strain; genetic transcription; microarray technology; microorganism classification; molecular cloning; polymerase chain reaction; proteomics; virulence

Coxiella burnetii is an obligate intracellular bacterium and the causative agent of the zoonosis human Q (query) fever. Acute Q fever normally manifests as a self-limiting influenza-like illness. Rare but serious chronic infections can occur that usually presents as endocarditis or hepatitis. The vast majority of human Q fever cases are acquired though contact with infected domestic livestock where the organism can be endemic. C. burnetii can chronically infect a variety of animals and is shed in large numbers in various secretions and products of parturition. Adding to the insidious nature of the organism is an infective dose approaching one organism and a remarkable extracellular stability approaching that of a bacterial spore. Environmental resistance also correlates with resistance to the degradative conditions of a phagolysosome-like parasitophorous vacuole (PV), Coxiella's niche within host macrophages. The impressive environmental stability of C. burnetii is likely due to the biogenesis of a highly resistant cell form termed the small cell variant (SCV). This form arises during a biphasic developmental cycle and is likely responsible for the majority of environmentally acquired cases of Q fever. Once internalized and sequestered in a PV, SCV morphologically differentiate into more metabolically and replicatively active large cell variants (LCV). Mature PV contain a mixture of SCV, LCV and intermediate forms. The molecular biology of C. burnetii morphological differentiation is poorly understood. An important area of future research includes defining the transcriptional capabilities of cell forms and the response of C. burnetii to lysosomal stress. Restriction fragment-length polymorphism analysis reveals considerable genomic DNA heterogeneity among C. burnetii strains. Moreover, strains can be grouped according to an association with human acute or chronic disease, suggesting that groups have unique virulence potential. Although the severity of disease and the potential for chronicity may involve patient factors, there is a clear association of C. burnetii isolates with disease outcome. The extent and biological relevance of strain variation is unknown. Strains of lower virulence may result in subclinical infections where diagnosis and treatment are delayed, resulting in chronic infections with serious consequence years or decades later. Genetic systems such as complementation, transposon mutagenesis, and allelic exchange are invaluable tools in the study of bacterial virulence. These methods require the introduction of foreign DNA into the bacterial recipient usually via electroporation. Genetic transformation generally requires strong selectable markers in the form of antibiotic resistance genes. While genetic transformation has been described for C. burnetii, the system is hampered by inadequate antibiotic selection, instability of introduced DNA, and the lack of efficient cloning methods for clonal isolation.

Coxiella burnetii是一种强制性细胞内细菌，也是人动物病Q（Query）发烧的病因。急性Q发烧通常表现为一种自限的流感样疾病。通常会出现罕见但严重的慢性感染，通常会出现作为心内膜炎或肝炎。绝大多数人类Q发烧病例是通过与感染的家庭牲畜接触的，那里的生物可能是地方性的。 C. burnetii可以长期感染各种动物，并在各种分泌物和分娩产物中大量脱落。加上生物体的阴险性质是一种感染剂量，接近一种生物体，而细胞外稳定性接近细菌孢子的剂量。环境抗性还与对吞噬体样寄生虫液泡（PV）的降解条件的抗性，Coxiella的宿主巨噬细胞内的coxiella的利基市场相关。 C. burnetii的令人印象深刻的环境稳定性可能是由于称为小细胞变体（SCV）的高度抗性细胞形式的生物发生。这种形式是在双相发育周期中产生的，很可能是大多数环保Q发烧案件的原因。一旦内化并在PV中进行了隔离，SCV在形态上会分化为更代谢和复制的大细胞变异（LCV）。成熟的PV包含SCV，LCV和中间形式的混合物。 C. burnetii形态学分化的分子生物学知之甚少。未来研究的一个重要领域包括定义细胞形式的转录能力以及伯氏梭菌对溶酶体应激的反应。 限制性片段长度多态性分析揭示了C. burnetii菌株之间相当大的基因组DNA异质性。此外，可以根据与人类急性或慢性疾病的关联来分组菌株，这表明群体具有独特的毒力潜力。尽管疾病的严重程度和慢性潜力可能涉及患者因素，但伯牛梭菌分离株与疾病结果有明显的关联。应变变异的程度和生物学相关性尚不清楚。较低的毒力菌株可能导致延迟诊断和治疗的亚临床感染，导致慢性感染数年或几十年后的严重后果。 诸如互补，转座子诱变和等位基因交换之类的遗传系统是细菌毒力研究的宝贵工具。这些方法通常需要通过电穿孔引入外源DNA到细菌受体中。遗传转化通常需要以抗生素抗性基因的形式进行强的可选标记。虽然已经描述了用于Burnetii的遗传转化，但由于抗生素选择不足，引入DNA的不稳定性以及缺乏克隆分离的有效克隆方法，该系统受到阻碍。