Coxiella Cell Variant Gene Regulation and Membrane Proteins

摘要 贝氏柯克斯体是一种称为Q热的急性致残性流感样疾病的病原体。这种病原体可引起慢性疾病，通常表现为肝炎或心内膜炎。具有非特异性症状的急性疾病难以诊断，慢性疾病需要长期抗生素治疗，在此期间患者依从性是有问题的。C.贝氏体感染广泛的脊椎动物和无脊椎动物宿主，并且在世界范围内发现。疾病控制和预防中心已经认识到C。Burnetii作为生物恐怖主义的潜在代理人。C.的特征值得进行这种分类的贝氏体包括气溶胶感染、低感染剂量（低至一个生物体）以及在环境中长期生存的能力。C.伯内特虫经历了一个双相发育周期， 环境稳定和化学抗性的小细胞变体（SCV）被认为是负责环境持久性的细胞形式，而更脆弱的大细胞变体（LCV）作为代谢和复制活性细胞变体。关于这种生物体的发育调控知之甚少，因此我们建议：1）检查已被证明可调节嗜肺军团菌形态分化的全局调控基因的动力学。控制C.贝氏体发育将是诱变的有希望的靶。环境稳定的SCV可能是负责感染新宿主的细胞形式。因此，我们建议：2）鉴定免疫显性SCV膜蛋白，然后可以用于亚单位疫苗。与其他专性胞内细菌一样，C.贝氏体可能在免疫活性宿主中表达基因，而当细菌被感染时这些基因不表达。 在细胞培养中生长。我们建议：3）将体外生长的毒性细菌的细菌基因表达与从感染小鼠的感染肺泡巨噬细胞分离的细菌进行比较。我们将与密歇根州立大学的艾伦·哈姆森博士就最后一个研究目标进行合作。

Abstract Coxiella burnetii is the etiologic agent of an acute, disabling influenza-like illness in humans termed Q fever. This pathogen can cause chronic disease that usually manifests as hepatitis or endocarditis. Acute disease with its nonspecific symptoms is difficult to diagnose and chronic disease requires long-term antibiotic treatment during which patient compliance is problematic. C. burnetii infects a wide range of vertebrate and invertebrate hosts and is found worldwide. The Centers for Disease Control and Prevention have recognized C. burnetii as a potential agent of bioterrorism. Characteristics of C. burnetii that warrant this classification include aerosolic infection, low infectious dose (as low as one organism), and the ability to survive for prolonged periods in the environment. C. burnetii undergoes a biphasic developmental cycle with the environmentally stable and chemically resistant small cell variant (SCV) thought to be the cell form responsible for environmental persistence, and the more fragile large cell variant (LCV) as the metabolically and replicatively active cell variant. Little is known about the regulation of development in this organism, so we propose to: 1) examine the kinetics of global regulatory genes that have been shown to regulate morphological differentiation in L pneumophila. Regulatory genes controlling C. burnetii development would be promising targets for mutagenesis. Environmentally stable SCV are likely the cell form responsible for infection of new hosts. We therefore propose to: 2) identify immunodominant SCV membrane proteins that could then be used in a subunit vaccine. As has been found for other obligate intracellular bacteria, C. burnetii likely expresses genes in an immunocompetent host that are not expressed when the bacteria are grown in cell culture. We propose to: 3) compare bacterial gene expression for virulent bacteria grown in vitro to bacteria isolated from infected alveolar macrophages from infected mice. We will be collaborating with Dr. Allen Harmsen at MSU on the last research goal.