Cellular and Developmental Biology of Coxiella burnetii

伯氏柯克斯体是一种专性胞内细菌，是人畜共患病Q(Query)热的病原体。急性Q热通常表现为一种自限性流感样疾病。罕见但严重的慢性感染可能会发生，通常表现为心内膜炎或肝炎。柯克斯氏菌表现出相当大的菌株多样性。菌株可以根据与人类急性或慢性疾病的关联进行分组，这表明这些群体具有独特的毒力潜力。绝大多数人类Q热病例是通过接触受感染的家畜而获得的，在那里这种生物可能是地方性的。伯氏梭菌可慢性感染多种动物，并在各种分泌物和分娩产物中大量排出。除了生物体的隐匿性外，还有接近一个生物体的感染量和接近细菌孢子的显着的细胞外稳定性。环境抗性还与对吞噬酶体样寄生虫空泡(PV)降解条件的抵抗有关，PV是柯克斯体在宿主巨噬细胞内的生态位。 伯氏梭菌令人印象深刻的环境稳定性可能是由于一种被称为小细胞变体(SCV)的高抗性细胞形式的生物发生。这种形式出现在一个双相发育周期期间，可能是大多数环境获得性Q热病例的原因。一旦内化和隔离在光伏病毒中，SCV在形态上分化为更具新陈代谢和复制活性的大细胞变体(LCV)。成熟的光伏病毒含有SCV、LCV和中间型的混合物。 伯氏华支睾吸虫形态分化的分子生物学尚不清楚。未来的重要研究领域包括：驱动发育的细胞条件和信号转导的鉴定，发育动力学，SCV和LCV对不同宿主的相对感染性，细胞形态的转录和翻译能力，以及赋予SCV和LCV独特生物学特性的生化组成。 在体外，伯氏梭菌在一系列上皮细胞、成纤维细胞和巨噬细胞样细胞系中复制。在体内，最初的目标是肺泡巨噬细胞，尽管该生物体随后可以在各种组织中传播和复制。在某些情况下，伯氏梭菌会持续感染，在最初暴露几个月或几年后会重新激活，导致严重的疾病，如心内膜炎。柯克斯体在持续感染期间逃避宿主免疫反应清除的机制尚不清楚，但可能涉及病原体和宿主因素。吞噬细胞树突状细胞(DC)是连接先天免疫反应和获得性免疫反应的特殊抗原提呈细胞。树突状细胞在控制伯氏梭菌复制中的作用尚不清楚。此外，不同毒力潜力的分离株在DC和原代人巨噬细胞中的生长特征尚不清楚。 伯氏梭菌在细胞内细菌中是独一无二的，它居住在一个大而宽敞的溶酶体样PV中。这种液泡的生物发生所需的细胞信号和囊泡运输途径尚不清楚。此外，PV管腔和膜的生化性质尚不清楚。在所有被检查的病例中，入侵细菌都会修改它们的PV以提高存活率和通常的生长。PV重塑的细菌效应器通常与调节囊泡运输的宿主分子相互作用。伯氏梭菌变种的性质和程度尚未确定。柯克斯氏菌含有嗜肺军团菌的IV型分泌器基因的近竞争拷贝，军团菌是嗜肺军团菌的亲缘关系。由于军团菌需要IV型功能性分泌物来建立其复制生态位，因此假设对柯克斯体也有类似的要求是合乎逻辑的。

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. Coxiella exhibits considerable strain diversity. Strains can be grouped according to an association with human acute or chronic disease, suggesting that groups have unique virulence potential. 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. Important areas of future investigation include identification of the cellular conditions and signal transduction that drive development, the kinetics of development, the relative infectivity of SCV and LCV for various hosts, the transcriptional and translational capabilities of cell forms, and the biochemical composition of SCV and LCV that confer their unique biological properties. In vitro C. burnetii replicates within an array of epithelial, fibroblast and macrophage-like cell lines. In vivo the initial target is the alveolar macrophage although the organism can subsequently disseminate to replicate within a wide variety of tissues. In some cases C. burnetii establishes a persistent infection that can reactivate months or years after initial exposure resulting in serious disease such as endocarditis. The mechanisms by which Coxiella evades clearance by the host immune response during persistent infection are unknown but likely involve both pathogen and host factors. Phagocytic dendritic cells (DC) are exceptional antigen presenting cells that bridge the innate and adaptive immune responses. The role of DC in controlling replication of C. burnetii is unknown. Moreover, the growth characteristics of isolates of differing virulence potential in both DC and primary human macrophages is poorly defined. C. burnetii is unique among intracellular bacteria in residing within a large and spacious lysosome-like PV. The cellular signaling and vesicular trafficking pathways necessary for biogenesis of this vacuole are unknown. Furthermore, the biochemical nature of the PV lumen and membrane are unknown. In all cases examined, invasive bacteria modify their PV to enhance survival and usually growth. Bacterial effectors of PV remodeling generally interact with host molecules that regulate vesicular trafficking. The nature and extent of modification of the C. burnetii PV has not been defined. Coxiella contains a near compete copy of the type IV secretion apparatus genes of Legionella pneumophila, a phylogenetically close relative. Because Legionella requires functional type IV secretion to establish its replicative niche, it is logical to assume a similar requirement for Coxiella.