Cellular and Developmental Biology of Coxiella burnetii

贝氏柯克斯体是一种专性胞内细菌，是人畜共患Q热的病原体。急性Q热通常表现为流感样疾病。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。柯克斯体具有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，表明组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获得的，在家畜中，这种生物体可能是地方性的。C.贝氏体可慢性感染多种动物，并在各种分泌物和分娩产物中大量脱落。增加了生物体的潜伏性质是接近一个生物体的感染剂量和接近细菌孢子的显著胞外稳定性。环境抗性也与对吞噬溶酶体样寄生虫空泡（PV）的降解条件的抗性相关，PV是宿主巨噬细胞内的柯克斯体的生态位。 C.贝氏体的感染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。这种形式出现在一个双相发育周期，并可能负责大多数环境获得性Q热病例。一旦在PV中内化和隔离，SCV在形态上分化成代谢和复制活性更高的大细胞变体（LCV）。成熟PV含有SCV、LCV和中间形式的混合物。 对C.贝氏体的形态分化知之甚少。未来研究的重要领域包括鉴定细胞条件和驱动发育的信号转导、发育动力学、SCV和LCV对各种宿主的相对感染性、细胞形式的转录和翻译能力以及赋予其独特生物学特性的SCV和LCV的生化组成。 在体内，柯克斯体最初的目标是肺泡巨噬细胞，尽管该生物体随后可以在多种组织内传播复制。急性疾病通常是自限性的，并在两周内消退。然而，在大多数情况下，疾病的免疫消退不会导致柯克斯体的完全清除。因此，在易感个体中，潜伏的微生物可以在最初暴露后数月或数年重新激活，导致严重疾病，如心内膜炎。解决急性感染的先天性和适应性免疫的组成部分在很大程度上是不确定的。此外，柯克斯体在持续感染期间逃避宿主免疫反应清除而复发的机制尚不清楚，但可能涉及病原体和宿主因素。吞噬性树突状细胞（DC）是一种特殊的抗原提呈细胞，在先天性免疫和适应性免疫反应中起桥梁作用。然而，DC在控制C.贝氏体和持续感染的免疫决定因素一样定义不明确。 C.贝氏菌在胞内细菌中是独特的，其存在于大而宽敞的溶酶体样PV中。这种液泡的生物发生所必需的细胞信号传导和囊泡运输途径尚不清楚。此外，肺静脉腔和膜的生化性质定义不明确。在所有检查的情况下，侵入性细菌修改其PV以提高存活率，通常是生长。PV重塑的细菌效应物通常与调节囊泡运输的宿主分子相互作用。C. Burnetii PV尚未定义。柯克斯体含有嗜肺军团菌IV型分泌器基因的近竞争拷贝，嗜肺军团菌是一种遗传学上的近亲。由于军团菌需要功能性IV型分泌物来建立其复制生态位，因此假设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 influenza-like illness. Rare but serious chronic infections can occur that usually present as endocarditis or hepatitis. Coxiella exhibits considerable strain diversity. Strains can be grouped according to associations with human acute or chronic disease, suggesting 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 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 vivo the initial target of Coxiella is the alveolar macrophage although the organism can subsequently disseminate to replicate within a wide variety of tissues. Acute disease is generally self-limiting and resolves within two weeks. However, in most cases immune resolution of disease does not result in complete clearance of Coxiella. Consequently, in predisposed individuals latent organisms can reactivate months or years after initial exposure to cause serious disease such as endocarditis. Components of innate and adaptive immunity that resolve acute infection are largely undefined. Moreover, mechanisms by which Coxiella evades clearance by the host immune response during persistent infection to recrudesce 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. However, the role of DC in controlling replication of C. burnetii is poorly defined as are the immunodeterminants of persistent infection. 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 poorly defined. 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.