Environmental Adaptation and Membrane Physiology of an Oral Pathogen

描述(由申请人提供)：放线菌伴生菌是一种革兰氏阴性的兼性厌氧细菌，在人类口腔和上呼吸道定居。这种细菌与局限性侵袭性牙周炎(LAP)密切相关。这种微生物是一种机会性病原体，会导致严重的全身疾病，包括肺炎、感染性心内膜炎，并可能导致心血管疾病。该菌的致病力被归因于包括粘附素、侵袭素和毒素分泌在内的毒力决定因素。这些因素必须转移两个不同的膜才能发挥功能。在放线菌伴生菌中，内膜和外膜的生物发生和蛋白质组成在很大程度上仍未确定。我们发现了一个新基因MORC，编码141 kDa的膜蛋白，功能未知。缺失突变体表现出外膜形态、膜通透性的变化，白毒素的分泌明显减少。这些发现支持MORC在维持膜形态和功能方面的重要性。形态发生蛋白(MORC)在革兰氏阴性菌中高度保守。在Aggregatibacter和相关属中，该基因位于一个三基因操纵子中，受一个启动子控制，对环境变化做出反应。这个操纵子可能受一个双组分信号转导系统的调节。该基因和操纵子结构在各种细菌物种中的保守意味着该蛋白在这些微生物的生物学中扮演着重要的角色。为了更好地了解MORC在膜生物发生和致病中的作用，我们提出了以下目标：1)MORC操纵子的分子特征；2)MORC功能结构域(S)的确定；以及3)MORC在白毒素分泌和膜生物发生中的作用。从上述目标的实现中获得的信息可用于开发直接针对MORC蛋白的治疗方法，或与现有治疗方法协同使用，以降低伴生放线菌和其他病原体的致病潜力。 与公共卫生相关：细菌是全世界严重威胁生命的感染的原因。了解这些病原体的生理学和结构的基本特性将有助于药物的开发，从而中断这些微生物的生命周期，防止细菌感染。

DESCRIPTION (provided by applicant): Aggregatibacter (Actinobacillus) actinomycetemcomitans is a gram-negative, facultative anaerobic bacterium that colonizes the human oral cavity and the upper respiratory tract. This bacterium is strongly associated with localized aggressive periodontitis (LAP). The organism is an opportunistic pathogen causing serious systemic diseases including pneumonia, infective endocarditis, and may contribute to cardiovascular disease. The pathogenicity of the organism has been ascribed to virulence determinants including adhesins, invasins and toxin secretion. These factors must translocate two distinct membranes to be functionally active. In A. actinomycetemcomitans, the biogenesis and protein composition of the inner and outer membranes remain largely undefined. We have identified a novel gene morC, encoding a 141 kDa membrane protein with previously unknown function. The null mutant showed changes in the morphology of the outer membrane, membrane permeability and a marked decreased secretion of leukotoxin. The importance of MorC to maintain membrane morphology and function is supported by these findings. The morphogenesis protein (MorC) is highly conserved among gram-negative human pathogens. In Aggregatibacter and related genera, the gene is located in a three-gene operon under the control of a promoter responsive to environmental changes. This operon may be regulated by a two-component signal transduction system. The conservation of this gene and the operon structure among a variety of bacterial species implies an important role of this protein in the biology of these microorganisms. To better understand the role of MorC in membrane biogenesis and pathogenicity, we propose the following aims: 1) molecular characterization of the morC operon; 2) determination of the functional domain(s) of MorC; and 3) determination of the role of MorC in leukotoxin secretion and membrane biogenesis. The information obtained from the accomplishment of the stated aims can be applied to the development of therapeutics directly targeted to the MorC protein or synergistically with existing therapies t reduce the pathogenic potential of A. actinomycetemcomitans and other pathogens. PUBLIC HEALTH RELEVANCE: Bacteria are the cause of serious, life threatening infections worldwide. Understanding the fundamental properties of the physiology and structure of these pathogens will aid in the development of medicines which interrupt the life cycle of these microorganisms and prevent bacterial infections.