Environmental Adaptation and Membrane Physiology of an Oral Pathogen

性状（由申请方提供）：伴放线放线杆菌（Actinobacillus）是一种革兰氏阴性兼性厌氧菌，定植于人体口腔和上呼吸道。这种细菌与局部侵袭性牙周炎（英语：localized aggressive periodontitis，简称牙周炎）密切相关。该微生物是一种机会致病菌，可引起严重的全身性疾病，包括肺炎、感染性心内膜炎，并可能导致心血管疾病。病原体的致病性已被归因于毒力决定因子，包括粘附素、侵袭素和毒素分泌。这些因子必须移位两种不同的膜才能发挥功能活性。以.放线菌共生体，生物起源和内外膜的蛋白质组成仍然在很大程度上不确定。我们已经确定了一个新的基因morC，编码一个141 kDa的膜蛋白与以前未知的功能。无效突变体表现出外膜形态的变化，膜通透性和白细胞毒素的分泌显着减少。这些发现支持了MorC对维持膜形态和功能的重要性。形态发生蛋白（MorC）在革兰氏阴性人类病原体中高度保守。在Aggregatibacter和相关属中，该基因位于响应环境变化的启动子控制下的三基因操纵子中。该操纵子可能受双组分信号转导系统调节。该基因和操纵子结构在多种细菌物种中的保守性意味着该蛋白在这些微生物学中的重要作用。为了更好地理解MorC在膜生物发生和致病性中的作用，我们提出以下目标：1）MorC操纵子的分子表征; 2）确定MorC的功能结构域;和3）确定MorC在白细胞毒素分泌和膜生物发生中的作用。从所述目的的实现中获得的信息可以应用于开发直接靶向MorC蛋白的治疗剂或与现有治疗剂协同降低A的致病潜力。放线菌共生菌和其他病原体。

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.