ANALYSIS OF THE BIOSYNTHESIS AND RELEASE OF ENDOTOXIN FROM N MENINGITIDIS

抗生素和脓毒症患者的现代管理大大改善了严重脑膜炎球菌病的预后。然而，在对脑膜炎球菌感染的认识、预防和治疗方面仍存在许多问题。在这些问题和许多其他问题得到解答之前，脑膜炎球菌感染将继续成为人类的祸害。这个程序的主要目的是更好地了解宿主和生物体因素参与这种感染的暴发性。我们在这个项目中的作用将是解决负责爆发性感染的生物体的各个方面。在感染的这种特征中被认为是重要的因素是在感染中发展的高度菌血症与生物体脱落大量含有外膜囊泡的LOS的倾向相结合。在这个项目中，我们将确定脑膜炎球菌脂质A是否可以通过酰基转移酶中负责取代羟基肉豆蔻酸的突变来修饰。人们认为脑膜炎球菌LOS是从生物体表面释放到外膜囊泡中的。我们将建议研究参与和调节脑膜炎球菌外膜形成和囊泡释放的分子因子。这一建议以三个假设为指导。第一种是N.脑膜炎可通过使负责将月桂酸取代为羟基肉豆蔻酸的KDO依赖性酰基转移酶突变而被修饰并使其毒性降低。第二个假设是脑膜炎球菌中的脂质A转化为与淋球菌脂质A相同的结构将停留在生物反应性较低的脑膜炎球菌LOS中。这一分析可能为我们提供线索的分子因素，决定脑膜炎球菌LOS的毒性。第三个假设是，basS/basR双组分调节因子（2CR）参与控制脑膜炎球菌膜生物合成和外膜囊泡的释放，并且该2CR受生物体环境的磷酸盐浓度控制。

Antibiotics and modern management of septic patients have greatly improved the outcome of serious meningococcal disease. However, many problems still exist in the understanding, prevention, and treatment of meningococcal infection. Until these and many other questions are answered, meningococcal infections will continue to be a scourge among human populations. The principle purpose of this program is to better understand the host and organism factors involved in the fulminant nature of this infection. Our role in this project will be to address aspects of the organism responsible for the fulminant nature of the infection. Factors thought to be important in this characteristic of the infection are the high grade bacteremia which develops in the infection combined with the propensity of the organisms to shed a large amount of LOS containing outer membrane vesicles. In this project, we will determine whether meningococcal lipid A can be modified by mutations in acyl transferases responsible for substitution of hydroxymyrestic acid. It has been considered that meningococcal LOS is released from the surface of the organism in outer membrane vesicles. We will propose to study the molecular factor involved in and regulating meningococcal outer membrane formation and vesicle release. This proposal is guided by three hypotheses. The first is that the lipid A of N. meningitidis can be modified and rendered less toxic by mutation of the kdo-dependent acyltransferases responsible for the substitution of lauric acid onto hydroxymyrestic acid. The second hypothesis is conversion of the lipid A in the meningococcus to a structure identical to the gonococcal lipid A will rest in a less biologically reactive meningococcal LOS. This analysis may give us clues to the molecular factors which determine the toxicity of meningococcal LOS. The third hypothesis is that basS/basR two component regulator (2CR) is involved in control of meningococcal membrane biosynthesis and the release of outer membrane vesicles and that this 2CR is controlled by the phosphate concentration of the organisms environment.