ANALYSIS OF THE BIOSYNTHESIS AND RELEASE OF ENDOTOXIN FROM N MENINGITIDIS

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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.