Neisseria meningitidis is a significant human pathogen which causes life- threatening septicemia and meningitis in children and adults. Even with antibiotic therapy, 7-15% of affected individuals succumb to the infection. In Africa and South America, epidemic meningococcal infection due to serogroups A and B results in mortality rates as high as 70%. Capsular polysaccharide vaccines effectively protect adults against infection by serogroups A, C, Y, and W135, but not serogroup B organisms, which cause the majority of disease in the U.S. These vaccines also have limited efficacy in young children, who account for the majority of epidemic and endemic disease. Thus, other vaccine antigens must be identified to achieve complete protection of the populace. The long-term objective of the proposed research is to determine whether the iron uptake system of N. meningitidis is such a target. We will focus on the role of iron-regulated outer membrane proteins (FeRPs) in iron uptake, because these proteins are susceptible to immune intervention. We will examine the mechanism of iron uptake, and whether antiFeRP monoclonal antibodies will block growth and iron uptake from transferrin. Our genetic evidence indicates that blocking the function of these FeRPs will inhibit iron uptake and suppress meningococcal growth. We will clone the genes for the outer membrane meningococcal receptor for human transferrin. We will also clone the gene for a meningococcal 70 kilodalton (kd) outer membrane FeRP. Our evidence suggests that the 70 kd FeRP is involved in removing iron from receptor- bound transferrin. The 70 kd FeRP is surface-exposed, and is a conserved antigen common to N. meningitidis and N. gonorrhoeae.
