Grant: Operating Grant

The bacterium Neisseria meningitidis is a major cause of meningitis and invasive infection in humans, yet it may also colonize humans without causing disease. This bacterium only lives in the human upper respiratory tract, and has evolved very specific interactions with human cells and proteins during its adaptation to this environment. The inability of this bacterium to colonize and cause disease in other animals has made it impossible to assess the relative importance of different bacterial proteins to infection and disease, or to truly evaluate vaccines before testing them in humans. To overcome this problem, we have undertaken to 'humanize' mice so that they express the human form of proteins that the bacteria interact with. This has proven fruitful, since our humanized mice are the first animals other than humans that can be infected with N. meningitidis. In this study, we plan to demonstrate the importance of bacterial proteins that allow the bacteria to effectively remove iron from the human iron-binding proteins, transferrin and lactoferrin, an activity required to allow bacterial growth in the tissues. For these experiments, we will take advantage of our strains of mice that express human transferrin, human lactoferrin, or both of these proteins. We will compare the relative ability of virulent N. meningitidis strains that we have mutated to be defective in one or more of their transferrin or lactoferrin binding proteins in the expectation that the human and bacterial proteins are both essential for infection and disease. Since these bacterial proteins appear to be ideal targets for vaccines, we will also engineer them so that they can be used to protect against N. meningitidis infection and disease. The humanized mice provide us with the first opportunity to evaluate the effectiveness of these vaccines, and we expect that these studies will demonstrate that our optimized vaccines will protect against infection by all strains of Neisseria meningitidis.