Patients with sickle cell disease experience a 400 fold increased risk of severe pneumococcal infection. Thisrisk is not shared by other encapsulated pathogens or by other anemias suggesting that there is a potentiallycausal relationship between severity of pneumococcal disease and the SS phenotype. This application seeks toinvestigate two aspects of pneumococcal infection in sickle cell disease. First we will take advantage of thepresence in this SS Center of a program in pneumococcal pathogenesis and expertise in creating an SStransplant mouse model (Project 4). These two programs will cooperate to characterize which step inpneumococcal invasion differs between wild type and SS mice. The steps of colonization and invasion will bedissected at the molecular level and intervention with specific receptor antagonists will be tested. We willfurther determine the level of protection from pneurnococcal disease afforded by progressive hematologiccorrection by transplantation.Second we will build on a strong history of this Center's study of the colonization of SS patients withantibiotic resistant pneumococci. The introduction of the new seven-valent conjugate pneumococcal vaccineinto the SS population has not been studied. We will determine its effect on nasopharyngeal carriage withspecific reference to antibiotic susceptibility and shifts away from vaccine serotypes. Further we will measurethe prevalence of a new property of antibiotic tolerance emerging in clinical isolates. Tolerance preventsantibiotic killing of pneumococci and may adversely affect the outcome of infection. Spread of this propertymay have implications for the efficacy of continued penicillin prophylaxis in this at risk population.
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