The major focus of Dr. Tuomanen's research is the molecular pathogenesis of invasion and inflammation induced by Streptococcus pneumoniae, the leading invasive bacterial pathogen of children. Virulence genes are identified by genetic screens as well as by analysis of the completed genome. To evaluate gene function, she tests the mutants' abilities (e.g., adherence, invasion, transmigration, induction of cytokine production, and cytoxicity) in models of the pulmonary epithelium, vascular endothelium, and blood-brain barrier. Cell lines and transfected cell systems augment this study with particular emphasis on perturbations in the biology of integrins, matrix adhesion, and chemokine receptors. By using these systems, a model of pneumococcal disease has been assembled. The bacteria adhere to nasopharyngeal, pulmonary, and endothelial cells. Upon cellular activation, the bacteria then adhere to chemokine receptors, particularly the platelet-activating factor receptor. This interaction allows bacterial entry into cells and results in transmigration. This sequence of events is then tested in mouse models of pneumonia and meningitis. The strengths of this laboratory are in the study of gram-positive molecular biology and genomics; gram-positive interactions with human cells and models of disease; and the emerging relationship of transformation, virulence, and autolysis. Areas of medical therapeutics applicable to this work include pneumococcal vaccine design, intervention in gram-positive sepsis/meningitis, new antibiotic development strategies, and interruption of the spread of genetic elements responsible for antibiotic resistance.