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Member, St. Jude Faculty
Chair, Infectious Diseases
Director, Children's Infection Defense Center (CIDC)
Co-Leader, Bacterial Pathogenesis, CIDC
Elaine Tuomanen, MD
MS320, Room E8057
St. Jude Children's Research Hospital
262 Danny Thomas Place
Memphis, TN 38105-3678
Phone: (901) 595-3114
FAX: (901) 505-3099
MD - McGill University, University Scholar
Molecular pathogenesis of Streptococcus pneumoniae invasion and inflammation
The major focus of this 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, we test 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 selectins, 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.
Mann B, van Opijnen, Wang J, Obert C, Wang Y-D, Carter R, McGoldrick DJ, Ridout G, Camilli A, Tuomanen EI, Rosch JW. Control of virulence by small RNAs in Streptococcus pneumoniae. PLoS Pathog 8(7):e1002788. doi:10.1371, 2012.
Garrison SP, Thornton JA, Hacker H, Webby R, Rehg JE, Parganas E, Zambetti GP, Tuomanen EI. The p53-target gene puma drives neutrophil-mediated protection against lethal bacterial sepsis. PLoS Pathog 6(12):e1001240, 2010.
Gaur AH, Bagga B, Barman S, Hayden R, Lamptey A, Hoffman JM, Bhojwani D, Flynn P, Tuomanen E, Webby R. Intravenous Zanamivir for Oseltamivir resistant pandemic A (H1N1) influenza infection. N Engl J Med 362:88-9, 2010.
Rosch JW, Hinojosa E, Pestina T, Hu Y, Boyd AR, Persons DA, Orihuela CJ, Tuomanen EI. Statins protect against lethal pneumococcal infection and cytolysin toxicity in experimental sickle cell disease. J Clin Invest 120:627-35, 2010.
Orihuela CJ, Mahdavi J, Thornton J, Mann B, Wooldridge KG, Abouseada N, Oldfield NJ, Self T, Ala¹Aldeen DAA, Tuomanen E. Laminin receptor initiates contact of bacteria with the blood brain barrier. J Clin Invest Jun;119(6):1638-46, 2009.
Miller ML, Gao G, Pestina T, Persons D, Tuomanen E. Hypersusceptibility to invasive pneumococcal infection in experimental sickle cell disease involves PAF receptor. J Infect Dis 195:581-584, 2007.
Fillon S, Soulis K, Murti G, Kaushal D, Radin JN, Orihuela CJ, Murray PJ, Weber JR, Tuomanen EI. Platelet activating factor receptor and innate immunity: uptake of Gram positive bacterial cell wall into host cells and cell-specific pathophysiology. J Immunol 177:6182-6191, 2006.
Obert C, Sublett J, Kaushal D, Barton T, Tuomanen EI, Orihuela CJ. Identification of the Streptococcus pneumoniae core genome and regions of diversity correlated with invasive pneumococcal disease. Infect Immun 74:4766-4777, 2006.
Radin JN, Orihuela CJ, Murti G, Guglielmo C, Murray PJ, Tuomanen EI. Β-arrestin 1 determines the traffic pattern of PAFr-mediated endocytosis of Streptococcus pneumoniae. Infect Immun 73:7827-7835, 2005.
Luo R, Mann B, Lewis WS, Rowe A, Heath R, Stewart ML, Hamburger AE, Sivakolundu S, Lacy E, Bjorkman PJ, Tuomanen E, Kriwacki RW. Solution structure of choline binding protein A of Streptococcus pneumoniae reveals a novel mode of interaction with its human receptor, plgR. EMBO 24:34-43, 2005.
Zweigner J, Jackowski S, Smith SH, Tuomanen EI. Bacterial inhibition of phosphatidylcholine synthesis triggers apoptosis in the brain. J Exp Med 200:99-106, 2004.
Webby RJ, Perez DR, Coleman JS, Guan Y, Knight JH, Gorvokova EA, McClain-Moss LR, Peiris JS, Rehg JE, Tuomanen EI, Webster RG. Responsiveness to a pandemic alert: use of reverse genetics for rapid development of influenza vaccines. Lancet 363:1099-1103, 2004.
Xue L, Orihuela CJ, Tuomanen E, Morris S. Defective development and function of follicular, marginal zone, and B1 B cells in Bc110-deficient mice. Nature Immunol 4:855-865, 2003.
Braun JS, Sublett JE, Freyer D, Mitchell TJ, Cleveland JL, Tuomanen EI, Weber JR. Pneumococcal pneumolysin and H2O2 mediate brain cell apoptosis during meningitis. J Clin Invest 109:19-27, 2002.
Zhang J-R, Mostov KE, Lamm ME, Tuomanen E. The polymeric immunoglobulin receptor translocates pneumococci across the human nasopharyngeal epithelial cells. Cell 102:1-20, 2000.
Novak R, Charpentier E, Braun JS, Tuomanen E. Signal transduction by a death signal peptide: uncovering the mechanism of bacterial killing by penicillin. Molec Cell 5:49-57, 2000.
Braun J, Bodner S, Cleveland J, Tuomanen EI. Neuroprotection by a caspase inhibitor in acute bacterial meningitis. Nature Medicine 5:298-302, 1999.
Yoshimura A, Lien E, Ingalls R, Tuomanen E, Dziarski R, Golenbock D. Cutting Edge: Recognition of gram-positive bacterial cell wall components by the innate immune system occurs via toll-like receptor 2. J Immunol 163:1-5, 1999.
Novak R, Henriques B, Charpentier E, Normark S, Tuomanen E. Emergence of vancomycin tolerance in Streptococcus pneumoniae. Nature 399:590-593, 1999.
Ring A, Weiser JN, Tuomanen EI. Pneumococcal trafficking across the blood-brain barrier: molecular analysis of a novel bi-directional pathway. J Clin Invest 1998; 102:347-360, 1998.
Rambukkana A, Salzer JL, Turchenco PD, Tuomanen E. Neural targeting of Mycobacterium leprae mediated by the G domain of the Laminin-α2 chain. Cell 88:811-821, 1997.
Cundell D, Gerard N, Gerard C, Tuomanen E. The platelet activating factor receptor anchors Streptococcus pneumoniae to human cells. Nature 377:435-438, 1995.
Sha W, Liou H, Tuomanen E, Baltimore D. Targeted disruption of the p50 subunit of NF-kB leads to multifocal defects in immune responses. Cell 80:321-330, 1995.
Spellerberg B, Prasad S, Cabellos C, Tuomanen E. Bacterial disaccharide tetrapeptide induces blood brain barrier permeability. J Exp Med 182:1037-1044, 1995.
Tuomanen E, Prasad S, George J, Hoepelman A, Ibsen P, Heron I. Starzyk R. Reversible opening of the blood brain barrier by antibacterial antibodies. Proc Natl Acad Sci 90:7824-7828, 1993.
Burroughs M, Rozdzinski E, Geelen S, Tuomanen E. A structure-activity relationship for induction of meningeal inflammation by muramyl peptides. J Clin Invest 92:297-302, 1993.
Tuomanen E. Breaching the blood brain barrier. Scientific American 268:80-84, 1993.
Last updated: February 2013