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Contact Information:

Dept. of Microbiology and Molecular Genetics
Harvard Medical School
200 Longwood Ave.
Boston, MA 02115

phone: 617-432-5099
fax: 617-738-7664
email:

Click here to visit the Lory Lab Website.

Research Summary

There are two major research efforts in the laboratory which are directed towards understanding the molecular basis of pathogenesis of human infections caused by opportunistic gram-negative bacteria. The projects are directed towards understanding the molecular basis of regulation of expression of virulence determinants by the microorganisms and the mechanism of targeting of these proteins to their site of action. We have used Pseudomonas aeruginosa as a model opportunistic pathogen, because of its importance in infections of individuals with cystic fibrosis, neutropenia, and as complications of burns and wounds. In each of these environments, the unique host-parasite relationship allows us to examination of a variety of bacterial factors that lead to colonization, persistence and resistance to host defenses.

The focus of the current work in the area of regulation is a broad attempt to define the complex genetic regulatory network, controlling virulence genes by employing genomic approaches. We are utilizing DNA microarrays (chips) to analyze global patterns of gene expression during P. aeruginosa infections, both in the bacterium and in the host. Using a DNA chip, containing sequences corresponding to every open reading frame in the P. aeruginosa genome, we are analyzing expression of genes in P. aeruginosa grown under a variety of conditions that are relevant to infection. We also use these chips to assess the consequences of mutation in regulatory genes which allows us to identify and characterize the basic mechanisms that coordinate the expression of thousands of bacterial genes during infection. In a complementary approach, we are utilizing DNA arrays of human genes to define novel signaling pathways in the host following adhesion of P. aeruginosa to human cells. Here, we are interested in discovering novel signaling pathways that allow humans to effectively mobilize their innate defense mechanisms. This approach will be also used to define the defects in host response in various disease states, such as the chronic respiratory infection of individuals with cystic fibrosis.

Secretion of toxins and the ability to adhere to epithelial cells are the two key components of the virulence mechanism of mucosal pathogens, including P. aeruginosa. The second area of research in the laboratory is concerned with export of protein toxins by gram-negative bacteria. Our work resulted in the discovery of a dedicated secretion machinery, which is responsible for the export of toxins from P. aeruginosa. Initial identification of genes encoding the components of the extracellular secretion machinery lead to a model for sorting of exported toxins, whereby the information within these proteins is recognized by the secretory apparatus, and an energy-dependent process leads to their sequential translocation across the membrane compartments of the bacterial cell envelope. Genetic and biochemical studies, currently under way in the laboratory, are used to define the functions of the components of the extracellular secretion machinery.

Selected Publications

Goodman, A., Kulasekara, B., Rietsch, A., Boyd, D., Smith, R., and Lory, S. (2004). A signaling network reciprocally regulates genes associated with acute infection and chronic persistence in Pseudomonas aeruginosa. Dev. Cell 7:745-754.

Kulasekara, H. D., Ventre, I., Kulasekara, B.R., Lazdunski, A., Filloux, A., and Lory S. (2005) A novel two component system controls the expression of Pseudomonas aeruginosa fimbrial cup genes. Mol. Microbiol. 55:368-380.

Ventre, I., Goodman, A.L., Vasseur, P., Soscia, C., Molin, S., Blevels, S., Lazdunski, A., Lory, S., and Filloux, A. (2006). Multiple sensors control reciprocal expression of Pseudomonas aeruginosa regulatory RNA and virulence genes. Proc. Natl. Acad. Sci. USA. USA. 103:171-6.

Kulasekara, H., Lee, V., Brencic, A., Urbach, J., Miyata, S., Lee, D.G., Neely, A.N., Hayakawa, Y., Ausubel, F.M., and Lory, S. (2006). Systematic analysis of Pseudomonas aeruginosa proteins with diguanylate cyclase and phosphodiesterase domains reveals a role for cyclic di-GMP in virulence. Proc. Natl. Acad. Sci. USA. USA. 103: 2839-2844.

Kulasekara, B.R., Kulasekara, H.D., Wolfgang, M.C., Stevens, L., Frank, D.W, and Lory, S. (2006). Acquisition and evolution of the exoU locus in Pseudomonas aeruginosa. J. Bacteriol. 188:4037-50.

Mougous, J.D., Cuff, M.E., Raunser, S., Shen, A., Zhou, M., Gifford, C.A., Goodman, A.L., Joachimiak, G., Ordonez, C.L., Lory, S., Walz, T., Joachimiak, A., and Mekalanos, J.J. (2006). A virulence locus of Pseudomonas aeruginosa encodes a protein secretion apparatus. Science. 312:1526-30.

Livny, J., Brencic, A., Lory, S., Waldor, M.K. (2006). Identification of 17 Pseudomonas aeruginosa sRNAs and prediction of sRNA-encoding genes in 10 diverse pathogens using the bioinformatic tool sRNAPredict2. Nucleic Acids Res. 34:3484-93.

Qiu, X., Gurkar, A.U., and Lory, S. (2006) Inter-strain transfer of the large pathogenicity island (PAPI-1) of Pseudomonas aeruginosa . Proc. Natl. Acad. Sci. USA. USA. 103:19830-5.

Lee, V.T., Pukatzki, S., Sato, H., Kikawada, E., Kazimirova, A.A., Huang, J., Li, X., Arm, J.P., Frank, D.W., Lory, S. ( 2007) PseudolipasinA is a Specific Inhibitor for PhospholipaseA2 Activity of Pseudomonas aeruginosa Cytotoxin ExoU. Infect Immun. In press.