Stephen Lory

Department of Microbiology and Molecular Genetics
Harvard Medical School
Warren Alpert Building, Rm 363
200 Longwood Avenue
Boston, MA 02115
Tel: (617) 432-5099
Fax: (617) 738-7664
Email: stephen_lory@hms.harvard.edu
6 postdoctoral fellows, 1 graduate student

Pseudomonas aeruginosa is a ubiquitous environmental bacterium capable of causing a variety of life-threatening human infections particularly in patients who are immunocompromised or who suffer from cystic fibrosis. In the Lory lab we research the genome-wide analysis of the evolution of virulence traits in this organism that allow it to cause a wide variety of acute and chronic infections. Several researchers in the lab are working on projects to develop tools to study the acquisition of genes by horizontal gene transfer, and the role of conjugative plasmids in shaping a genome of this organism. We are particularly interested in the influence of horizontally acquired regulatory elements on the transcription of the conserved core genes and the role of single nucleotide polymorphisms in shaping the final phenotype of P. aeruginosa during chronic colonization.

Our current work also focuses on defining regulatory networks that control gene expression with emphasis on the regulation of virulence genes. Genetic studies led to the discovery of a number of signaling networks that are capable of sensing environmental cues and transiting this information to regulatory factors that coordinate the activation and the repression of hundreds of genes. These factors facilitate the survival of this organism during infection. Many of these signals are assimilated using transcriptional and post-transcriptional mechanisms and most projects study molecular details that function at distinct steps in this signaling process. We have also discovered that several second messengers (cyclic AMAP and cyclic-diGMP) play a role in controlling the expression of two important virulence functions: the formation of biofilms and the production of various exotoxins. The specific regulatory targets of these small molecules still need to be defined. Collectively, our work should provide a framework for understanding the complex interactions of bacteria with their host during infections and yield insights into therapeutic interventions.

References:

• Goodman, A., Kulasekara, B.R., 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.
• 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. (2006). Proc. Natl. Acad. Sci. USA. USA. 103: 2839-2844.