Stephen Lory, Ph.D.

Research Summary

The major research efforts in the laboratory are directed towards understanding the molecular basis of pathogenesis of human infections caused by opportunistic gram-negative bacteria. The projects aim to better understand the molecular basis of regulation of expression of determinants of pathogenicity by the microorganisms, starting from signal perception and transmission, regulation of gene expression at the transcriptional and post-transcriptional levels and the targeting mechanisms of the virulence factors 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, patients with neutropenia, or those with serious 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 signaling pathways and genetic regulatory networks, controlling virulence determinants. The areas investigated include the analyses of the functions of the various phosphorylation-based signaling pathways in assimilating and transmitting environmental cues leading to selective and controlled transcription specific genes encoding virulence factors. Recently discovered small regulatory RNAs, responsible for the post-transcriptional control of genes are also investigated in the lab. The lab has a major effort in determining the role of cyclic nucleotides in coordinating expression and function of factors involved in the formation of different polysaccharide matrices and secreted toxins that are major virulence determinants expressed by P. aeruginosa during chronic infections.

Another area of research in the laboratory focuses on studying the evolution of virulence traits in P. aeruginosa.  We have identified several mobile elements, arranged in blocks of genes (so called genomic islands) that can move between bacteria, resulting in re-shaping of the genetic repertoire of individual recipient strains. The mechanisms and the consequences of this type of horizontal gene transfer, particularly if it leads to the acquisition of new virulence traits, will be analyzed in several infection models.

Selected Publications

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, BR  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.

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. 103:19830-5.

Merighi M., Lee V.T.,  Hyodo M.,  Hayakawa Y. and  Lory S. (2007) The second messenger bis-(3’-5’)-cyclic-GMP and its PilZ domain-containing receptor Alg44 are required for alginate biosynthesis in Pseudomonas aeruginosa . Mol. Microbiol 65:876-9.

Lee V.T, Matewish J.M., Kessler J.L., Hyodo M., Hayakawa Y., and Lory S. (2007) A cyclic-di-GMP receptor required for bacterial exopolysaccharide production. Mol. Microbiol 65:1474-84.

Arnoldo A.,  Curak J., Kittanakom S., Chevelev I.,  Lee V.T., Sahebol-Amri M., Koscik B.,   Ljuma L., Roy P. J., Bedalov A.,  Nislow C., Merrill R.,  Lory S., Stagljar I. (2008) Identification of small molecule inhibitors of Pseudomonas aeruginosa Exotoxin S using a yeast phenotypic screen. PLoS Genetics  29:4 e1000005)

Mathee K., Narasimhan G., Qiu X., Camilo Valdes C., Matewish J.M., Koehrsen M.,   Rokas A., Yandava C.N.,   Engels R., Zeng E., Olavarietta R.,  Doud M., Smith R.,    Montgomery P., White J., Godfrey P.A., Kodira C., Birren B., Galagan J. and Lory S. (2008).  Dynamics of Pseudomonas aeruginosa genome evolution. Proc. Natl. Acad. Sci. USA. USA. 105:3100-5.

Huang J., Lesser C., and Lory S (2008) The essential role of the CopNproteinfor Chlamydia pneumoniae intracellular growth. Nature. 456:112-5.

Goodman AL.,  Merighi M., M Hyodo M., Ventre I.,  Filloux A., and Lory S. (2009). Direct interaction between sensor kinase proteins mediates acute and chronic disease phenotypes in a bacterial pathogen Genes and Development  23:249-59.
          
Brencic, A.  McFarland, C,   McManus, H.R., Castang, S., Mogno, I., Dove, S.L. and    Lory, S. (2009). The GacS/GacA signal transduction system of Pseudomonas aeruginosa acts exclusively through its control over the transcription of the RsmY and RsmZ regulatory small RNAs. Mol. Microbiol. 73:434-45

Klepac-Ceraj V,  Lemon K.P.,   Martin T.R, Allgaier M., Kembel S.W., Knapp A.A.,  Lory S.,   Brodie E.L., Lynch S.V., Bohannan B.J.M., Green J.L.,  Maurer B.A. and  Kolter R.G. (2010).  Relationship between cystic fibrosis respiratory tract bacterial communities and age, genotype, antibiotics and Pseudomonas aeruginosa.  Environmental Microbiol.  In press.