Cammie Lesser

Department of Microbiology and Molecular Genetics
University Park

Bacterial Pathogenesis Laboratories
65 Landsdowne St., Room 417
Cambridge, MA 02139
Tel: (617) 768-8349
Fax: (617) 768-8738
Email: clesser@partners.org
Web Page: The Lesser Lab Page
2 postdoctoral fellows, 1 graduate student, 2 undergraduate students

Research in our lab uses a variety of innovative approaches to understand how bacterial pathogens co-opt the basic machinery of eukaryotic host cells to promote infection and ultimately cause disease. Our work focuses on both identifying and determining the roles in pathogenesis of proteins that are directly injected into host cells by specialized bacterial secretion systems. Many of these proteins, referred to as effectors, target cellular processes conserved among all eukaryotes. This conserved targeting often results in growth inhibition when these proteins are expressed in the model eukaryote, the yeast Saccharomyces cerevisiae. For example we have observed that ~50% of known effectors but almost none of >1,200 bacterial house keeping proteins inhibit growth when expressed in yeast. We are currently exploring new ways to identify and functionally characterize effector proteins from a variety of bacteria including enteric gram-negative rods, Mycobacterium tuberculosis and Francisella tularensis.

A major effort in our laboratory has been the development of a yeast systems biology approach to determine the modes of action and eukaryotic targets of bacterial effector proteins. We have developed technologies that permit us to efficiently and systematically conduct genome-wide phenotypic screens with the complete sets of isogenic yeast strain collections that either no longer express or overexpress each annotated yeast ORF. We screen these strain collections to identify ORFs whose overexpression or lack of expression either alleviate growth inhibition due to expression of toxic effector proteins or exacerbate growth inhibition due to expression of effectors that minimally affect growth. In parallel, we complement these genetic approaches by using a variety of proteomic approaches to identify interactions between bacterial effectors and eukaryotic proteins. Alternatively, we gain potentially clues to the functions of the effectors by genome-wide profiling alternations in mRNA expression patterns due to expression of the bacterial proteins in yeast. By integrating the results of our screens with the wealth of information available regarding yeast biology, we have been successfully in determining roles of effector proteins in manipulating several host cell processes including regulation of MAPK signaling pathways as and ubiquitin-mediate protein degradation pathways. Current efforts are underway to dissect the mechanisms of action of these and other effector proteins in mammalian cell culture and animal models of infection. Interestingly, our studies in yeast are providing novel insights into Shigella regulation of the host innate immune response.

References:

• Lesser, C.F. and Miller, S.I. (2001) Tractable Saccharomyces cerevisiae is model system for studying pathogenic bacterial proteins: introducing bacterial virulence proteins into yeast provides valuable insights about their interactions with host components. ASM News. 67(9), 448-455.
• Kramer, R.W., Slagowski, N.L., Eze, N.A., Giddings, K.S., Morrison, M.F., Siggers, K.A., Starnbach, M.N. and Lesser, C.F. (2007) Yeast functional genomic screens lead to identification of a role for a bacterial effector in innate immunity regulation. PLoS Pathogens, 3(2): e21.
• Slagowski, N.L., Kramer, R.W., Morrison, M.F., LaBaer, J. and Lesser, C.F. (2008) A functional genomic yeast screen to identify pathogenic bacterial proteins. PLoS Pathogens, 4(1):e9.
• Huang, J., Lesser, C.F. and Lory, S. I. (2008) The essential role of the CopN protein for Chlamydia pneumoniae intracellular growth. Nature, in press.