Contact Information:
Dept. of Microbiology and
Molecular Genetics
Harvard Medical School
200 Longwood Ave.
Boston, MA 02115
phone: 617-432-4156
fax: 617-738-7664
darren_higgins@hms.harvard.edu
Higgins Lab Home
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Research Summary
Bacterial pathogens that grow within mammalian cells are responsible for multiple diseases and millions of deaths worldwide. Our group uses a combination of molecular genetics, tissue culture systems, high resolution microscopy, and in vivo mouse infection models to determine the pathogen-specific and cell biological mechanisms involved in intracellular bacterial pathogenesis.
We primarily utilize Listeria monocytogenes as a model pathogen for understanding the molecular determinants of intracellular pathogenesis and cell-mediated immunity. Several virulence determinants necessary for the intracellular growth and spread of L. monocytogenes have been identified. However, the precise requirement for many of these factors is poorly characterized. Current research in our lab is aimed at understanding the precise function and temporal requirement of these determinants at every stage of intracellular infection. Other studies within our group involve determining the mechanisms of coordinate regulation of bacterial gene expression during intracellular infection and the contribution of host-specific factors that are required for intracellular infection.
Another significant part of our research effort is developing improved strategies for delivering macromolecules (DNA, RNA and protein) to mammalian cells. We have developed non-pathogenic bacterial strains expressing recombinant pore-forming cytolysins that can be used to deliver macromolecules to mammalian cells both in vitro and in vivo. Moreover, we have shown that killed bacterial preparations can be used to deliver antigenic proteins for presentation on MHC class I molecules to cytotoxic T-lymphocytes (CTL). Current research projects involve developing cytolysin-mediated delivery strategies for generating vaccine formulations, and for identifying novel CTL antigens by targeting expression libraries of intracellular pathogens to antigen presenting cells in vitro and screening for presentation to pathogen-specific CTL lines. The goal of this research is to characterize CTL antigens that are important for protective immune responses and develop improved vaccine strategies for intracellular pathogens.
Selected Publications
Agaisse, H., Burrack, L.S., Philips, J.A., Rubin, E.J., Perrimon, N. and Higgins, D.E. (2005) Genome-wide RNAi screen for host factors required for intracellular bacterial infection. Science. Published online July 14.
Gründling, A., Burrack, L.S., Bouwer, H.G.A. and Higgins, D.E. (2004) Listeria monocytogenes regulates flagellar motility gene expression through MogR, a transcriptional repressor required for virulence. Proc. Natl. Acad. Sci. U.S.A. 101(33): 12318-12323.
Gründling, A., Gonzalez, M.D. and Higgins, D.E. (2003) Requirement of the Listeria monocytogenes broad-range phospholipase PC-PLC during infection of human epithelial cells. J. Bacteriol. 185(21): 6295-6307.
Radford, K.J., Higgins, D.E., Pasquini, S., Cheadle, E.J., Carta, L., Jackson, A.M., Lemoine, N.R., and Vassaux, G. (2002) A recombinant E. coli vaccine to promote MHC class I-dependent antigen presentation: application to cancer immunotherapy. Gene Therapy 9: 1455-1463.
Dancz, C.E., Haraga, A., Portnoy, D.A. and Higgins, D.E. (2002) Inducible control of virulence gene expression in Listeria monocytogenes: temporal requirement of listeriolysin O during intracellular infection. J. Bacteriol. 184(21): 5935-5945.
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