Dept. of Microbiology and Immunobiology
Harvard Medical School
77 Avenue Louis Pasteur
Boston, MA 02115
Pathogens that grow within human cells are responsible for multiple diseases and millions of deaths worldwide. The primary goal of our research is to elucidate both the pathogen and host cell-specific mechanisms involved in the growth and spread of intracellular bacterial pathogens. Specific areas of emphasis include (1) determining the mechanisms of coordinate regulation of bacterial gene expression during intracellular infection, (2) characterizing host-specific factors that are required for intracellular bacterial pathogenesis, (3) identifying pathogen-specific antigens that stimulate protective cellular immune responses during infection and (4) developing novel vaccine strategies for intracellular bacterial pathogens.
We take a multidisciplinary approach in our investigations employing molecular genetics, cell biology, high-resolution microscopy, structural biology, tissue culture and mouse infection models. Because of its rich history as a model intracellular pathogen for immunological and cell biological research, we primarily utilize the bacterium Listeria monocytogenes in our studies. Our lab has pioneered multiple approaches to understand the mechanisms of intracellular bacterial pathogenesis and the host immune response to infection. These approaches include the development of inducible genetic systems to determine the temporal requirement and function of bacterial virulence determinants, the use of RNAi to conduct genome-wide screens to identify host factors required for intracellular bacterial infection, the identification of novel regulators of gene expression that govern bacterial motility and virulence, and the development of systems to rapidly identify which proteins from the entire proteome of a pathogen can serve as antigens to stimulate protective cellular immune responses for novel vaccine formulations.
Shen, A., Higgins, D.E., and Panne, D. (2009) Recognition of AT-rich DNA binding sites by the MogR repressor. Structure 17(5): 769-777.
Lieberman, L.A., and Higgins, D.E. (2009) A small-molecule screen identifies the antipsychotic drug pimozide as an inhibitor of Listeria monocytogenes infection. Antimicrob. Agents Chemother. 53(2): 756-764.
Kirchner, M., and Higgins, D.E. (2008) Inhibition of ROCK activity allows InlF-mediated invasion and increased virulence of Listeria monocytogenes. Mol. Microbiol. 68(3): 749-767.
Birmingham, C.L., Canadien, V., Kaniuk, N.A., Steinberg, B.E., Higgins, D.E., and Brumell, J.H. (2008) Listeriolysin O allows Listeria monocytogenes replication in macrophage vacuoles. Nature. 451(7176): 350-354.
Shen, A., Kamp, H.D., Gründling, A., and Higgins, D.E. (2006) A bifunctional O-GlcNAc transferase governs flagellar motility through anti-repression. Genes Dev. 20(23): 3283-3295.
Bouwer, H.G.A., Alberti-Segui, C., Montfort, M.J., Berkowitz, N.D., and Higgins, D.E. (2006) Directed antigen delivery as a vaccine strategy for an intracellular bacterial pathogen. Proc. Natl. Acad. Sci. U.S.A. 103(13): 5102-5107.
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 309(5738): 1248-1251.