Frederick M. Ausubel
Karl Winnacker Distinguished Investigator, Department of Molecular Biology, Massachusetts General Hospital
Studies on the molecular basis of host-microbe interactions.
My laboratory is developing high throughput screening technologies to identify novel antimicrobial compounds using a whole-animal Caenorhabditis elegans infection model. This work is based on the observation that a remarkably large number of human pathogenic bacteria and yeasts infect and kill C. elegans. Each of these pathogens is studied by simply replacing C. elegans’ normal food source (Escherichia coli strain OP50) with a pathogen, and monitoring the survival of the nematodes over time. This simple feeding-based pathogenicity model coupled with powerful genetic and genomic technologies, including RNAi feeding libraries, makes C. elegans an attractive model in which to dissect C. elegans innate immune response signaling pathways, to study pathogen-encoded virulence factors, and to identify novel antimicrobial compounds. The latter is possible because C. elegans is small enough to fit in the wells of a standard 384-well multi-well plate and because they can be infected with a pathogen that causes a lethal persistent infection. It therefore possible to screen for low molecular weight compounds that cure the infection. The endpoint of the assay is a live worm. This assay not only identifies traditional antibiotics that kill free-living bacteria, but also compounds that target bacterial virulence or host immunity. Importantly, key aspects of the innate immune response has been conserved between nematodes and mammals, increasing the probability that immune-enhancing compounds identified using C. elegans will also be active in mammalian models. We have developed a fully automated assay that uses a robot to distribute a set number of C. elegans animals to wells and automated imaging analysis to distinguish live from dead worms. We are currently working with about 50 compounds identified from a screen of 50,000 compounds using a C. elegans – Enterococcus faecalis infection model.
Kim, D.H., Feinbaum, R., Alloing, G., Emerson, F.E., Garsin, D.A., Inoue, H., Tanaka-Hino, M., Hisamoto, N., Matsumoto, K., Tan, M.-W. and Ausubel, F.M. (2002) A conserved p38 MAP kinase signaling pathway in Caenorhabditis elegans innate immunity. Science 297: 623-626.
Moy, T.I., Ball, A.R., Anklesaria, Z., Casadei, G., Lewis, K. and Ausubel, F.M. (2006) Identification of novel antimicrobials using a live-animal infection model. Proc. Natl. Acad. Sci. USA 103:10414-10419.
Troemel, E.R., Chu, S.W., Reinke, V., Lee, S.S., Ausubel, F.M. and Kim, D.H. (2006) p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans. PLoS Genet. 2:e183.
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