Research Interests:

We have developed a novel model system to identify previously unknown virulence-related genes in the human bacterial pathogens Pseudomonas aeruginosa, Salmonella typhimurium Staphylococcus aureus and Enterococcus faecalis, and to identify host innate immunity genes that are involved in the defense response against pathogenic microorganisms. We have identified a P. aeruginosa clinical isolate, strain PA14, that is not only infectious in several mouse models, but also causes disease in the model plant Arabidopsis thaliana and in the insects Drosophila melanogaster and Galleria mellonella (wax moth caterpillar). Moreover, PA14 also kills the nematode Caenorhabditis elegans. S. typhimurium, S. aureus and E. faecalis also kill C. elegans. From the perspective of the pathogen, the advantage of using model genetic hosts is that thousands of bacterial clones from a mutagenized library can be individually screened for avirulent mutants in separate plants, in separate insects or on separate petri plates seeded with C. elegans. The advantage of studying pathogenesis in model genetic hosts is that genetic analysis can be used to identify host genes involved in pathogen defense by screening for more susceptible or more resistant mutants.

Surprisingly, many previously known Gram negative and Gram positive bacterial pathogenesis-related genes that are required for mammalian pathogenesis are also required for pathogenesis in the model hosts. We have therefore screened for non-pathogenic P. aeruginosa, S. typhimurium and E. faecalis transposon-induced mutants in the Arabidopsis, C. elegans, or G. mellonella models in an attempt to identify previously unknown bacterial virulence-related genes. To date we have identified a total of 32 P. aeruginosa, 11 E. faecalis and 15 S. typhimurium genes, mutations in which result in a decrease in virulence in at least one of the non-vertebrate hosts. Many of these mutants are less pathogenic in the mouse model as well. About half of these virulence factors that were identified in the screens correspond to previously unknown genes.

From the host perspective, we have isolated a set of Arabidopsis and C. elegans mutants that exhibit enhanced susceptibility or enhanced resistance to various pathogens. Specifically, we have shown that highly conserved MAPK signaling cascades are involved in the innate immune responses in both Arabidopsis and C. elegans as they are in mammals. We have also studied a set of existing C. elegans mutants for susceptibility to PA14 killing and using these mutants we have demonstrated that a small molecule (a phenazine) excreted by P. aeruginosa plays a key role in C. elegans killing, most likely by exposing C. elegans to high levels of oxidative stress.

Selected Publications:

Mahajan-Miklos, S., M.-W. Tan, L.G. Rahme and F.M. Ausubel (1999) Molecular mechanisms of bacterial virulence elucidated using a Pseudomonas aeruginosa-Caenorhabditis elegans pathogenesis model. Cell 96:47-56.

Aballay, A., P. Yorgey and F.M. Ausubel (2000) Salmonella typhimurium proliferates and establishes a persistent infection in the intestine of Caenorhabditis elegans. Current Biology 10:1539-1542.

Kim, D.H., R. Feinbaum, G. Alloing, F.E. Emerson, D.A. Garsin, H. Inoue, M. Tanaka-Hino, N. Hisamoto, K. Matsumoto, M.-W. Tan and F.M. Ausubel (2002) A conserved p38 MAP kinase signaling pathway in Caenorhabditis elegans innate immunity. Science 297: 623-626.