Frederick Ausubel Laboratory
Welcome to the Laboratory of Fred Ausubel in the Department of Molecular Biology at The Massachusetts General Hospital, a joint department with the Department of Genetics at the Harvard Medical School. The laboratory's primary interest is in identifying and characterizing the molecular aspects of the process of signal transduction in prokaryotes and in hosts that interact with prokaryotes, from the discovery of virulence factors in bacteria and fungus to host defense responses in plants, insects, worms and mammals. These pathogen-host interactions are explored a variety of ways, both experimentally and computationally.
The responses by which multicellular eukaryotic hosts defend themselves from pathogen attack have only recently begun to be subjected to rigorous genetic analysis. This sort of analysis requires a tractable genetic system for the host and well-characterized host-pathogen interactions. Whereas vertebrates, with the possible exception of zebrafish, are generally unsuitable for such studies, Arabidopsis thaliana, Caenorhabditis elegans and Drosophila melanogaster offer many advantages for the genetic analysis ofhost-pathogen interactions. Our laboratory pioneered the use of direct screens for identifying Arabidopsis mutants that exhibit aberrant responses to pathogen attack. Similarly, the Ausubel Laboratory pioneered the development of C. elegans pathogenicity models that have shown that C. elegans does indeed mount an innate immune defense response to pathogens that can be dissected by traditional genetic analysis. Our studies support the hypothesis that key features of host defense responses, as well as the offensive strategies employed by pathogenic microbes, have ancient origins.
Our laboratory is now divided 50/50 between the Arabidopsis and C. elegans systems. The rationale is that there is a growing body of evidence demonstrating that many of the underlying mechanisms of microbial pathogenesis and corresponding host defense responses are similar in plants and animals and that the study of Arabidopsis and C. elegans defense responses will be synergistic. One example of how bacterial virulence factors are similar in plant and animal pathogens is the conservation of so-called type III protein secretory mechanisms that are involved in the translocation of proteinaceous virulence factors into host cells. Another example is our discovery that Pseudomonas aeruginosa utilizes a shared subset of virulence factors to infect both plants and animals. From the host perspective, there are key similarities in the signaling pathways involved in animal immune responses and this conservation may extend to aspects of the plant defense response. Taken together, these observations argue strongly that a comparative analysis of Arabidopsis and C. elegans is likely to identify ancient components of the eukaryotic host defense response. An excellent example of the synergism between the Arabidopsis and C. elegans projects in our lab is the identification of MAPK signaling cascades as conserved components of the innate immune signaling in both organisms.
The use of experimentally tractable model hosts allows us to perform genetics on both sides of the host-pathogen interaction. To better understand the suite of bacterial virulence factors that are used to inflict damage on the host and to circumvent the host’s defense responses, we are developing genomic tools for a pathogenic isolate of P. aeruginosa, strain PA14, which is extremely virulent in both the Arabidopsis and C. elegans models. A full-genome, non-redundant library of defined transposon insertions will allow for high-throughput, saturating screens to identify novel virulence factors, and candidate strains will be selected for studies utilizing combinatorial genetics between sets of host and pathogen mutants.
About Fred Ausubel
Frederick M. Ausubel is Professor of Genetics at Harvard Medical School and is the Ernst Winnacker Distinguished Investigator in the Department of Molecular Biology at Massachusetts General Hospital. Dr. Ausubel received his B.S. in Chemistry from the University of Illinois in 1966 and his Ph.D. in Biology from the Massachusetts Institute of Technology in 1972. Formerly, he was Assistant and Associate Professor in the Department of Cellular and Developmental Biology at Harvard University.
Dr. Ausubel’s scientific work concerns host-microbe interactions. In the 1970s and 1980s, his laboratory worked on the molecular basis of symbiotic nitrogen fixation, the process by which legumes, in concert with a bacterial symbiont, convert atmospheric nitrogen into ammonia. Currently, the laboratory is investigating microbial pathogenesis and host defense in the plant Arabidopsis thaliana and the nematode Caenorhabditis elegans. The laboratory has also adopted a genomics approach to study virulence in the opportunistic bacterial pathogen Pseudomonas aeruginosa strain PA14, which remarkably is a “multi-host” pathogen of both plants and animals. The laboratory is particularly interested in those aspects of pathogenesis and the host innateimmune response that have been conserved in evolution.
Dr. Ausubel was elected to the National Academy of Sciences in 1994, the American Academy of Microbiology in 2002, and the American Academy of Arts and Sciences in 2003. In addition to serving on a variety of editorial boards, Dr. Ausubel is founding editor of the widely-read Current Protocols in Molecular Biology.