Dr. Hoffmann and his colleagues' expected the innate immune system in the fly to be completely different from that in a mammal, but they were in for a surprise. Within a few years, thanks to Dr. Hoffmann's lab and the work of several other labs in mammals, including those of Charles A. Janeway, MD, and Bruce A. Beutler, MD, they showed that flies and mammals share many of the mechanisms of innate immunity. "These range from receptors for microbial aggressors, to intracellular signaling cascades, which control the expression of immune response genes, and the genes encoding potent antimicrobial peptides," Dr. Hoffmann explained.
Genomic analysis enabled the Hoffmann group to set the date for the emergence of innate immunity. "Innate immunity appeared with multicellularity, possibly one billion years ago. The various zoological phyla have played with a toolbox of genes encoding receptors, adaptors, kinases, transactivators, and antimicrobial peptides according to their own agendas, essentially their own environments and pathogens," he said.
At the crux of the Hoffmann lab body of work is the Toll receptor, a protein that straddles the cell membranes of immune system "sentinel" cells, detecting molecular nametags of pathogens from the outside and transducing messages to the inside, activating and orchestrating defense against infection.
The Toll receptor had been discovered in 1985 as a regulator of embryo polarity, but Dr. Hoffmann's group linked it to fungal infection in flies in 1996 and then to Gram-positive bacterial infections. During this time Dr. Hoffmann became director of the CNRS Institute of Cellular and Molecular Biology. A year later, Dr. Janeway and his lab at Yale discovered Toll-like receptors that activate and amplify the specific, adaptive immune response in humans.
Dr. Hoffmann acknowledged many scientists and labs wh
|Contact: Phyllis Edelman|
Genetics Society of America