Multicellular life arose about a billion years ago in a world that had long been dominated by unicellular microbes. It’s clear that multicellularity allowed for the evolution of an elaborate and sophisticated defense system. It is also evident that the microbes, at least many of the ones we recognize today as pathogens, were not standing idle during the last three billion years. Far from being a ‘bag of enzymes’, the bacteria have evolved elaborate and sophisticated ways of their own to mollify host defense responses. A clear example of an ‘anti-host system’ can be found in many species of Gram-negative bacteria that employ a protein secretion system (designated as type III) that delivers virulence factors directly into eukaryotic cells. Our lab is interested in deciphering the activities of these virulence factors within the eukaryotic host cell.

 ‘Cellular Microbiology’ Not surprisingly since they are designed to be active within eukaryotic cells, the majority of the virulence factors secreted by bacterial type III systems possess eukaryotic-like domains or motifs. It thought that the genes encoding some of the type III virulence factors were in fact acquired from eukaryotic genomes. An unmodified eukaryotic protein itself would likely not be of much use for a bacterium since such a protein would still be responsive to normal cellular regulatory processes. Instead, ‘captured’ genes would be expected to undergo extensive modifications that would result in them becoming beneficial to the bacterium and, conversely, detrimental to the host in which they originally evolved to serve. Therefore, these virulence factors we observe today likely are the products of two sequential (and opposing) lines of evolution. Conveniently, many of these virulence factors expressed by the pathogenic yersiniae possess similar activities in animal and yeast cells. What this means is that we can apply a well-developed genetic system to identify and characterize the cellular activities of these virulence factors. By performing large-scale mutagenesis screens, we have discovered that the ancient stress-activated eIF2 signaling pathway plays a pivotal role in how eukaryotic cells interact with microbial pathogens.