| Citation | David Holden is distinguished for genetic studies of microbial pathogenicity. He made a seminal breakthrough by inventing signature-tagged mutagenesis (STM), an in vivo genetic screen for indentifying virulence genes. Until then, these genes were identified by screening individual mutants. In STM, tagging with different DNA signatures allows simultaneous screening of many mutant strains in the same animal. First applied to Salmonella typhimurium, STM identified a novel secretion system (SPI-2), vital for systemic infection. Now, STM is used by academic and industrial scientists world-wide for the identification of virulence determinants of the major bacterial pathogens and fungi. Some of the genes identified are being used for the development of new therapeutic drugs and for the design of vaccines. Recently, Holden developed another powerful and widely applicable technique (involving competitive infections with single and double mutant strains in the same host) to identify virulence gene interactions in vivo. In this way, he identified a bacterial protein which maintains the integrity of the host-cell vacuolar membrane surrounding S typhimurium providing novel information on how this pathogen avoids the human immune system. |