In vivo gene expression and the adaptive response: from pathogenesis to vaccines and antimicrobials

Microbial pathogens possess a repertoire of virulence determinants that eac h make unique contributions to fitness during infection. Analysis of these in vivo-expressed functions reveals the biology of the infection process, e ncompassing the bacterial infection strategies and the host ecological and environmental retaliatory strategics designed to combat them (e.g. thermal, osmotic, oxygen, nutrient and acid stress). Many of the bacterial virulenc e functions that contribute to a successful infection are normally only exp ressed during infection. A genetic approach was used to isolate mutants tha t ectopically expressed many of these functions in a laboratory setting. La ck of DNA adenine methylase (Dam) in Salmonella typhimurium abolishes the p referential expression of many bacterial virulence genes in host tissues. D am(-) Salmonella were proficient in colonization of mucosal sites but were defective in colonization of deeper tissue sites. Additionally, Dam(-) muta nts were totally avirulent and effective as live vaccines against murine ty phoid fever. Since dam is highly conserved in many pathogenic bacteria that cause significant morbidity and mortality worldwide, Dams are potentially excellent targets for both vaccines and antimicrobials.