Transcriptional Adaptation ofShigella flexneriduring Infection of Macrophages and Epithelial Cells: Insights into the Strategies of a Cytosolic Bacterial Pathogen

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Abstract
Shigella flexneri, the etiologic agent of bacillary dysentery, invades epithelial cells as well as macrophages and dendritic cells and escapes into the cytosol soon after invasion. Dissection of the global gene expression profile of the bacterium in its intracellular niche is essential to fully understand the biology ofShigellainfection. We have determined the complete gene expression profiles forS. flexneriinfecting human epithelial HeLa cells and human macrophage-like U937 cells. Approximately one quarter of theS. flexnerigenes showed significant transcriptional adaptation during infection; 929 and 1,060 genes were up- or down-regulated within HeLa cells and U937 cells, respectively. The keyS. flexnerivirulence genes,ipa-mxi-spaandicsA, were drastically down-regulated during intracellular growth. This theme seems to be common in bacterial infection, because the Ipa-Mxi-Spa-like type III secretion systems were also down-regulated during mammalian cell infection bySalmonella entericaserovar Typhimurium andEscherichia coliO157. The bacteria experienced restricted levels of iron, magnesium, and phosphate in both host cell types, as shown by up-regulation of thesitABCDsystem, themgtAgene, and genes of thephoBRregulon. Interestingly,ydeOand other acid-induced genes were up-regulated only in U937 cells and not in HeLa cells, suggesting that the cytosol of U937 cells is acidic. Comparison with the gene expression of intracellularSalmonellaserovar Typhimurium, which resides within theSalmonella-containing vacuole, indicated thatS. flexneriis exposed to oxidative stress in U937 cells. This work will facilitate functional studies of hundreds of novel intracellularly regulated genes that may be important for the survival and growth strategies ofShigellain the human host.