Pathogenesis of EPEC infection. (a) Electron micrograph of a culture of EPEC bacteria grown under conditions that lead to the production of type IV fimbria known as bundle-forming pili (BFP). BFP are required for bacterial aggregation and localized adherence to epithelial cells. (b) Electron micrograph of an EPEC bacterium engaged in attaching and effacing activity with a host intestinal epithelial cell. Note the loss of microvilli and the formation of a cuplike pedestal to which the bacterium is intimately attached. (c) A model of EPEC pathogenesis. A bacterial aggregate, connected by bundles of BFP fibers, is shown near an intestinal epithelial cell (panel 1). As infection proceeds, the bacteria detach from the pilus fibers, disaggregate, and become connected to the host cell through a surface appendage that contains EspA (panel 2). It is believed that Tir, EspB, and EspF travel through this appendage to the host cell. EspF is not required for attaching and effacing activity but plays a role in disruption of intestinal barrier function and host cell death. EspB and Tir are required for attaching and effacing activity (panel 3). The bacterial outer membrane protein intimin, composed of three immunoglobulin-like extracellular domains (D₀–D₂, light blue) and a receptor-binding lectin-like domain (D₃, dark blue), binds to Tir in the host cell membrane (panel 4). Tir forms a four-helix bundle composed of two molecules each containing two antiparallel α helices connected by a hairpin loop. One intimin molecule binds to each loop of the dimer. Wiskott-Aldrich syndrome protein (WASP) is recruited to the pedestal where it activates the Arp2/3 complex to nucleate and polymerize actin.