Not all extracellular pathogens that colonize an epithelium exert their effect through toxins. Enteropathogenic E. coli (EPEC), which causes diarrhea in young children, uses a type III secretion system (see Figure 23–7) to deliver its own special receptor protein (called Tir) into the plasma membrane of a host intestinal epithelial cell (Figure 23–16). The extracellular domain of Tir binds to the bacterial surface protein intimin, triggering actin polymerization in the host cell that results in the formation of a unique cell-surface protrusion called a pedestal; this pushes the tightly adherent bacteria up about 10 μm from the host-cell membrane, thereby promoting bacterial movement along the cell surface. A similar strategy is used by vaccinia virus (the virus that was used as a vaccine to eradicate smallpox) to form mobile pedestals, which promote spread of the virus from cell to cell. The study of how EPEC and vaccinia virus promote actin polymerization has been of major importance in understanding how intracellular signaling pathways regulate the cytoskeleton in normal, uninfected cells (discussed in Chapter 16). Although pedestal formation promotes the spread of these pathogens, the sympoms of EPEC infection (severe diarrhea) are caused by the loss of absorptive microvilli and disruption of signaling pathways in epithelial cells, which are triggered by Tir and other effector proteins.
Many pathogens have to enter host cells to cause disease. These intracellular pathogens include all viruses and many bacteria and protozoa. Each of these has a preferred niche for replication and survival within host cells. Bacteria and protozoa replicate either in the cytosol or within a membrane-enclosed compartment. While most RNA viruses replicate within the cytosol, most DNA viruses replicate in the nucleus. Life inside a host cell has several advantages. The pathogens are not accessible to antibodies, nor are they easy targets for phagocytic cells (discussed in Chapter 24); furthermore, intracellular bacteria and protozoa are bathed in a rich source of nutrients, and viruses have access to the host cell’s biosynthetic
Figure 23–16 Interaction of enteropathogenic E. coli (ePeC) with host intestinal epithelial cells. (A) When EPEC contacts an epithelial cell in the lining of the human gut, it delivers a bacterial protein called Tir into the host  cell through a type III secretion system.  Tir then inserts into the plasma membrane of the host cell, where it functions as a receptor for the bacterial adhesin protein intimin. Next, a host-cell protein tyrosine kinase phosphorylates the intracellular domain of Tir on tyrosines. Phosphorylated Tir recruits host-cell proteins (including an adaptor protein, a WASp protein, and the Arp 2/3 complex) that trigger actin polymerization (see Figure 16–16). Consequently, a branched network of actin filaments assembles underneath the bacterium, forming an actin pedestal (Movie 23.4). (B) EPEC on a pedestal. In this fluorescence micrograph, the DNA of the EPEC and host cell is labeled in blue, Tir protein is labeled in green, and host-cell actin filaments are labeled in red. The inset shows a close-up view of the two upper bacteria on pedestals. (B, from