its host and survive passage through the stomach to the colon. Once inside of the colon, S. flexneri can penetrate the epithelium in three ways: 1) The bacterium can alter the tight junctions between the epithelial cells, allowing it to cross into the sub-mucosa. 2) It can penetrate the highly endocytic M cells that are dispersed in the epithelial layer and cross into the sub-mucosa. 3) After reaching the sub-mucosa, the bacteria can be phagocytosed by macrophages and induce apoptosis, cell death. This releases cytokines that recruit polymorphonuclear cells (PMN) to the sub-mucosa. S. flexneri still in the lumen of the colon traverse the epithelial lining as the PMNs cross into the infected area. The influx of PMN cells across the epithelial layer in response to Shigella disrupts the integrity of the epithelium allowing lumenal bacteria to cross into the sub-mucosa in an M-cell independent mechanism. S. flexneri uses these three methods to reach the sub-mucosa to penetrate the epilithelial cells from the basolateral side. The bacterium has four known invasion plasmid antigens: IpaA, IpaB, IpaC, and IpaD. When S. flexneri makes contact with the basolateral side of an epithelial cell, IpaC and IpaB are fused together to make a pore in the epithelial cell membrane. It then uses a type-III secretion system (T3SS) to insert the other Ipa proteins into the cytoplasm of the epithelial cell. S. flexneri can pass to neighboring epithelial cells by using its own outer membrane protein, IcsA, to activate the host's actin assembly machinery. The IcsA protein is first localized to one pole of the bacterium where it will then bind with the host's protein, Neural Wiskott-Aldrich Syndrome Protein (N-WASP). This IcsA/N-WASP complex then activates the Actin-related protein (Arp) 2/3 Complex. Arp 2/3 Complex is the protein responsible for rapidly initiating actin polymerization and propelling the bacteria forward. When S. flexneri reaches the adjoining membrane, it creates a protrusion into the neighboring cell's cytoplasm. The bacteria becomes surrounded by two layers of cellular membrane. It then uses another IpaBC complex to make a pore and enter the next cell. VacJ is a protein that is also needed by S. flexneri to exit the protrusion. Its exact function is still being studied but it is known that intercellular spread is greatly impaired without it. Bacterial replication within the epithelial cell is detrimental to the cell but it is proposed that epithelial cell death is largely