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Critical for disease is the ability of<jats:italic>Shigella<\/jats:italic>to use an actin\u2010based motility (ABM) process to spread between cells of the colonic epithelium. ABM transports bacteria to the periphery of host cells, allowing the formation of plasma membrane protrusions that mediate spread to adjacent cells. Here we demonstrate that efficient protrusion formation and cell\u2010to\u2010cell spread of<jats:italic>Shigella<\/jats:italic>involves bacterial stimulation of host polarized exocytosis. Using an exocytic probe, we found that exocytosis is locally upregulated in bacterial protrusions in a manner that depends on the<jats:italic>Shigella<\/jats:italic>type III secretion system. Experiments involving RNA interference (RNAi) indicate that efficient bacterial protrusion formation and spread require the exocyst, a mammalian multi\u2010protein complex known to mediate polarized exocytosis. In addition, the exocyst component Exo70 and the exocyst regulator RalA were recruited to<jats:italic>Shigella<\/jats:italic>protrusions, suggesting that bacteria manipulate exocyst function. Importantly, RNAi\u2010mediated depletion of exocyst proteins or RalA reduced the frequency of protrusion formation and also the lengths of protrusions, demonstrating that the exocyst controls both the initiation and elongation of protrusions. Collectively, our results reveal that<jats:italic>Shigella<\/jats:italic>co\u2010opts the exocyst complex to disseminate efficiently in host cell monolayers.<\/jats:p>","DOI":"10.1111\/mmi.14827","type":"journal-article","created":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T11:21:28Z","timestamp":1633519288000},"page":"1328-1346","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["<i>Shigella flexneri<\/i>subverts host polarized exocytosis to enhance cell\u2010to\u2010cell spread"],"prefix":"10.1111","volume":"116","author":[{"given":"Thilina U. 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