In addition to infecting intestinal epithelial cells, Shigella infect macrophages within the intestinal lamina propria and Peyer’s patches. Macrophages are both activated and killed by intracellular Shigella. Macrophage respond by GBP-dependent recognition of Shigella and inflammasome activation, which triggers the release of pro-inflammatory cytokines and inflammatory cell death. From a genetic screen, we discovered a role for human proteins not previously known to contribute to these innate immune responses. Using cell biology, protein biochemistry, and primary and cell culture-based assays, we are working to uncover the mechanisms by which these, other host factors, and bacterial proteins contribute to innate immune responses.