In summary, we have identified specifically the ire-1-xbp-1 and atf-6 ER stress transducer pathways as components of cellular defenses against a PFT. While p38 MAPK was previously demonstrated to function in this regard [6] , we have discovered a major and unexpected downstream target of this pathway for PFT defenses, namely the UPR. These results demonstrate the fundamental requirement for specific cell responses to bacterial PFTs and support the notion of intrinsic cellular defenses (or INCED, formerly, cellular non-immune defenses), a budding concept in immunity that emphasizes the intrinsic ability of epithelial cells to defend against bacterial toxins and the importance of these defenses as a supplement to the innate immune and adaptive immune systems [36] . Additionally, the differential importance of the three ER stress transducer pathways in response to Cry5B versus tunicamycin, the differential activation of ire-1-xbp-1 by p38 MAPK in response to Cry5B versus tunicamycin, and the divergent pathways regulated by p38 MAPK in protective responses reveal how studying pathogenesis can uncover a wonderful complexity and new connections among intracellular pathways.