Salmonella stimulates pro-inflammatory signaling through p21-activated kinases bypassing innate immune receptors

Microbial infections are most often countered by inflammatory responses initiated through the recognition of conserved microbial products by innate immune receptors resulting in pathogen expulsion (1–6). However, inflammation can also lead to pathology. Therefore, tissues such as the intestinal epithelium, which are exposed to microbial products, are subject to stringent negative regulatory mechanisms to prevent signaling through innate immune receptors (6–11). This presents a challenge to the enteric pathogen Salmonella Typhimurium, which requires intestinal inflammation to compete against the resident microbiota and to acquire the nutrients and electron acceptors that sustain its replication(12,13). We show here that S. Typhimurium stimulates pro-inflammatory signaling by a unique mechanism initiated by effector proteins delivered by its type III protein secretion system. These effectors activate Cdc42 and the p21-activated kinase 1 (PAK1) leading to the recruitment of TRAF6 and TAK1 and the stimulation of NF-κB inflammatory signaling. Removal of Cdc42, PAK1, TRAF6, or TAK1 prevented the ability of S. Typhimurium to stimulate NF-κB signaling in cultured cells. Oral administration of a highly specific PAK inhibitor blocked Salmonella-induced intestinal inflammation and bacterial replication in the mouse intestine, although it resulted in a significant increase in bacterial loads in systemic tissues. Thus S. Typhimurium stimulates inflammatory signaling in the intestinal tract by engaging critical downstream signaling components of innate immune receptors. Furthermore, these findings illustrate the unique balance that emerges from host/pathogen co-evolution in that pathogen-initiated responses that help pathogen replication are also important to prevent pathogen spread to deeper tissues.