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Salmonella stimulates pro-inflammatory signalling through p21-activated kinases bypassing innate immune receptors.
| Content Provider | Europe PMC |
|---|---|
| Author | Sun, Hui Kamanova, Jana Lara-Tejero, Maria Galán, Jorge E. |
| Abstract | 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 replication12,13. 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. |
| Related Links | https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC6158040&blobtype=pdf |
| Journal | Nature microbiology [Nat Microbiol] |
| Volume Number | 3 |
| DOI | 10.1038/s41564-018-0246-z |
| PubMed Central reference number | PMC6158040 |
| Issue Number | 10 |
| PubMed reference number | 30224799 |
| e-ISSN | 20585276 |
| Language | English |
| Publisher Date | 2018-09-17 |
| Access Restriction | Open |
| Rights License | Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms) |
| Subject Keyword | Salmonella pathogenesis innate immunity NF-κB p21-activated kinase PAK1 PAK2 Cdc42 TRAF6 TAK1 bacterial pathogenesis type III protein secretion host-pathogen interactions intestinal inflammation host-pathogen co-evolution inflammatory bowel disease |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Genetics Immunology Microbiology Applied Microbiology and Biotechnology Microbiology (medical) |
