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


Microbial infections are most often countered by inflammatory responses that are initiated through the recognition of conserved microbial products by innate immune receptors and result in pathogen expulsion1,2,3,4,5,6. However, inflammation can also lead to pathology. Tissues such as the intestinal epithelium, which are exposed to microbial products, are therefore subject to stringent negative regulatory mechanisms to prevent signalling through innate immune receptors6,7,8,9,10,11. 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 signalling by a unique mechanism initiated by effector proteins that are delivered by its type III protein secretion system. These effectors activate Cdc42 and the p21-activated kinase 1 (PAK1) leading to the recruitment of TNF receptor-associated factor 6 (TRAF6) and mitogen-activated protein kinase kinase kinase 7 (TAK1), and the stimulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inflammatory signalling. The removal of Cdc42, PAK1, TRAF6 or TAK1 prevented S. Typhimurium from stimulating NF-κB signalling in cultured cells. In addition, 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 the bacterial loads in systemic tissues. Thus, S. Typhimurium stimulates inflammatory signalling in the intestinal tract by engaging critical downstream signalling components of innate immune receptors. 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.

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Fig. 1: S. Typhimurium stimulates pro-inflammatory signalling through Cdc42 and its effector kinase PAK1.
Fig. 2: PAK1–TRAF6–TAK1 mediates S. Typhimurium pro-inflammatory signalling downstream of Cdc42.
Fig. 3: S. Typhimurium stimulates TAK1-dependent PAK1 phosphorylation, which is essential for pro-inflammatory signalling.
Fig. 4: PAK-mediated pro-inflammatory signalling is required for S. Typhimurium replication within the intestine and for the host response that limits systemic infection.

Data availability

All data generated or analysed during this study are included in this published article (and the Supplementary Information).


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We thank J. Chernoff for providing the PAK1–/– mice and members of the Galán laboratory for careful reading of the manuscript. This work was supported by the National Institute of Allergy and Infectious Diseases grant AI055472 (to J.E.G.).

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Authors and Affiliations



H.S. and J.E.G. designed the research and analysed data. H.S., J.K. and M.L.-T. performed the research. H.S. and J.E.G. wrote the manuscript with input from all the authors.

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Correspondence to Jorge E. Galán.

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Supplementary information

Supplementary Information

Supplementary Figures 1–20, Supplementary Tables 5–7.

Reporting Summary

Supplementary Table 1

LC–MS/MS analyses of CDC42-interacting proteins in uninfected cells.

Supplementary Table 2

LC–MS/MS analyses of CDC42-interacting proteins in S. Typhimurium infected cells.

Supplementary Table 3

LC-MS/MS analyses of PAK1-interacting proteins in uninfected cells.

Supplementary Table 4

LC–MS/MS analyses of PAK1-interacting proteins in S. Typhimurium-infected cells.

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Sun, H., Kamanova, J., Lara-Tejero, M. et al. Salmonella stimulates pro-inflammatory signalling through p21-activated kinases bypassing innate immune receptors. Nat Microbiol 3, 1122–1130 (2018).

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