Salmonella Enteritidis GalE Protein Inhibits LPS-Induced NLRP3 Inflammasome Activation

Microbial infection can trigger the assembly of inflammasomes and promote secretion of cytokines, such as IL-1 beta and IL-18. It is well-known that Salmonella modulates the activation of NLRC4 (NLR family CARD domain-containing protein 4) and NLRP3 (NLR family pyrin domain-containing 3) inflammasomes, however the mechanisms whereby Salmonella avoids or delays inflammasome activation remain largely unknown. Therefore, we used Salmonella Enteritidis C50336 Delta fliC transposon library to screen for genes involved in modulating inflammasomes activation. The screen revealed the galactose metabolism-related gene galE to be essential for inflammasome activation. Here, we found that inflammasome activation was significantly increased in J774A.1 cells or wild-type bone marrow-derived macrophages (BMDMs) during infection by Delta fliC Delta galE compared to cells infected with Delta fliC. Importantly, we found that secretion of IL-1 beta was Caspase-1-dependent, consistent with canonical NLRP3 inflammasome activation. Furthermore, the virulence of Delta fliC Delta galE was significantly decreased compared to Delta fliC in a mouse model. Finally, RNA-seq analysis showed that multiple signaling pathways related to the inflammasome were subject to regulation by GalE. Taken together, our results suggest that GalE plays an important role in the regulatory network of Salmonella evasion of inflammasome activation.

Automated summary

The GalE gene in Salmonella plays a crucial role in modulating inflammasome activation, affecting multiple signaling pathways. Deletion of the GalE gene leads to increased inflammasome activation during Salmonella infection, and the virulence of the Delta fliC Delta galE strain is significantly decreased.