Salmonella enterica serovar typhimurium effectors spiA and spiC promote replication by modulating iron metabolism and oxidative stress.

Salmonella enterica serovar Typhimurium (S. Typhimurium) poses a major threat to the health and safety of animal-derived foods worldwide. Recently, we have reported that S. Typhimurium uses iron to promote its own proliferation, leading to iron metabolism disorders. However, the mechanism by which S. Typhimurium induces iron metabolism disturbances remains unclear. In this study, we found that the S. Typhimurium effectors spiA and spiC promote the expression of iron regulatory protein 2 (IRP2), transferrin receptor 1 (TfR1) and divalent metal transporter protein 1 (DMT1) and inhibit the expression of ferroportin after transfection with the recombinant plasmids pEGFP-C1-spiA and pEGFP-C1-spiC, which in turn contributes to the accumulation of iron and oxidative stress. Furthermore, we aimed to verify the role of these two effector proteins in S. Typhimurium-induced disorders of iron metabolism. We constructed spiA or spiC mutant strains and their corresponding complementation strains. Our data showed that when spiA or spiC was knocked out, the upregulation of iron metabolism proteins (IRP2, TfR1 and DMT1), the accumulation of iron and oxidative stress caused by the wild-type strain were clearly alleviated in vitro and in vivo, which plays a key role in reducing the intracellular replication of S. Typhimurium and attenuating pathological damage to the liver and ileum of mice. Our findings highlighted that S. Typhimurium induces the disruption of iron metabolism via the virulence factors spiA and spiC, thereby facilitating S. Typhimurium proliferation and causing oxidative damage to the liver and ileum, which provides prospective insights into the search for effective antimicrobial targets for the defense against salmonellosis.