Spic, a member of the ETS family of transcription factors, has diverse functions. In embryonic stem cells (ESCs), it marks ground state pluripotency, regulating one-carbon metabolism and histone methylation by controlling the flux of S-adenosyl methionine to S-adenosyl-L-homocysteine, thus modulating H3R17me2 and H3K4me3 histone marks [1]. In macrophages, it is induced by Toll-like receptor (TLR) signaling via a nuclear factor κB (NF-κB)-dependent mechanism, downregulating pro-inflammatory cytokines and promoting iron efflux [2].

In Salmonella, SpiC, a protein of T3SS2, is essential for the survival of Salmonella within macrophages and plays a vital role in its pathogenesis. A Salmonella Pullorum spiC mutant shows proper virulence, high immune protection, and can be administered orally, making it a desirable live attenuated Salmonella vaccine candidate [4,5]. SpiC is required for the secretion of Salmonella Pathogenicity Island 2 type III secretion system proteins and may target the function of mammalian Hook3 protein to alter cellular trafficking and prevent phagosome-lysosome fusion [3,6]. In zebrafish, Spic guides the in-situ generation of metaphocytes from local progenitors, and metaphocytes are the major IL-22BP-producing cells essential for barrier immunity [7].

In summary, Spic is crucial in multiple biological processes such as pluripotency regulation in ESCs, immune response and iron metabolism in macrophages, and pathogenesis of Salmonella. The study of Spic using genetic models like the Salmonella spiC mutant has provided insights into its role in disease-related processes, highlighting its potential as a target for vaccine development and understanding disease mechanisms.