Spermine suppresses <i>Salmonella</i> -induced macrophage innate immune responses via inhibition of the cGAS-STING and TLR4 pathways

ABSTRACT Polyamines integrate metabolism with innate immunity; however, their antibacterial roles remain unresolved. Here, we show that spermine suppresses innate immune responses against Salmonella enterica serovar Typhimurium infection in macrophages. Exogenous spermine blunted pro-inflammatory responses and increased intracellular bacterial burden in vitro and in vivo . Pharmacologic depletion or back-conversion of endogenous polyamines enhanced pro-inflammatory responses, revealing an intrinsic brake. Mechanistically, spermine promoted B-to-Z conformational switching of bacterial genomic DNA, which attenuated cGAS-STING activation; chloroquine or cerium chloride modulations validated DNA topology control. Genetic and pharmacologic dissection indicated that either TLR4 or cGAS-STING is sufficient for spermine’s suppression, whereas their combined blockade abolished it. These findings highlight coordinated immune evasion at the metabolism-DNA interface, offering therapeutic targets for infection control. IMPORTANCE In our research, we set out to understand how a small, naturally occurring molecule called spermine shapes the first line of defense against Salmonella , a common cause of foodborne illness. We discovered that when Salmonella infects our immune cells, it cleverly causes the levels of spermine to drop. When we experimentally added spermine back, we found that it hampered the immune response, allowing the bacteria to thrive. Delving deeper, we uncovered a two-pronged strategy used by spermine. It not only dampens a primary alarm pathway that detects bacteria on the cell surface but also employs a more subtle tactic inside the cell. Spermine changes the physical shape of the bacterial DNA, twisting it into a form that our internal surveillance systems, like the cGAS-STING pathway, cannot easily recognize. This disguise allows the bacteria to go undetected. Our findings reveal a fascinating mechanism of immune evasion and suggest that controlling spermine levels could be a promising therapeutic strategy for either boosting our defenses against Salmonella infections or calming inflammatory diseases.