Elucidating the Molecular Mechanisms of Host Susceptibility to Salmonella Typhimurium Infection by IFN-I Signaling

Abstract

Salmonella enterica serovar Typhimurium (ST) is considered a non-typhoidal strain of Salmonella, which causes progressive diseases in susceptible mice, resembling typhoid-like fever. Salmonella infection occurs due to the ingestion of contaminated food and water supplies and is a major public health concern. In immunocompromised individuals, this strain can be fatal, with reports of an estimated 2 million deaths each year. This makes understanding the molecular mechanisms behind ST infection of vital importance. Type I interferons (IFN-I) are crucial in the immune response, but their role against bacterial infections remains elusive. While IFN-I signaling is critical for antiviral immunity, we show that IFN-I signaling promotes susceptibility to ST infection. Despite reduced innate immune pathways such as TLR and IFNγ signaling, Ifnar1⁻ᐟ⁻ BMDMs exhibit enhanced resistance against ST, indicating the involvement of non-canonical protective mechanisms. We find that the induction of interferon-stimulated genes by IFN-I signaling suppresses protein synthesis, which limits antimicrobial activity during ST infection. In contrast, Ifnar1⁻ᐟ⁻ BMDMs display increased protein synthesis and metabolic activity, supporting improved intracellular control of ST. Notably, Irf9⁻ᐟ⁻ BMDMs display increased and sustained STAT1 signaling while maintaining this metabolically active state, resulting in enhanced survival and resistance compared to Ifnar1⁻ᐟ⁻ mice. Together, these findings demonstrate that IFN-I signaling drives translational repression to restrict immunometabolic responses necessary for controlling ST infection.