Amino acid decarboxylation preserves Salmonella fitness during phagocyte-derived oxidative stress

Successful establishment of infection by non-typhoidal Salmonella depends upon its ability to resist the antimicrobial defenses of the host innate immune response. To withstand the membrane depolarization that potentiates the killing activity of reactive oxygen species (ROS) produced by the phagocyte NADPH oxidase, Salmonella employs metabolic adaptations that maintain intracellular pH homeostasis and membrane energetics. Here, we identify amino acid decarboxylation as a critical determinant of Salmonella virulence and resistance to the oxidative pressures within the host environment. The proton-consuming decarboxylation of L-arginine preserves intracellular ∆pH and enhances Salmonella survival against the bactericidal effects of ROS, while downstream polyamine biosynthesis aids in bacterial recovery following ROS exposure. Polyamines alone cannot substitute for the immediate, protective impact of proton-consuming decarboxylation during oxidative stress killing. Specifically, we show that Salmonella relies on the combined activity of the inducible arginine AdiA and the ornithine SpeF decarboxylases for resistance to oxidative stress, and that this activity is essential for Salmonella virulence during systemic infection. Together, amino acid decarboxylation and polyamine biosynthesis play complementary, but distinct roles in Salmonella adaptation to phagocyte-derived oxidative stress, providing a new framework for understanding how amino acid catabolism influences bacterial survival in the host.

Salmonellae have been causing disease in humans since at least the Neolithic Revolution, yet non-typhoidal Salmonella infections remain a significant public health challenge. The success of Salmonella as a pathogen stems, in part, from its ability to subvert and survive the host response of macrophages. The amino acid L-arginine is critical for Salmonella enterica serovar Typhimurium virulence and resistance to reactive oxygen species produced by the phagocyte NADPH oxidase. The precise mechanisms by which L-arginine fosters oxidative stress resistance have remained unclear. In this report, we demonstrate that Salmonella relies on the proton-consuming decarboxylation of L-arginine and ornithine to promote resistance against the acute cytotoxicity emanating from the phagocyte NADPH oxidase. On the other hand, polyamines synthesized downstream of L-arginine and ornithine decarboxylation aid in the recovery phase. Our findings redefine the physiological role of amino acid decarboxylation, establishing it as a critical defense mechanism against oxidative stress that is functionally distinct from polyamine biosynthesis. By disentangling the regulatory and functional roles of individual decarboxylases, our study clarifies a long-standing ambiguity in the field and highlights how Salmonella exploits complementary metabolic pathways during its adaptation to oxidative stress in the host.