SUMMARY Neutrophils hinder bacterial growth by a variety of antimicrobial mechanisms, including the production of reactive oxygen species and the secretion of proteins that sequester nutrients essential to microbes. A major player in this process is calprotectin, a host protein that exerts antimicrobial activity by chelating zinc and manganese. Here we show that the intestinal pathogen Salmonella enterica serovar Typhimurium employs specialized metal transporters to evade calprotectin sequestration of manganese, allowing the bacteria to outcompete commensals and thrive in the inflamed gut. The pathogen’s ability to acquire manganese in turn promotes function of SodA and KatN, enzymes that utilize the metal as a cofactor to detoxify reactive oxygen species. This manganese-dependent SodA activity allows the bacteria to evade neutrophil killing mediated by calprotectin and reactive oxygen species. Thus, manganese acquisition enables S. Typhimurium to overcome host antimicrobial defenses and support its competitive growth in the intestine.

Transition metal ions are essential micronutrients for all living organisms. In mammals, these ions are often protein-bound and sequestered within cells, limiting their availability to microbes. Moreover, in response to infection, mammalian hosts further reduce the availability of metal nutrients by activating epithelial cells and recruiting neutrophils, both of which release metal-binding proteins with antimicrobial function. Microorganisms, in turn, have evolved sophisticated systems to overcome these limitations and acquire the metal ions essential for their growth. Here we review some of the mechanisms employed by the host and by pathogenic microorganisms to compete for transition metal ions, with a discussion of how evading “nutritional immunity” benefits pathogens. Furthermore, we provide new insights on the mechanisms of host-microbe competition for metal ions in the mucosa, particularly in the inflamed gut.

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Treatment of intracellular bacterial pathogens with antibiotic therapy often requires a long course of multiple drugs. A barrier to developing strategies that enhance antibiotic efficacy against these pathogens is our poor understanding of the intracellular nutritional environment that maintains bacterial persistence. The intracellular pathogen Brucella abortus survives and replicates preferentially in alternatively activated macrophages (AAMs); however, knowledge of the metabolic adaptations promoting exploitation of this niche is limited. Here we show that one mechanism promoting enhanced survival in AAMs is a shift in macrophage arginine utilization from production of nitric oxide (NO) to biosynthesis of polyamines, induced by interleukin 4 (IL-4)/IL-13 treatment. Production of polyamines by infected AAMs promoted both intracellular survival of B. abortus and chronic infection in mice, as inhibition of macrophage polyamine synthesis or inactivation of the putative putrescine transporter encoded by potIHGF reduced both intracellular survival in AAMs and persistence in mice. These results demonstrate that increased intracellular availability of polyamines induced by arginase-1 expression in IL-4/IL-13-induced AAMs promotes chronic persistence of B. abortus within this niche and suggest that targeting of this pathway may aid in eradicating chronic infection.

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