Manganese Utilization in Salmonella Pathogenesis: Beyond the Canonical Antioxidant Response

Abstract

The metal ion manganese (Mn2+) is equally coveted by hosts and bacterial pathogens. The host restricts Mn2+ in the gastrointestinal tract and Salmonella-containing vacuoles, as part of a process generally known as nutritional immunity. Salmonella enterica serovar Typhimurium counteract Mn2+ limitation using a plethora of metal importers, whose expression is under elaborate transcriptional and posttranscriptional control. Mn2+ serves as cofactor for a variety of enzymes involved in antioxidant defense or central metabolism. Because of its thermodynamic stability and low reactivity, bacterial pathogens may favor Mn2+-cofactored metalloenzymes during periods of oxidative stress. This divalent metal catalyzes metabolic flow through lower glycolysis, reductive tricarboxylic acid and the pentose phosphate pathway, thereby providing energetic, redox and biosynthetic outputs associated with the resistance of Salmonella to reactive oxygen species generated in the respiratory burst of professional phagocytic cells. Combined, the oxyradical-detoxifying properties of Mn2+ together with the ability of this divalent metal cation to support central metabolism help Salmonella colonize the mammalian gut and establish systemic infections.

Temporal profiling ofSalmonellatranscriptional dynamics during macrophage infection using a comprehensive reporter library

“…4D ). Our findings are consistent with adaptive regulation of manganese levels by S. Tm in response to host Mn 2+ sequestration in the SCV 63 .…”

The small protein MntS evolved from a signal peptide and acquired a novel function regulating manganese homeostasis inEscherichia coli

“…Bacteria harbor two main types of high-affinity Mn importers, MntH, a member of the NRAMP family, and the ABC cassette importer SitABCD/MntABC (29,33,34). Strains lacking Mn importers show sensitivity to ROS, metabolic limitations, and reduced virulence (25,35). At least five classes of dedicated Mn exporters are present across bacteria, loss of which causes sensitivity to high Mn via mismetallation of critical proteins and often also causes decreased virulence (10,29,30,36).…”

The small protein MntS evolved from a signal peptide and acquired a novel function regulating manganese homeostasis in Escherichia coli

“…Bacteria harbor two main types of high‐affinity Mn importers: MntH, a member of the NRAMP family, and the ABC‐cassette importer SitABCD/MntABC (Bartsevich & Pakrasi, 1995; Bosma et al., 2021; Kehres et al., 2002). Strains lacking Mn importers show sensitivity to ROS, metabolic limitations, and reduced virulence (Juttukonda & Skaar, 2015; Uppalapati & Vazquez‐Torres, 2022). At least five classes of dedicated Mn exporters are present across bacteria, loss of which causes sensitivity to high Mn via mismetallation of critical proteins and often also causes decreased virulence (Bosma et al., 2021; Martin et al., 2017; Martin & Waters, 2022; Waters, 2020).…”

“…Due to these essential roles, many pathogenic and symbiotic bacteria require Mn to survive in eukaryotic host tissues (Davies & Walker, 2007;Juttukonda & Skaar, 2015;Lisher & Giedroc, 2013;Papp-Wallace & Maguire, 2006). Other bacteria require Mn for cellular differentiation and energy production (Gralnick & Newman, 2007;Jakubovics & Jenkinson, 2001;Kehres & Maguire, 2003;Vinyard et al, 2013). However, despite its beneficial functions, excess Mn can be toxic, likely by displacing other metals and rendering key proteins inactive (Bosma et al, 2021;Chandrangsu et al, 2017;Martin et al, 2015Martin et al, , 2017Martin & Waters, 2022;Pi et al, 2020).…”

“…Mn helps catalyze diverse chemical reactions in all cells and is important for certain redox reactions and sugar-phosphate-using enzymes, such as specific kinases and phosphatases (Chan et al, 2000;Martin et al, 2017;Nicastro et al, 2022). Mn is also necessary for processes such as the innate immune response, cyclic dinucleotide signaling, phage defense systems, stress-related signal transduction, carbohydrate metabolism, and photosynthesis (Galperin & Chou, 2022;Kehres & Maguire, 2003;Martin et al, 2017;Nicastro et al, 2022;Rostol et al, 2021;Steinchen et al, 2021;Tal et al, 2021;Vinyard et al, 2013;Wang et al, 2018;Wiedenheft et al, 2009;Yan et al, 2015).…”