Managing Manganese: The Role of Manganese Homeostasis in Streptococcal Pathogenesis

Abstract

Pathogenic streptococci require manganese for survival in the host. In response to invading pathogens, the host recruits nutritional immune effectors at infection sites to withhold manganese from the pathogens and control bacterial growth. The manganese scarcity impairs several streptococcal processes including oxidative stress defenses, de novo DNA synthesis, bacterial survival, and virulence. Emerging evidence suggests that pathogens also encounter manganese toxicity during infection and manganese excess impacts streptococcal virulence by manganese mismetallation of non-cognate molecular targets involved in bacterial antioxidant defenses and cell division. To counter host-imposed manganese stress, the streptococcal species employ a sophisticated sensory system that tightly coordinates manganese stress-specific molecular strategies to negate host induced manganese stress and proliferate in the host. Here we review the molecular details of host-streptococcal interactions in the battle for manganese during infection and the significance of streptococcal effectors involved to bacterial pathophysiology.

Keywords: bacterial virulence; manganese homeostasis; manganese toxicity; manganese uptake; nutritional immunity; streptococcal infection.

FIGURE 1

Manganese (Mn) homeostasis during streptococcal infections. During infection, neutrophils release calprotectin (CP) at infection sites (left panel). CP sequesters Mn from the invading pathogen to inhibit streptococcal growth. The intracellular Mn deficiency impairs the activity of Mn-dependent superoxide dismutases (SOD) and ribonucleotide reductases (RNR), which leads to defective antioxidant defenses against superoxide (O²⁻) and de novo DNA synthesis, respectively. The CP-imposed Mn deficiency is sensed by Mn-sensing metalloregulator, MtsR, and the Mn-free MtsR relieves the repression of ABC family Mn importer mtsABC. The Mn uptake during nutrient-limiting growth conditions in streptococci is mediated primarily by ABC transporters. In some streptococcal species, secondary transporters belonging to NRAMP- and ZIP-family transporters are also involved in Mn acquisition. During Mn sufficiency (middle panel), MtsR binds to Mn, interacts with promoters, and represses the expression of target genes including mtsABC. The optimal Mn levels in the cytosol promotes the activity of SOD and RNR. During Mn toxicity (right panel), the Mn efflux pump MntE detoxifies bacterial cytosol of excess Mn and promotes streptococcal survival. In the absence of MntE, high cytosolic Mn levels lead to mismetallation of peroxide sensing regulator (PerR) with Mn and results in defective antioxidant responses. Furthermore, Mn mismetallated PhpP phosphatase dephosphorylates cell division kinases StkP and MapZ, which causes improper cell division and altered bacterial cell morphologies.