Regulation of Staphylococcus aureus MntC Expression and Its Role in Response to Oxidative Stress

Abstract

Staphylococcus aureus is a successful human pathogen that has developed several approaches to evade the immune system, including resistance strategies to prevent oxidative killing by immune cells. One mechanism by which this evasion occurs is by production of superoxide dismutase enzymes, which require manganese as a cofactor. Manganese is acquired by the manganese transporter MntABC. One component of this operon, MntC, has been proposed as a potential vaccine candidate due to its early in vivo expression and its ability to provide protection in preclinical models of staphylococcal infection. In the current study, we interrogate the role of this protein in protecting S. aureus from oxidative stress. We demonstrate that mutation of mntC in a number of invasive S. aureus clinical isolates results in increased sensitivity to oxidative stress. In addition, we show that while downregulation of mntC transcription is triggered upon exposure to physiological concentrations of manganese, MntC protein is still present on the bacterial surface at these same concentrations. Taken together, these results provide insight into the role of this antigen for the pathogen.

Synergy between Nutritional Immunity and Independent Host Defenses Contributes to the Importance of the MntABC Manganese Transporter during Staphylococcus aureus Infection

“…In contrast to those culture-based studies, loss of MntABC resulted in virulence defects in several animal models of infection, implicating this pathway as the dominant Mn import system in the host (12,(42)(43)(44). Although in vitro growth defects associated with loss of MntABC have been reported, those previous studies investigated conditions that are presumed to represent metal-replete environments (42,44). As CP has a greater affinity for Mn than MntC (45), this raises the possibility that MntABC may not be the primary transporter responsible for resisting host-imposed Mn starvation.…”

“…Surprisingly, although loss of MntC, the Mn-recruiting protein of the ABC import pathway, resulted in a modest reduction in superoxide dismutase (SOD) activity, a ΔmntC mutant was not more sensitive to CP in the presence or absence of oxidative stress (12). In contrast to those culture-based studies, loss of MntABC resulted in virulence defects in several animal models of infection, implicating this pathway as the dominant Mn import system in the host (12,(42)(43)(44). Although in vitro growth defects associated with loss of MntABC have been reported, those previous studies investigated conditions that are presumed to represent metal-replete environments (42,44).…”

Associations of pathogen‐specific and host‐specific characteristics with disease outcome in patients with Staphylococcus aureus bacteremic pneumonia

“…These antigens were previously validated as important virulence factors involved in adhesion, evasion of immune responses, cell and tissue damage, biofilm formation and inflammation. [15][16][17][18][19][20][21][22] As shown in Figure 1, patients with S. aureus bacteremic pneumonia had elevated levels of IgGs against eight of nine measured antigens as compared with uninfected control subjects: AT (3.2-fold, P = 0.0002), delta toxin (2.95-fold, P = 0.0003), ClfA (2.51-fold, P = 0.0006), ClfB (1.9-fold, P = 0.01), FnbpA (2.12-fold, P = 0.0042), SdrC (1.74-fold, P = 0.0225), LukAB (3.9-fold, P < 0.0001) and MntC (7.28-fold, P < 0.0001). In contrast, serum S. aureus-specific IgG levels in patients with gram-negative bacteremia (with and without pneumonia) were similar to those in uninfected subjects.…”

Targeting fundamental pathways to disrupt Staphylococcus aureus survival: clinical implications of recent discoveries

“…Diminished manganese uptake renders MntABC mutants highly sensitive to killing by human neutrophils (18) and growth deficient (19). Moreover, MntABC deficiency in invasive clinical isolates similarly renders these strains sensitive to oxidative stress (20). MntC is the manganese-binding surface component of MntABC; it directly competes with host calprotectin, a critical mediator of metal sequestration (21), and vaccination against MntC is protective in a murine model of S. aureus bacteremia (22).…”

“…(B) Numerous critical steps have been identified for the acquisition of host metals by S. aureus. The MntABC transporter delivers manganese, which, among other roles, is a required cofactor for superoxide dismutase (17)(18)(19)(20). α-Hemolysin-mediated (Hla-mediated) RBC lysis liberates host heme, resulting in a bacterial iron source via the Isd system (10-13).…”