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

Radin, Jana N.; Zhu, Jamie; Brazel, Erin B.; McDevitt, Christopher A.; Kehl-Fie, Thomas E.

doi:10.1128/iai.00642-18

Cited by 34 publications

(39 citation statements)

References 87 publications

(189 reference statements)

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“…While evidence showing a major reduction in the levels of intracellular Mn pools and the most severe phenotypes was restricted to the ΔsloC ΔmntH double mutant, deletion of sloC alone significantly impaired growth of S. mutans in the chemically defined media lacking both Mn and Fe as well as in the presence of calprotectin. This finding is in agreement with previous observations made with S. aureus showing that the staphylococcal SloABC homologue, named MntABC, was more important than MntH during infection and that loss of mntABC alone resulted in a virulence defect (45). The apparent more prominent role of SloABC than of MntH seen under these specific conditions is likely due to its dual function in Fe and Mn uptake.…”

Section: Discussionsupporting

confidence: 92%

“…Though the enzyme is cambialistic (capable of using either Mn or Fe), studies have shown that the Mn-bound SOD is much more active than Fe-bound SOD (63). Evidence has suggested that restriction of the Mn-dependent SOD by metal sequestration is an important aspect of the contribution of calprotectin to nutritional immunity for S. aureus pathogenesis and that the staphylococcal MntH and MntABC manganese transporters are critical for infection (45,58).…”

Section: Discussionmentioning

confidence: 99%

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Manganese Uptake, Mediated by SloABC and MntH, Is Essential for the Fitness of Streptococcus mutans

Kajfasz

Katrak

Ganguly

et al. 2020

mSphere

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Early epidemiological studies implicated manganese (Mn) as a possible caries-promoting agent, while laboratory studies have indicated that manganese stimulates the expression of virulence-related factors in the dental pathogen Streptococcus mutans. To better understand the importance of manganese homeostasis to S. mutans pathophysiology, we first used RNA sequencing to obtain the global transcriptional profile of S. mutans UA159 grown under Mn-restricted conditions. Among the most highly expressed genes were those of the entire sloABC operon, encoding a dual iron/manganese transporter, and an uncharacterized gene, here mntH, that codes for a protein bearing strong similarity to Nramp-type transporters. While inactivation of sloC, which encodes the lipoprotein receptor of the SloABC system, or of mntH alone had no major consequence for the overall fitness of S. mutans, simultaneous inactivation of sloC and mntH (ΔsloC ΔmntH) impaired growth and survival under Mn-restricted conditions, including in human saliva or in the presence of calprotectin. Further, disruption of Mn transport resulted in diminished stress tolerance and reduced biofilm formation in the presence of sucrose. These phenotypes were markedly improved when cells were provided with excess Mn. Metal quantifications revealed that the single mutant strains contained intracellular levels of Mn similar to those seen with the parent strain, whereas Mn was nearly undetectable in the ΔsloC ΔmntH strain. Collectively, these results reveal that SloABC and MntH work independently and cooperatively to promote cell growth under Mn-restricted conditions and that maintenance of Mn homeostasis is essential for the expression of major virulence attributes in S. mutans. IMPORTANCE As transition biometals such as manganese (Mn) are essential for all forms of life, the ability to scavenge biometals in the metal-restricted host environment is an important trait of successful cariogenic pathobionts. Here, we showed that the caries pathogen Streptococcus mutans utilizes two Mn transport systems, namely, SloABC and MntH, to acquire Mn from the environment and that the ability to maintain the cellular levels of Mn is important for the manifestation of characteristics that associate S. mutans with dental caries. Our results indicate that the development of strategies to deprive S. mutans of Mn hold promise in the combat against this important bacterial pathogen.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Manganese Uptake, Mediated by SloABC and MntH, Is Essential for the Fitness of Streptococcus mutans

Kajfasz

Katrak

Ganguly

et al. 2020

mSphere

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“…In particular, the effect of CP on iron uptake by S. aureus varies tremendously depending on the medium because extensive inhibition of iron uptake by S. aureus was observed in LB, whereas negligible change occurred in Tris/TSB. Along these lines, metal inventory data from studies of the competition between CP and S. aureus showed that CP only reduced manganese acquisition by S. aureus strain Newman following growth in TSB or Tris/TSB (20,50). Taken together, these data indicate the importance of considering the effect of growth conditions on bacterial metabolism in studies of CP and, more broadly, nutritional immunity.…”

Section: Calprotectin Induces Iron Starvation In P Aeruginosamentioning

confidence: 86%

The human innate immune protein calprotectin induces iron starvation responses in Pseudomonas aeruginosa

Zygiel

Nelson

Brewer

et al. 2019

Journal of Biological Chemistry

160

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Most microbial pathogens have a metabolic iron requirement, necessitating the acquisition of this nutrient in the host. In response to pathogen invasion, the human host limits iron availability. Although canonical examples of nutritional immunity are host strategies that limit pathogen access to Fe(III), little is known about how the host restricts access to another biologically relevant oxidation state of this metal, Fe(II). This redox species is prevalent at certain infection sites and is utilized by bacteria during chronic infection, suggesting that Fe(II) withholding by the host may be an effective but unrecognized form of nutritional immunity. Here, we report that human calprotectin (CP; S100A8/S100A9 or MRP8/MRP14 heterooligomer) inhibits iron uptake and induces an iron starvation response in Pseudomonas aeruginosa cells by sequestering Fe(II) at its unusual His 6 site. Moreover, under aerobic conditions in which the Fe(III) oxidation state is favored, Fe(II) withholding by CP was enabled by (i) its ability to stabilize this redox state in solution and (ii) the production and secretion of redox-active, P. aeruginosa-produced phenazines, which reduce Fe(III) to Fe(II). Analyses of the interplay between P. aeruginosa secondary metabolites and CP indicated that Fe(II) withholding alters P. aeruginosa physiology and expression of virulence traits. Lastly, examination of the effect of CP on cell-associated metal levels in diverse human pathogens revealed that CP inhibits iron uptake by several bacterial species under aerobic conditions. This work implicates CP-mediated Fe(II) sequestration as a component of nutritional immunity in both aerobic and anaerobic milieus during P. aeruginosa infection.

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“…Deletion of these genes did not affect growth in metal sufficient media (38). μg/mL adenine) and 62% calprotectin buffer (20 mM Tris pH 7.5, 100 mM NaCl, 3 mM CaCl 2 ), and 0-240 μg/mL recombinant calprotectin (65,91). At 8 hours post-inoculation, growth was assessed by measuring optical density (OD 600nm ) and plating serial dilutions to quantitate CFU.…”

Section: Bacterial Strains and Growth Conditions Streptococcus Agalamentioning

confidence: 99%

Identification of zinc-dependent mechanisms used by Group BStreptococcusto overcome calprotectin-mediated stress

Burcham

Breton

Radin

et al. 2020

Preprint

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Nutritional immunity is an elegant host mechanism used to starve invading pathogens of necessary nutrient metals. Calprotectin, a metal binding protein, is produced abundantly by neutrophils and is found in high concentrations within inflammatory sites during infection. Group B Streptococcus (GBS) colonizes the gastrointestinal and female reproductive tracts and is commonly associated with severe invasive infections in newborns such as pneumonia, sepsis, and meningitis. Though GBS infections induce robust neutrophil recruitment and inflammation, the dynamics of GBS and calprotectin interactions remain unknown. Here we demonstrate that disease and colonizing isolate strains exhibit susceptibility to metal starvation by calprotectin. We constructed a mariner transposon (Krmit) mutant library in GBS and identified 258 genes that contribute to surviving calprotectin stress. Nearly 20% of all underrepresented mutants following treatment with calprotectin, are predicted metal transporters, including known zinc systems. As calprotectin binds zinc with picomolar affinity, we investigated the contribution of GBS zinc uptake to overcoming calprotectin-imposed starvation. Quantitative RT-PCR revealed a significant upregulation of genes encoding zinc-binding proteins, adcA, adcAII, and lmb, following calprotectin exposure, while growth in calprotectin revealed a significant defect for a global zinc acquisition mutant (ΔadcAΔadcAIIΔlmb) compared to the GBS WT strain. Further, mice challenged with the ΔadcAΔadcAIIΔlmb mutant exhibited decreased mortality and significantly reduced bacterial burden in the brain compared to mice infected with WT GBS; this difference was abrogated in calprotectin knockout mice. Collectively, these data suggest that GBS zinc transport machinery are important for combatting zinc-chelation by calprotectin and establishing invasive disease.ImportanceGBS asymptomatically colonizes the female reproductive tract but is a common causative agent of meningitis. GBS meningitis is characterized by extensive infiltration of neutrophils, carrying high concentrations of calprotectin, a metal chelator. To persist within inflammatory sites and cause invasive disease, GBS must circumvent host starvation attempts. Here, we identified global requirements for GBS survival during calprotectin challenge, including known and putative systems involved in metal ion transport. We characterized the role of zinc import in tolerating calprotectin stress in vitro, and in a mouse model of infection. We observed that a global zinc-uptake mutant was less virulent compared to the parental GBS strain and found calprotectin knockout mice to be equally susceptible to infection by WT and mutant strains. These findings suggest that calprotectin production at the site of infection results in a zinc-limited environment and reveals the importance of GBS metal homeostasis to invasive disease.

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

Cited by 34 publications

References 87 publications

Manganese Uptake, Mediated by SloABC and MntH, Is Essential for the Fitness of Streptococcus mutans

Manganese Uptake, Mediated by SloABC and MntH, Is Essential for the Fitness of Streptococcus mutans

The human innate immune protein calprotectin induces iron starvation responses in Pseudomonas aeruginosa

Identification of zinc-dependent mechanisms used by Group BStreptococcusto overcome calprotectin-mediated stress

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