A streptococcal NRAMP homologue is crucial for the survival of <scp><i>S</i></scp><i>treptococcus agalactiae</i> under low pH conditions

Shabayek, Sarah; Bauer, Richard J.; Mauerer, Stefanie; Mizaikoff, Boris; Spellerberg, Barbara

doi:10.1111/mmi.13335

Cited by 35 publications

(41 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Phagocytic cells sequester iron to improve the clearance of pathogens, including bacteria (45). Other transition metals, specifically manganese and zinc, are also actively sequestered by the host during infection in order to hinder bacterial growth (46), and a Mn 2ϩ /Fe 2ϩ transporter has been shown to play a role in GBS intracellular survival in macrophages (47). We compared the survival of the S. agalactiae wild-type strain and its isogenic ⌬lmb ⌬adcA ⌬adcAII mutant strain in the widely used murine macrophage cell line RAW 264.7.…”

Section: Resultsmentioning

confidence: 99%

The Adc/Lmb System Mediates Zinc Acquisition in Streptococcus agalactiae and Contributes to Bacterial Growth and Survival

et al. 2016

View full text Add to dashboard Cite

The Lmb protein of Streptococcus agalactiae is described as an adhesin that binds laminin, a component of the human extracellular matrix. In this study, we revealed a new role for this protein in zinc uptake. We also identified two Lmb homologs, AdcA and AdcAII, redundant binding proteins that combine with the AdcCB translocon to form a zinc-ABC transporter. Expression of this transporter is controlled by the zinc concentration in the medium through the zinc-dependent regulator AdcR. Triple deletion of lmb, adcA, and adcAII, or that of the adcCB genes, impaired growth and cell separation in a zinc-restricted environment. Moreover, we found that this Adc zinc-ABC transporter promotes S. agalactiae growth and survival in some human biological fluids, suggesting that it contributes to the infection process. These results indicated that zinc has biologically vital functions in S. agalactiae and that, under the conditions tested, the Adc/Lmb transporter constitutes the main zinc acquisition system of the bacterium. IMPORTANCEA zinc transporter, composed of three redundant binding proteins (Lmb, AdcA, and AdcAII), was characterized in Streptococcus agalactiae. This system was shown to be essential for bacterial growth and morphology in zinc-restricted environments, including human biological fluids. S treptococcus agalactiae (group B streptococcus [GBS]) is aGram-positive commensal bacterium of the human gastrointestinal and uro-genital tracts. GBS carriage is mostly asymptomatic in healthy adults, and this bacterium is detected in the vagina of approximatively 30% of pregnant women. Maternal carriage is the main source of transmission to neonates, in which S. agalactiae can cause invasive infections (pneumonia, septicemia, and meningitis), with an overall mortality rate of approximately 10% (1, 2). GBS is also an emergent pathogen among the elderly and in adults with underlying diseases (1, 3).The ability of GBS to colonize different niches and cause infection is multifactorial, and many virulence-associated proteins have been identified (4, 5). Binding of GBS adhesins to components of the extracellular matrix constitutes a crucial first step in the process of infection (6-9). Among them, the Lmb protein has been identified as a GBS receptor for laminin, a glycosylated multidomain protein found in all human tissues (10). The gene encoding Lmb is located on a transposon with the scpB and sht genes, which encode a C5a peptidase and a histidine triad protein, respectively (11, 12). The lmb promoter region is a hot spot for the integration of two mobile genetic elements. One of them is associated with increased expression of lmb, resulting in increased binding of strains harboring the transposon to laminin (13). It has also been shown that Lmb may promote bacterial invasion in human brain microvascular endothelial cell lines (14).Lmb is clustered by sequence homology as a metal-binding receptor. Indeed, Lmb has strong homology with the zinc-binding proteins AdcA and Lbp of other streptococcal species (15, 16). Th...

show abstract

Section: Resultsmentioning

confidence: 99%

The Adc/Lmb System Mediates Zinc Acquisition in Streptococcus agalactiae and Contributes to Bacterial Growth and Survival

et al. 2016

View full text Add to dashboard Cite

show abstract

“…At this time, the dominant role of MntH2 in CAUTI is less clear. Recent work in Streptococcus agalactiae showed that the Nramp-type MntH is induced at low pH and facilitates macrophage and acid stress survival [60]. However, in the experiments reported herein, urine pH of infected mice remained stable at ~ 6.5 over the infection period (data not shown), suggesting that transcriptional induction of mntH2 in urine cannot be attributed to a low pH response.…”

Section: Discussionmentioning

confidence: 57%

Manganese acquisition is essential for virulence ofEnterococcus faecalis

Colomer-Winter

Flores-Mireles

Baker

et al. 2018

Preprint

View full text Add to dashboard Cite

Manganese (Mn) is an essential micronutrient that is not readily available to pathogens during infection due to an active host defense mechanism known as nutritional immunity. To overcome this nutrient restriction, bacteria utilize high-affinity transporters that allow them to compete with host metal-binding proteins. Despite the established role of Mn in bacterial pathogenesis, little is known about the relevance of Mn in the pathophysiology of E. faecalis. Here, we identified and characterized the major Mn acquisition systems of E. faecalis. We discovered that the ABC-type permease EfaCBA and two Nramp-type transporters, named MntH1 and MntH2, work collectively to promote cell growth under Mn-restricted conditions. The simultaneous inactivation of EfaCBA, MntH1 and MntH2 (ΔefaΔmntH1ΔmntH2 strain) led to drastic reductions (>95%) in intracellular Mn content, severe growth defects in body fluids (serum and urine) ex vivo, significant loss of virulence in Galleria mellonella, and virtually complete loss of virulence in rabbit endocarditis and murine catheter-associated urinary tract infection (CAUTI) models. Despite the functional redundancy of EfaCBA, MntH1 and MntH2 under in vitro or ex vivo conditions and in the invertebrate model, dual inactivation of efaCBA and mntH2 (ΔefaΔmntH2 strain) was sufficient to prompt maximal sensitivity to calprotectin, a Mn- and Zn-chelating host antimicrobial protein, and for the loss of virulence in mammalian models. Interestingly, EfaCBA appears to play a prominent role during systemic infection, whereas MntH2 was more important during CAUTI. The different roles of EfaCBA and MntH2 in these sites could be attributed, at least in part, to the differential expression of efaA and mntH2 in cells isolated from hearts or from bladders. Collectively, this study demonstrates that Mn acquisition is essential for the pathogenesis of E. faecalis and validates Mn uptake systems as promising targets for the development of new antimicrobials.

show abstract

“…The Smu770c protein shared 76% identity with the S. agalactiae (Group B Streptococcus ) MntH and 60 and 54% identity with E. faecalis MntH1 and MntH2 proteins, respectively. Of note, the S. agalactiae MntH and E. faecalis MntH1 and MntH2 have been recently assigned a role in Mn uptake [27, 34]. Other genes upregulated in the absence of Mn were several belonging to the CRISPR2- cas operon ( smu1753c - smu1764c ; >4-fold), as well as 3 of 4 genes from the smu995-998 operon (>2-fold), recently shown to code for an Fe transport system [35].…”

Section: Resultsmentioning

confidence: 99%

“…The ability to withstand acid stress is a major virulence attribute of S. mutans that sets it apart as a cariogenic organism when compared to less aciduric commensal streptococci. Recently, the S. agalactiae MntH was shown to play a crucial role in low pH survival [34]. To probe the significance of Mn in acid stress, cultures of parent and mutant strains were grown in FMC adjusted to pH 7.0 (control) or pH 5.5 (acid stress) containing the concentration of Mn indicated in the original recipe (130 μM Mn), or with the minimal concentration of Mn (3 μM Mn) that sustains optimal growth of the Δ sloC Δ mntH strain in FMC (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Although Nramp-type proteins have been shown to transport different types of trace metal ions such as Fe, Mn and Zn [37], recent studies with S. agalactiae and E. faecalis revealed that the closest homologs of the S. mutans MntH are primarily involved in Mn transport [27, 34]. This appears to be the case for the S. mutans MntH as the intracellular levels of Fe or Zn were not affected by mntH inactivation (Fig.…”

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

Manganese uptake, mediated by SloABC and MntH, is essential for the fitness ofStreptococcus mutans

Kajfasz

Katrak

Ganguly

et al. 2019

Preprint

View full text Add to dashboard Cite

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 the entire sloABC operon, encoding a dual iron/manganese transporter, and an uncharacterized gene, herein 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 mntH alone had no major consequence on the overall fitness of S. mutans, simultaneous inactivation of sloC and mntH (ΔsloCΔmntH) 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 contain similar intracellular levels of Mn as the parent strain, whereas Mn was nearly undetectable in the ΔsloCΔmntH strain. Collectively, these results reveal that SloABC and MntH work independently and cooperatively to promote cell growth under Mn-restricted conditions, and that mauitanence of Mn homeostasis is essential for the expression of major virulence attributes in S. mutans.IMPORTANCEAs trace biometals such as manganese (Mn) are important for all forms of life, the ability to regulate biometals availability during infection is an essential trait of successful bacterial pathogens. 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.

show abstract

A streptococcal NRAMP homologue is crucial for the survival of Streptococcus agalactiae under low pH conditions

Cited by 35 publications

References 70 publications

The Adc/Lmb System Mediates Zinc Acquisition in Streptococcus agalactiae and Contributes to Bacterial Growth and Survival

The Adc/Lmb System Mediates Zinc Acquisition in Streptococcus agalactiae and Contributes to Bacterial Growth and Survival

Manganese acquisition is essential for virulence ofEnterococcus faecalis

Manganese uptake, mediated by SloABC and MntH, is essential for the fitness ofStreptococcus mutans

Contact Info

Product

Resources

About