Manganese acquisition is essential for virulence of<i>Enterococcus faecalis</i>

Colomer-Winter, Cristina; Flores-Mireles, Ana L.; Baker, Shannon P.; Frank, Kristi L.; Lynch, Aaron J L; Hultgren, Scott J.; Kitten, Todd; Lemos, José A.

doi:10.1101/323832

Cited by 14 publications

(19 citation statements)

References 74 publications

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“…Some bacteria even have multiple Mn uptake systems. Enterococcus faecalis, for example, has three Mn uptake systems, at least two of which are dedicated to Mn uptake (Colomer-Winter et al, 2018). The knockout of all three systems resulted in poor growth.…”

Section: Impact Of Selected Genes On Growthmentioning

confidence: 99%

Adaptation of the Alphaproteobacterium Rhodobacter sphaeroides to stationary phase

McIntosh

Eisenhardt

Remes

et al. 2019

Environmental Microbiology

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Summary Exhaustion of nutritional resources stimulates bacterial populations to adapt their growth behaviour. General mechanisms are known to facilitate this adaptation by sensing the environmental change and coordinating gene expression. However, the existence of such mechanisms among the Alphaproteobacteria remains unclear. This study focusses on global changes in transcript levels during growth under carbon‐limiting conditions in a model Alphaproteobacterium, Rhodobacter sphaeroides, a metabolically diverse organism capable of multiple modes of growth including aerobic and anaerobic respiration, anaerobic anoxygenic photosynthesis and fermentation. We identified genes that showed changed transcript levels independently of oxygen levels during the adaptation to stationary phase. We selected a subset of these genes and subjected them to mutational analysis, including genes predicted to be involved in manganese uptake, polyhydroxybutyrate production and quorum sensing and an alternative sigma factor. Although these genes have not been previously associated with the adaptation to stationary phase, we found that all were important to varying degrees. We conclude that while R. sphaeroides appears to lack a rpoS‐like master regulator of stationary phase adaptation, this adaptation is nonetheless enabled through the impact of multiple genes, each responding to environmental conditions and contributing to the adaptation to stationary phase.

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Section: Impact Of Selected Genes On Growthmentioning

confidence: 99%

Adaptation of the Alphaproteobacterium Rhodobacter sphaeroides to stationary phase

McIntosh

Eisenhardt

Remes

et al. 2019

Environmental Microbiology

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“…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%

“…This suspicion was then confirmed by findings that the Δ sloC Δ mntH strain could not grow in unsupplemented BHI after a second passage (data not shown). To assess the metal requirements of the mutant strains in a more controlled fashion, growth of the parent UA159 and mutant strains was also monitored in the chemically-defined FMC medium (Fe- and Mn-replete, Table 2), and in FMC depleted of Mn (Mn < 90 nM), Fe (Fe < 90 nM), or both [27]. In complete FMC, growth of all mutant strains was indistinguishable from that of the parent strain (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%

“…Beyond the oral environment, the ability to scavenge Mn in environments in which this metal is known to be restricted, such as the bloodstream and internal organs, has proven to be an essential trait for bacterial pathogens. In fact, a growing number of Mn transport systems have been identified as major virulence factors, including examples where loss of Mn transporters rendered organisms closely related to S. mutans , such as Streptococcus pneumoniae and Enterococcus faecalis, virtually avirulent in animal infection models [27, 28]. In S. mutans , previous characterization of pathways associated with Mn homeostasis has been restricted to the metalloregulator SloR and the ABC-type transporter SloABC [29–33].…”

Section: Introductionmentioning

confidence: 99%

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

Kajfasz

Katrak

Ganguly

et al. 2019

Preprint

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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 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.

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Enterococcus faecalismanganese exporter MntE alleviates manganese toxicity and is required for mouse gastrointestinal colonization

Lam

Wong

Chong

et al. 2020

Preprint

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26Bacterial pathogens encounter a variety of nutritional environments in the human host, 27 including nutrient metal restriction and overload. Uptake of manganese (Mn) is essential for 28 Enterococcus faecalis growth and virulence; however, it is not known how this organism 29 prevents Mn toxicity. In this study, we examine the role of the highly conserved MntE 30 transporter in E. faecalis Mn homeostasis and virulence. We show that inactivation of mntE 31 results in growth restriction in the presence of excess Mn, but not other metals, demonstrating 32 its specific role in Mn detoxification. Upon growth in the presence of excess Mn, an mntE 33 mutant accumulates intracellular Mn, iron (Fe), and magnesium (Mg), supporting a role for 34 MntE in Mn and Fe export, and a role for Mg in offsetting Mn toxicity. Growth of the mntE 35 mutant in excess Fe also results in increased levels of intracellular Fe, but not Mn or Mg, 36 providing further support for MntE in Fe efflux. Inactivation of mntE in the presence of 37 excess iron also results in the upregulation of glycerol catabolic genes and enhanced biofilm 38 growth, and addition of glycerol is sufficient to augment biofilm growth for both the mntE 39 mutant and its wild type parental strain, demonstrating that glycerol availability significantly 40 enhances biofilm formation. Finally, we show that mntE contributes to infection of the 41 antibiotic-treated mouse gastrointestinal (GI) tract, suggesting that E. faecalis encounters 42 excess Mn in this niche. Collectively, these findings demonstrate that the manganese exporter 43 MntE plays a crucial role in E. faecalis metal homeostasis and virulence. 44 45 nutritional immunity (1, 4-6). To counteract these host-mediated defences, many bacterial 51 pathogens including Enterococci encode dedicated systems to acquire Mn. 52 53Bacteria encode conserved ABC and NRAMP-family transporters for manganese uptake (1, 54 2). In Enterococcus faecalis, three manganese uptake systems have been described: the ABC-55 type transporter encoded by efaCBA and two NRAMP transporters encoded by mntH1 and 56 mntH2 (7). These three Mn transport systems are functionally redundant since deletion of all 57 three transporter systems (efaCBA, mntH1, mntH2) is required to abrogate intracellular Mn 58 accumulation, rendering the triple mutant severely impaired in growth (7). Furthermore, 59 deletion of both efaCBA and mntH2, or all three transporters together results in attenuated 60 colonization in rabbit endocarditis and mouse catheter-associated urinary tract infection 61 (CAUTI) models (7). Together these observations demonstrate that the ability to acquire Mn 62 is essential for E. faecalis virulence. 64In contrast to Mn influx mechanisms that have been characterized in E. faecalis, Mn export 65 pathways have not been described. The contribution of Mn export to bacterial pathogenesis 66 and virulence has been demonstrated for some bacterial species (8-15) and is dependent on 67 two widely characterized classes of exporters -MntE, a cat...

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Manganese acquisition is essential for virulence ofEnterococcus faecalis

Cited by 14 publications

References 74 publications

Adaptation of the Alphaproteobacterium Rhodobacter sphaeroides to stationary phase

Adaptation of the Alphaproteobacterium Rhodobacter sphaeroides to stationary phase

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

Enterococcus faecalismanganese exporter MntE alleviates manganese toxicity and is required for mouse gastrointestinal colonization

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