A manganese-independent aldolase enables Staphylococcus aureus to resist host-imposed metal starvation
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ABSTRACT:
ORGANISM(S): Staphylococcus aureus
PROVIDER: GSE202268 | GEO | 2022/12/19
REPOSITORIES: GEO
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Project description:The preferred carbon source of Staphylococcus aureus and many other pathogens is glucose, and its consumption is critical during infection. However, glucose utilization increases the cellular demand for manganese, a nutrient sequestered by the host as a defense against invading pathogens. Therefore, bacteria must balance glucose metabolism with the increasing demand that metal-dependent processes, such as glycolysis, impose upon the cell. A critical regulator that enables S. aureus to resist nutritional immunity is the ArlRS two-component system. This work revealed that ArlRS regulates the expression of FdaB, a metal-independent fructose 1,6-bisphosphate aldolase. Further investigation revealed that when S. aureus is metal-starved by the host, FdaB functionally replaces the metal-dependent isozyme FbaA, thereby allowing S. aureus to resist host-imposed metal starvation in culture. Although metal-dependent aldolases are canonically zinc-dependent, this work uncovered that FbaA requires manganese for activity and that FdaB protects S. aureus from manganese starvation. Both FbaA and FdaB contribute to the ability of S. aureus to cause invasive disease in wild-type mice. However, the virulence defect of a strain lacking FdaB was reversed in calprotectin-deficient mice, which have defects in manganese sequestration, indicating that this isozyme contributes to the ability of this pathogen to overcome manganese limitation during infection. Cumulatively, these observations suggest that the expression of the metal-independent aldolase FdaB allows S. aureus to alleviate the increased demand for manganese that glucose consumption imposes, and highlights the cofactor flexibility of even established metalloenzyme families. IMPORTANCE Staphylococcus aureus and other pathogens consume glucose during infection. Glucose utilization increases the demand for transition metals, such as manganese, a nutrient that the host limits as a defense mechanism against invading pathogens. Therefore, pathogenic bacteria must balance glucose and manganese requirements during infection. The two-component system ArlRS is an important regulator that allows S. aureus to adapt to both glucose and manganese starvation. Among the genes regulated by ArlRS is the metal-independent fructose 1,6-bisphosphate aldolase fdaB, which functionally substitutes for the metal-dependent isoenzyme FbaA and enables S. aureus to survive host-imposed manganese starvation. Unexpectedly, and differing from most characterized metal-dependent aldolases, FbaA requires manganese for activity. Cumulatively, these findings reveal a new mechanism for overcoming nutritional immunity as well as the cofactor plasticity of even well-characterized metalloenzyme families.
| S-EPMC9973326 | biostudies-literature
Project description:A manganese-independent aldolase enables Staphylococcus aureus to resist host-imposed metal starvation
| PRJNA835310 | ENA
Project description:During infection the host imposes manganese and zinc starvation on invading pathogens. Despite this, Staphylococcus aureus and other successful pathogens remain capable of causing devastating disease. However, how these invaders adapt to host-imposed metal starvation and overcome nutritional immunity remains unknown. We report that ArlRS, a global staphylococcal virulence regulator, enhances the ability of S. aureus to grow in the presence of the manganese-and zinc-binding innate immune effector calprotectin. Utilization of calprotectin variants with altered metal binding properties revealed that strains lacking ArlRS are specifically more sensitive to manganese starvation. Loss of ArlRS did not alter the expression of manganese importers or prevent S. aureus from acquiring metals. It did, however, alter staphylococcal metabolism and impair the ability of S. aureus to grow on amino acids. Further studies suggested that relative to consuming glucose, the preferred carbon source of S. aureus, utilizing amino acids reduced the cellular demand for manganese. When forced to use glucose as the sole carbon source S. aureus became more sensitive to calprotectin compared to when amino acids are provided. Infection experiments utilizing wild type and calprotectin-deficient mice, which have defects in manganese sequestration, revealed that ArlRS is important for disease when manganese availability is restricted but not when this essential nutrient is freely available. In total, these results indicate that altering cellular metabolism contributes to the ability of pathogens to resist manganese starvation and that ArlRS enables S. aureus to overcome nutritional immunity by facilitating this adaptation.
| S-EPMC5130280 | biostudies-literature
Project description:The host restricts the availability of zinc to prevent infection. To overcome this defense, Staphylococcus aureus and Pseudomonas aeruginosa rely on zincophore-dependent zinc importers. Synthesis of the zincophore staphylopine by S. aureus and its import are both necessary for the bacterium to cause infection. In this study, we sought to elucidate how loss of zincophore efflux impacts bacterial resistance to host-imposed zinc starvation. In culture and during infection, mutants lacking CntE, the staphylopine efflux pump, were more sensitive to zinc starvation imposed by the metal-binding immune effector calprotectin than those lacking the ability to import staphylopine. However, disruption of staphylopine synthesis reversed the enhanced sensitivity phenotype of the ΔcntE mutant to calprotectin, indicating that intracellular toxicity of staphylopine is more detrimental than the impaired ability to acquire zinc. Unexpectedly, intracellular accumulation of staphylopine does not increase the expression of metal importers or alter cellular metal concentrations, suggesting that, contrary to prevailing models, the toxicity associated with staphylopine is not strictly due to intracellular chelation of metals. As P. aeruginosa and other pathogens produce zincophores with similar chemistry, our observations on the crucial importance of zincophore efflux are likely to be broadly relevant.IMPORTANCEStaphylococcus aureus and many other bacterial pathogens rely on metal-binding small molecules to obtain the essential metal zinc during infection. In this study, we reveal that export of these small molecules is critical for overcoming host-imposed metal starvation during infection and prevents toxicity due to accumulation of the metal-binding molecule within the cell. Surprisingly, we found that intracellular toxicity of the molecule is not due to chelation of cellular metals.
| S-EPMC7148132 | biostudies-literature
Project description:ArlRS is a two-component regulatory system in Staphylococcus aureus. Here we use RNA-sequencing to compare gene expression in a wild-type USA300 strain and an isogenic arlRS mutant.
2020-04-29 | GSE130887 | GEO
Project description:The human opportunistic pathogen Staphylococcus aureus produces numerous small regulatory RNAs (sRNAs) for which functions are still poorly understood. Here, we focused on an atypical and large sRNA called RsaC. Its length varies between different isolates due to the presence of repeated sequences at the 5' end while its 3' part is structurally independent and highly conserved. Using MS2-affinity purification coupled with RNA sequencing (MAPS) and quantitative differential proteomics, sodA mRNA was identified as a primary target of RsaC sRNA. SodA is a Mn-dependent superoxide dismutase involved in oxidative stress response. Remarkably, rsaC gene is co-transcribed with the major manganese ABC transporter MntABC and, consequently, RsaC is mainly produced in response to Mn starvation. This 3'UTR-derived sRNA is released from mntABC-RsaC precursor after cleavage by RNase III. The mature and stable form of RsaC inhibits the synthesis of the Mn-containing enzyme SodA synthesis and favors the oxidative stress response mediated by SodM, an alternative SOD enzyme using either Mn or Fe as co-factor. In addition, other putative targets of RsaC are involved in oxidative stress (ROS and NOS) and metal homeostasis (Fe and Zn). Consequently, RsaC may balance two interconnected defensive responses, i.e. oxidative stress and metal-dependent nutritional immunity.
| S-EPMC6765141 | biostudies-literature
Project description:Manganese (Mn) is an essential micronutrient critical for the pathogenesis of Staphylococcus aureus, a significant cause of human morbidity and mortality. Paradoxically, excess Mn is toxic, therefore maintaining intracellular Mn homeostasis is required for survival. To identify gene candidates that contribute to manganese detoxification, we compared the transcriptional response of S. aureus cells exposed to 1 mM MnCl2 and those that were untreated.
2019-01-01 | GSE124285 | GEO
Project description:For Staphylococcus aureus it was shown previously that aminocoumarinecoumarin antibiotics such as novobiocin lead to immediate down-regulation of recA expression and thereby inhibition of the SOS response, the mutation frequency and the recombination capacity. Aminocoumarinecoumarin function by inhibition of the ATPase activity of the gyrase subunit B. Here we analysed the global impact of the DNA relaxing agent novobiocin on gene expression in S. aureus. By use of a novobiocin resistant mutant, it became evident that the change in recA expression is due to gyrase inhibition. Microarray analysis and Northern blot hybridization revealed that the expression of a distinct set of genes is increased (e.g. recF-gyrB-gyrA, rib operon and ure operon …)), or decreased (e.g. arlRS, recA, lukA, hlgC, fnbA) by novobiocin. The two-component ArlRS system was previously found to decrease the supercoiling level in S. aureus. Thus, down-regulation of arlRS might in part compensate for the relaxing effect of novobiocin. Novobiocin resulted in down-regulation of several of arlRS repressed target genes in an arl mutant. Global analysis and gene mapping of supercoiling sensitive genes did not give indications that they are clustered in the genome. Promoter fusion assays confirmed that responsiveness of a given gene is intrinsic to the promoter region but independent of the chromosomal location. The results indicate that molecular property of the spacers of a given promoter dictatesa given promoter rather than chromosomal topology dictates the responsiveness towards changes in supercoiling rather than chromosomal topology.
2014-09-08 | GSE50157 | GEO
Project description:For Staphylococcus aureus it was shown previously that aminocoumarinecoumarin antibiotics such as novobiocin lead to immediate down-regulation of recA expression and thereby inhibition of the SOS response, the mutation frequency and the recombination capacity. Aminocoumarinecoumarin function by inhibition of the ATPase activity of the gyrase subunit B. Here we analysed the global impact of the DNA relaxing agent novobiocin on gene expression in S. aureus. By use of a novobiocin resistant mutant, it became evident that the change in recA expression is due to gyrase inhibition. Microarray analysis and Northern blot hybridization revealed that the expression of a distinct set of genes is increased (e.g. recF-gyrB-gyrA, rib operon and ure operon M-bM-^@M-&)), or decreased (e.g. arlRS, recA, lukA, hlgC, fnbA) by novobiocin. The two-component ArlRS system was previously found to decrease the supercoiling level in S. aureus. Thus, down-regulation of arlRS might in part compensate for the relaxing effect of novobiocin. Novobiocin resulted in down-regulation of several of arlRS repressed target genes in an arl mutant. Global analysis and gene mapping of supercoiling sensitive genes did not give indications that they are clustered in the genome. Promoter fusion assays confirmed that responsiveness of a given gene is intrinsic to the promoter region but independent of the chromosomal location. The results indicate that molecular property of the spacers of a given promoter dictatesa given promoter rather than chromosomal topology dictates the responsiveness towards changes in supercoiling rather than chromosomal topology. We analyzed S. aureus global gene expression changes to the treatment of novobiocin
2014-09-08 | E-GEOD-50157 | biostudies-arrayexpress
Project description:The human opportunistic pathogen Staphylococcus aureus has developed multiple strategies to adapt to various environments, to fight and escape the immune system, to spread and persist in host tissues. It is responsible for numerous diseases ranging from benign skin infections to more serious such as endocarditis or septicemia. The pathogenicity is due to the production of a multitude of virulence factors, whose synthesis is finely regulated by a combination of regulatory proteins and small non-coding RNAs (sRNAs). Our study reveals an unexpected function of an atypical sRNA, RsaC, which is at the heart of networks controlling defence responses to oxidative stress, manganese import and nutrition immunity. This work highlights a novel mechanism required for S. aureus to survive into its host.
2019-11-11 | PXD013225 | Pride