Carbon storage regulator CsrA plays important roles in multiple virulence-associated processes of Clostridium difficile

Gu, Huawei; Qi, Huayu; Chen, Shuyi; Shi, Kun; Wang, Haiying; Wang, Jufang

doi:10.1016/j.micpath.2018.05.052

Cited by 16 publications

(22 citation statements)

References 39 publications

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“…The ferric uptake regulator Fur also directly influences glycine reduction and hydrogen formation from pyruvate in response to low iron condition (Figure 2; Ho and Ellermeier, 2015; Berges et al., 2018). Finally, the small regulatory RNA CsrA serves as carbon storage regulator influencing the genes of glycogen mobilization (Figure 2; Gu et al., 2018). Obviously, a complex regulatory network headed by the pleiotropic regulators CcpA and CodY co-regulates metabolism and toxin production.…”

Section: Regulation Of C Difficile Energy Metabolismmentioning

confidence: 99%

Metabolism the Difficile Way: The Key to the Success of the Pathogen Clostridioides difficile

2019

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Strains of Clostridioides difficile cause detrimental diarrheas with thousands of deaths worldwide. The infection process by the Gram-positive, strictly anaerobic gut bacterium is directly related to its unique metabolism, using multiple Stickland-type amino acid fermentation reactions coupled to Rnf complex-mediated sodium/proton gradient formation for ATP generation. Major pathways utilize phenylalanine, leucine, glycine and proline with the formation of 3-phenylproprionate, isocaproate, butyrate, 5-methylcaproate, valerate and 5-aminovalerate. In parallel a versatile sugar catabolism including pyruvate formate-lyase as a central enzyme and an incomplete tricarboxylic acid cycle to prevent unnecessary NADH formation completes the picture. However, a complex gene regulatory network that carefully mediates the continuous adaptation of this metabolism to changing environmental conditions is only partially elucidated. It involves the pleiotropic regulators CodY and SigH, the known carbon metabolism regulator CcpA, the proline regulator PrdR, the iron regulator Fur, the small regulatory RNA CsrA and potentially the NADH-responsive regulator Rex. Here, we describe the current knowledge of the metabolic principles of energy generation by C. difficile and the underlying gene regulatory scenarios.

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Section: Regulation Of C Difficile Energy Metabolismmentioning

confidence: 99%

Metabolism the Difficile Way: The Key to the Success of the Pathogen Clostridioides difficile

2019

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“…For example in B. subtilis, there is an increase of hag gene expression after inhibition of csrA [26]. In C. acetobutylicum, csrA is involved in the regulation of the assembly of flagella [8], whereas in C. difficile, it has been reported that the overexpression of csrA resulted in a defect in the flagella generating a decrease in motility [13]. CsrA is a highly conserved RNA binding protein whose main role could be the regulation of flagellar assembly, suggesting that it is performing the same function in B. licheniformis, since the csrA gene shows a remarkable phylogenetic distribution and is restricted mainly to those bacterial genomes encoding flagellin [28].…”

Section: Discussionmentioning

confidence: 99%

“…However, in Gram positive bacteria, it has been reported only in C. acetobutylicum and C. difficile [8,12,13]. In B. subtilis CsrA regulates the synthesis of flagellin by inhibiting the hag gene translation, although the antagonist is the protein Fliw [12].…”

Section: Introductionmentioning

confidence: 99%

“…In C. acetobutylicum, CsrA is involved in flagellum regulation, central carbon metabolism, sporulation and the control of transport systems such as iron, oligopeptides and the phosphotransferase system [8]. In C. difficile, it also controls multiple virulence processes including toxin production, motility and adhesion, as well as in carbon metabolism [13].…”

Section: Introductionmentioning

confidence: 99%

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Carbon Storage Regulator A (csrA) Gene Regulates Motility and Growth of Bacillus licheniformis in the Presence of Hydrocarbons

Angel¹,

Segura²,

Jiménez³

et al. 2020

Microbiology and Biotechnology Letters

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The global carbon storage regulator (Csr) system is conserved in bacteria and functions as a regulator in the exponential and stationary phases of growth in batch culture. The Csr system plays a role in the central carbon metabolism, virulence, motility, resistance to oxidative stress, and biofilm formation. Although the Csr was extensively studied in Gram negative bacteria, it has been reported only in the control of motility in Bacillus subtilis among Gram positive bacteria. The goal of this study was to explore the role of the csrA gene of Bacillus licheniformis M2-7 on motility and the bacterial ability to use hydrocarbons as carbon source. We deleted the csrA gene of B. licheniformis M2-7 using the plasmid pCsr-L, harboring the spectinomycin cassette obtained from the plasmid pHP45-omega2. Mutants were grown on culture medium supplemented with 2% glucose or 0.1% gasoline and motility was assessed by electron microscopy. We observed that CsrA negatively regulates motility by controlling the expression of the hag gene and the synthesis of flagellin. Notably, we showed the ability of B. licheniformis to use gasoline as a unique carbon source. Our results demonstrated that CsrA is an indispensable regulator for the growth of B. licheniformis M2-7 on gasoline.

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“…CsrA typically binds to multiple specific sites that are located nearby or overlapping the cognate Shine-Dalgarno (SD) sequence in the target transcripts (16, 17). The roles of CsrA in Bacillus subtilis have been also reported (17-20). Yakhnin et al (17) first reported that CsrA in B. subtilis can regulate translation initiation of the flagellin (hag) by preventing ribosome binding to the hag transcript.…”

Section: Introductionmentioning

confidence: 94%

FliW and CsrA govern flagellin (FliC) synthesis and play pleiotropic roles in virulence and physiology of Clostridioides difficile R20291

Zhu

Wang

2021

Preprint

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Clostridioides difficile is a Gram-positive, spore-forming, and toxin-producing anaerobe that can cause nosocomial antibiotic-associated intestinal disease. In C. difficile, the expression of flagellar genes is coupled to toxin gene regulation and bacterial colonization and virulence. The flagellin FliC is responsible for pleiotropic gene regulation during in vivo infection. However, how fliC expression is regulated is unclear. In Bacillus subtilis, flagellin homeostasis and motility are coregulated by flagellar assembly factor FliW, Flagellin Hag (FliC homolog), and CsrA (Carbon storage regulator A), which is referred to as partner-switching mechanism "FliW-CsrA-Hag". In this study, we characterized FliW and CsrA functions by deleting or overexpressing fliW, csrA, and fliW-csrA in C. difficile R20291. We showed that both fliW deletion or csrA overexpression in R20291, and csrA complementation in R20291ΔWA (fliW-csrA codeletion) dramatically decreased FliC production, however, fliC gene transcription was unaffected. While suppression of fliC translation by csrA overexpression was mostly relieved when fliW was coexpressed, and no significant difference in FliC production was detected when only fliW was complemented in R20291ΔWA. Further, loss of fliW led to increased biofilm formation, cell adhesion, toxin production, and pathogenicity in a mouse model of C. difficile infection (CDI), while fliW-csrA codeletion decreased toxin production and mortality in vivo. Taken together, these data suggest that CsrA negatively modulates fliC expression and FliW indirectly affects fliC expression through inhibition of CsrA post-transcriptional regulation, which seems similar to the "FliW-CsrA-Hag" switch in B. subtilis. Our data also suggest that "FliW-CsrA-fliC/FliC" can regulate many facets of C. difficile R20291 pathogenicity.

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Carbon storage regulator CsrA plays important roles in multiple virulence-associated processes of Clostridium difficile

Cited by 16 publications

References 39 publications

Metabolism the Difficile Way: The Key to the Success of the Pathogen Clostridioides difficile

Metabolism the Difficile Way: The Key to the Success of the Pathogen Clostridioides difficile

Carbon Storage Regulator A (csrA) Gene Regulates Motility and Growth of Bacillus licheniformis in the Presence of Hydrocarbons

FliW and CsrA govern flagellin (FliC) synthesis and play pleiotropic roles in virulence and physiology of Clostridioides difficile R20291

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