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Identification of linear epitopes on the flagellar proteins of Clostridioides difficile.

ABSTRACT: Clostridioides difficile (C. difficile) is an opportunistic anaerobic bacterium that causes severe diseases of the digestive tract of humans and animals. One of the possible methods of preventing C. difficile infection is to develop a vaccine. The most promising candidates for vaccine antigens are the proteins involved in the adhesion phenomena. Among them, the FliC and FliD are considered to be suitable candidates. In this paper, the FliC and FliD protein polypeptide epitopes were mapped in silico and by using PEPSCAN procedure. We identified four promising epitopes: ¹¹⁷QRMRTLS¹²³, ²⁰⁵MSKAG²⁰⁹ of FliC and ²²⁶NKVAS²³⁰, ³⁰⁶TTKKPKD³¹² of FliD protein. We showed that ¹¹⁷QRMRTLS¹²³ sequence is not only located in TLR5-binding and activating region, as previously shown, but forms an epitope recognized by C. difficile-infected patients' antibodies. ²⁰⁵MSKAG²⁰⁹ is a C. difficile-unique, immunogenic sequence that forms an exposed epitope on the polymerized flagella structure which makes it a suitable vaccine antigen. ²²⁶NKVAS²³⁰ and ³⁰⁶TTKKPKD³¹² are well exposed and possess potential protective properties according to VaxiJen analysis. Our results open the possibility to use these epitopes as suitable anti-C. difficile vaccine antigens.

SUBMITTER: Razim A

PROVIDER: S-EPMC8113543 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The response to iron limitation of several bacteria is regulated by the ferric uptake regulator (Fur). The Fur-regulated transcriptional, translational and metabolic networks of the Gram-positive, pathogen Clostridioides difficile were investigated by a combined RNA sequencing, proteomic, metabolomic and electron microscopy approach. At high iron conditions (760 g/l) the C. difficile fur mutant displayed a growth deficiency compared to wild type C. difficile cells. Several iron transporters were found induced by Fur regulation during low iron (11 g/l) conditions. The major adaptation to low iron conditions was observed for the central energy metabolism. Most ferredoxin-dependent amino acid fermentations were found significantly down regulated (had, etf, acd, grd, trx, bdc, hbd). The substrates of these pathways phenylalanine, leucine, glycine and some initial intermediates (phenylpyruvate, oxo-isocaproate, 3-hydroxy-butanoyl-CoA, crotonyl-CoA) were found accumulated, while some end product like isocaproate and butanoate were found reduced. Flavodoxin (fldX) formation and riboflavin biosynthesis (rib) were found enhanced, most likely to replace the missing ferredoxins. Proline reductase (prd), the corresponding ion pumping RNF complex (rnf) and the reaction product 5-aminovalerate were significantly enhanced. An ATP forming ATPase (atpCDGAHFEB,) of the F0F1-type was found induced while the formation of a V-type, mostly proton-pumping, ATP-consuming ATPase (atpDBAFCEKI, was decreased. The [Fe-S] enzyme-dependent pyruvate formate lyase (pfl), formate dehydrogenase (fdh) and hydrogenase (hyd) branch of glucose utilization and glycogen biosynthesis (glg) were significantly reduced, leading to an accumulation of glucose and pyruvate. The formation of [Fe-S] enzyme carbon monoxide dehydrogenase (coo) was inhibited. An intensive remodeling of the cell wall was observed most likely to increase antibiotic resistance. Polyamine biosynthesis (spe) was found induced leading to an accumulation of spermine, spermidine and putrescine. The fur mutant lost most of its flagella. Finally, the CRISPR/Cas and a prophage encoding operon were downregulated. Fur binding sites were found upstream of 20 of the regulated genes. Overall, adaptation to low iron conditions in C. difficile focused on an increase of iron import, significant decrease in metabolic iron utilization and protection during the complex transition.

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Identification of linear epitopes on the flagellar proteins of Clostridioides difficile.

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