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Marvaud, J.; Bouttier, S.; Saunier, J.; Kansau, I. Role of Flagella during Pathogenesis. Encyclopedia. Available online: https://encyclopedia.pub/entry/55246 (accessed on 15 April 2024).
Marvaud J, Bouttier S, Saunier J, Kansau I. Role of Flagella during Pathogenesis. Encyclopedia. Available at: https://encyclopedia.pub/entry/55246. Accessed April 15, 2024.
Marvaud, Jean-Christophe, Sylvie Bouttier, Johanna Saunier, Imad Kansau. "Role of Flagella during Pathogenesis" Encyclopedia, https://encyclopedia.pub/entry/55246 (accessed April 15, 2024).
Marvaud, J., Bouttier, S., Saunier, J., & Kansau, I. (2024, February 20). Role of Flagella during Pathogenesis. In Encyclopedia. https://encyclopedia.pub/entry/55246
Marvaud, Jean-Christophe, et al. "Role of Flagella during Pathogenesis." Encyclopedia. Web. 20 February, 2024.
Role of Flagella during Pathogenesis
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Clostridioides difficile is an important pathogen for humans with a lead in nosocomial infection, but it is also more and more common in communities. The disruption of the gut microbiota by an antibiotic treatment enables the colonization of the gut by C. difficile and provides a metabolic niche for the bacteria with a transient increase in the nutrient availability. The flagellar apparatus possibly contributes to its settling in the following ways: (a) by providing force-driven motility to nutrients, (b) by promoting adherence to host cells, (c) by promoting biofilm formation, and (d) by acting as an immunomodulator by triggering proinflammatory cytokines through the Toll-like receptor 5 (TLR5) signaling pathway.

Clostridioides difficile flagellum motility

1. Motility to Nutrients

The C. difficile genome contains a single predicted methyl-accepting chemotaxis protein within a putative chemotaxis operon, suggesting that C. difficile may regulate its flagellar motility in response to nutrients. Notably, Courson et al. demonstrated that the epidemic C. difficile strain R20291 exhibits regulated motility in the presence of components of intestinal mucus or glucose by modulating its swimming velocity and not its tumble frequency [1].
The motility of C. difficile in diverse media have been poorly studied. The mucosal layer in the lower intestine presents a certain viscosity that could impact the mobility of the bacteria and the contribution of the flagella. Indeed, with diverse C. difficile strains, Schwanbeck et al. characterized the swimming of the motile fraction in media with polyvinylpyrrolidone, a 360 MDa long-chained polymer, or with mucins, both of which can form gel-like structures. They observed that C. difficile displayed an unusual motility phenotype for peritrichous bacteria, with alternating, short, back-and-forth run phases of 0.5–3 bacterial lengths, corresponding to ~3–15 μm [2]. Battaglioli et al. studied the relevance of a rich environment in proline found during dysbiosis to C. difficile colonization. They showed the scavenging of proline by the bacteria, and that, with a strain mutated on an enzyme essential in the proline fermentation pathway, the colonization was drastically reduced [3]. Interestingly, a minimal medium defined by Schwanbeck et al. implied the presence of proline for the maximal and stable swimming motility of the bacterium. The amino acid cysteine, as well as a carbohydrate source, were indispensable [4].

2. Adherence to Host Cells

The role of the flagella in the adhesion of C. difficile to the epithelium is controversial. Tasteyre et al. showed that C. difficile crude flagella extracted as well as purified recombinant FliD and FliC proteins bound to immobilized axenic mouse cecal mucus but not to porcine stomach mucin in immunodot analyses [5]. Further, Dingle et al., using 630-strain mutants without flagella (mutated on the flagellin or on the flagellar cap protein), demonstrated that they adhered more efficiently to epithelial Caco-2 cells than the wild-type strain [6]. The complete lack of flagellin modification also significantly reduces the adhesion of C. difficile to Caco-2 intestinal epithelial cells [7]. But Baban et al. showed that flagellar mutants of strain R20291 adhered less than the parental strain in vitro [8]. They raised the question of the importance of the flagella in vivo and showed that a paralyzed mutant of strain R20191 outcompeted the aflagellated mutant in colonization and adherence, confirming the role of flagella in the adhesion process. However, flagella and motility were not needed for successful colonization with the strain 630Δerm, as there was no difference between the wild-type and flagellar mutants in diverse mouse models. It seems that the need for flagellation for adhesion and colonization depends on the strain and its regulation mechanisms of the flagellar locus.
Moreover, in another animal model largely used to study CDI, a hamster model, FliC or FliD were nonessential for cecal colonization, and flagellar mutant strains were more virulent, indicating either that flagella are unnecessary for virulence or that the repression of motility may be a pathogenic strategy employed by C. difficile in hamsters [6].

3. Role in Biofilm

The flagellum plays an important role in biofilm formation. For example, in Pseudomonas aeruginosa, flagella are not necessary for the initial attachment or biofilm formation, but the cell appendages play roles in the biofilm development and structure [9].
C. difficile, like other nosocomial pathogens, has also been found to produce biofilms in vitro and biofilm-like structures in vivo on the intestinal mucosal surfaces of infected mice [10]. Also, C. difficile biofilm is suspected to be involved in the persistence of the bacteria and responsible for the recurrence often found in C. difficile infections [11].
In C. difficile planktonic cells, low c-di-GMP resulted in high flagellum expression, while, during the biofilm formation, c-di-GMP in higher concentrations induced a decrease in the flagellum expression, as it was noticed for the flagellin gene fliC, which is significantly decreased in biofilm samples relative to planktonic samples [12][13]. However, Ðapa et al. observed a significant decrease in the biofilm accumulation for a fliC mutant compared to the wild-type strain after several days but not at earlier times. They suggested that flagella may be more important for later stages in biofilm formation [14]. In nature, biofilms are known to be usually formed by multiple microbial species. Engevik et al. reported that the addition of Fusobacterium nucleatum enhanced C. difficile biofilm formation and extracellular polysaccharide production, and that the interaction of the two bacteria resulted in aggregation. Interestingly, the proteins responsible for the aggregation were found with RadD, an arginine-dependent adhesin for F. nucleatum, and with the flagellin FliC for C. difficile [15].

4. Acting as Immunomodulators by Triggering Proinflammatory Cytokines through the Toll-like Receptor 5 (TLR5) Signaling Pathway

Flagellin belongs to molecules containing a pathogen-associated molecular pattern (PAMP), which is recognized by the Toll-like receptor 5 (TLR5). The pathogenesis of C. difficile early in the course of infection is predominantly characterized by acute intestinal inflammation mediated by the inducible innate immune response. Indirectly, Jarchum et al. showed the potential role of flagellin in the development of the immune response. In fact, they demonstrated that the administration of purified Salmonella-derived flagellin prevents intestinal damage during C. difficile infection [16]. Yoshino et al. showed that FliC induced the activation of NF-κB in HEK293T cells, as well as p38 mitogen-activated protein kinase, and promoted the production of interleukin-8 and CCL20 of two other intestinal epithelial cell lines, HT29 cells and Caco-2 cells [17]. Also, Batah et al. showed that the interaction of flagellin and TLR5 predominantly activates NF-κB and, to a lesser degree, the MAPK pathways, leading to the up-regulation of the proinflammatory gene expression and the synthesis of proinflammatory mediators [18]. TLR5 is predominately present on the basolateral side of the epithelial cells, and it has been hypothesized that the toxins TcdB and/or TcdA of C. difficile allow the flagellin to reach TLR5 by disturbing the integrity of the cellular junctions. Such synergy of action was found by the authors of [19].
Flagellin could also be an immunomodulator via its recognition by a specific intracellular inflammasome. Chebly et al. assessed whether the flagellin of C. difficile, an extracellular bacterium, could internalize into epithelial cells and activate the NLRC4 inflammasome. This was demonstrated by confocal microscopy with the observation of the internalization of FliC tagged with a green fluorescent protein (GFP) into the intestinal Caco-2/TC7 cell line. Further, the activation of NLRC4, the cleavage of pro-caspase-1 into two subunits, p20 and p10, and also the cleavage of gasdermin D, were shown, suggesting that the caspase-1 and NLRC4 inflammasome activation by FliC contributes to the inflammatory process of C. difficile infection [20].

References

  1. Courson, D.S.; Pokhrel, A.; Scott, C.; Madrill, M.; Rinehold, A.J.; Tamayo, R.; Cheney, R.E.; Purcell, E.B. Single Cell Analysis of Nutrient Regulation of Clostridioides (Clostridium) difficile Motility. Anaerobe 2019, 59, 205–211.
  2. Schwanbeck, J.; Oehmig, I.; Groß, U.; Zautner, A.E.; Bohne, W. Clostridioides difficile Single Cell Swimming Strategy: A Novel Motility Pattern Regulated by Viscoelastic Properties of the Environment. Front. Microbiol. 2021, 12, 715220.
  3. Battaglioli, E.J.; Hale, V.L.; Chen, J.; Jeraldo, P.; Ruiz-Mojica, C.; Schmidt, B.A.; Rekdal, V.M.; Till, L.M.; Huq, L.; Smits, S.A.; et al. Clostridioides difficile Uses Amino Acids Associated with Gut Microbial Dysbiosis in a Subset of Patients with Diarrhea. Sci. Transl. Med. 2018, 10, eaam7019.
  4. Schwanbeck, J.; Oehmig, I.; Groß, U.; Bohne, W. Clostridioides difficile Minimal Nutrient Requirements for Flagellar Motility. Front. Microbiol. 2023, 14, 1172707.
  5. Tasteyre, A.; Barc, M.C.; Collignon, A.; Boureau, H.; Karjalainen, T. Role of FliC and FliD Flagellar Proteins of Clostridium difficile in Adherence and Gut Colonization. Infect. Immun. 2001, 69, 7937–7940.
  6. Dingle, T.C.; Mulvey, G.L.; Armstrong, G.D. Mutagenic Analysis of the Clostridium difficile Flagellar Proteins, FliC and FliD, and Their Contribution to Virulence in Hamsters. Infect. Immun. 2011, 79, 4061–4067.
  7. Valiente, E.; Bouché, L.; Hitchen, P.; Faulds-Pain, A.; Songane, M.; Dawson, L.F.; Donahue, E.; Stabler, R.A.; Panico, M.; Morris, H.R.; et al. Role of Glycosyltransferases Modifying Type B Flagellin of Emerging Hypervirulent Clostridium difficile Lineages and Their Impact on Motility and Biofilm Formation. J. Biol. Chem. 2016, 291, 25450–25461.
  8. Baban, S.T.; Kuehne, S.A.; Barketi-Klai, A.; Cartman, S.T.; Kelly, M.L.; Hardie, K.R.; Kansau, I.; Collignon, A.; Minton, N.P. The Role of Flagella in Clostridium difficile Pathogenesis: Comparison between a Non-Epidemic and an Epidemic Strain. PLoS ONE 2013, 8, e73026.
  9. Klausen, M.; Heydorn, A.; Ragas, P.; Lambertsen, L.; Aaes-Jørgensen, A.; Molin, S.; Tolker-Nielsen, T. Biofilm Formation by Pseudomonas Aeruginosa Wild Type, Flagella and Type IV Pili Mutants. Mol. Microbiol. 2003, 48, 1511–1524.
  10. Soavelomandroso, A.P.; Gaudin, F.; Hoys, S.; Nicolas, V.; Vedantam, G.; Janoir, C.; Bouttier, S. Biofilm Structures in a Mono-Associated Mouse Model of Clostridium difficile Infection. Front. Microbiol. 2017, 8, 2086.
  11. Vuotto, C.; Donelli, G.; Buckley, A.; Chilton, C. Clostridium difficile Biofilm. In Updates on Clostridium difficile in Europe: Advances in Microbiology, Infectious Diseases and Public Health Volume 8; Mastrantonio, P., Rupnik, M., Eds.; Advances in Experimental Medicine and Biology; Springer International Publishing: Cham, Switzerland, 2018; pp. 97–115. ISBN 978-3-319-72799-8.
  12. Purcell, E.B.; McKee, R.W.; McBride, S.M.; Waters, C.M.; Tamayo, R. Cyclic Diguanylate Inversely Regulates Motility and Aggregation in Clostridium difficile. J. Bacteriol. 2012, 194, 3307–3316.
  13. Maldarelli, G.A.; Piepenbrink, K.H.; Scott, A.J.; Freiberg, J.A.; Song, Y.; Achermann, Y.; Ernst, R.K.; Shirtliff, M.E.; Sundberg, E.J.; Donnenberg, M.S.; et al. Type IV Pili Promote Early Biofilm Formation by Clostridium difficile. Pathog. Dis. 2016, 74, ftw061.
  14. Ðapa, T.; Leuzzi, R.; Ng, Y.K.; Baban, S.T.; Adamo, R.; Kuehne, S.A.; Scarselli, M.; Minton, N.P.; Serruto, D.; Unnikrishnan, M. Multiple Factors Modulate Biofilm Formation by the Anaerobic Pathogen Clostridium difficile. J. Bacteriol. 2013, 195, 545–555.
  15. Engevik, M.A.; Danhof, H.A.; Auchtung, J.; Endres, B.T.; Ruan, W.; Bassères, E.; Engevik, A.C.; Wu, Q.; Nicholson, M.; Luna, R.A.; et al. Fusobacterium Nucleatum Adheres to Clostridioides difficile via the RadD Adhesin to Enhance Biofilm Formation in Intestinal Mucus. Gastroenterology 2021, 160, 1301–1314.e8.
  16. Jarchum, I.; Liu, M.; Lipuma, L.; Pamer, E.G. Toll-like Receptor 5 Stimulation Protects Mice from Acute Clostridium difficile Colitis. Infect. Immun. 2011, 79, 1498–1503.
  17. Yoshino, Y.; Kitazawa, T.; Ikeda, M.; Tatsuno, K.; Yanagimoto, S.; Okugawa, S.; Yotsuyanagi, H.; Ota, Y. Clostridium difficile Flagellin Stimulates Toll-like Receptor 5, and Toxin B Promotes Flagellin-Induced Chemokine Production via TLR5. Life Sci. 2013, 92, 211–217.
  18. Batah, J.; Denève-Larrazet, C.; Jolivot, P.-A.; Kuehne, S.; Collignon, A.; Marvaud, J.-C.; Kansau, I. Clostridium difficile Flagella Predominantly Activate TLR5-Linked NF-κB Pathway in Epithelial Cells. Anaerobe 2016, 38, 116–124.
  19. Batah, J.; Kobeissy, H.; Bui Pham, P.T.; Denève-Larrazet, C.; Kuehne, S.; Collignon, A.; Janoir-Jouveshomme, C.; Marvaud, J.-C.; Kansau, I. Clostridium difficile Flagella Induce a Pro-Inflammatory Response in Intestinal Epithelium of Mice in Cooperation with Toxins. Sci. Rep. 2017, 7, 3256.
  20. Chebly, H.; Marvaud, J.-C.; Safa, L.; Elkak, A.K.; Kobeissy, P.H.; Kansau, I.; Larrazet, C. Clostridioides difficile Flagellin Activates the Intracellular NLRC4 Inflammasome. Int. J. Mol. Sci. 2022, 23, 12366.
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