Clostridium difficile infection pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.

Overview

Spores of C. difficile are transmitted via the fecal-oral route to the human host. Spore ingestion may be community-acquired (soil and food) or healthcare-associated (hospitals and clinics). Following ingestion, the acid-resistant spores of C. difficile are able to survive the human gastric acidity. C. difficile does not result in clinical manifestations in the majority of cases, whereby normal GI flora resists the growth of C. difficile, and the host immune responses adequately clear the infection before the development of clinical manifestations. However, in susceptible patients, C. difficile releases 2 major virulence factors: Exotoxins A and B (TcdA and TcdB), which act synergically and mediate adhesion to the colonic mucosa, luminal fluid accumulation, and development of pseudomembranous colitis. These toxins are able to glycosylate Rho GTPase (involved in actin cytoskeleton) and cause the formation of abnormal G-actin (leading to characteristic rounding of cells). Additionally, they stimulate macrophage-induced cytokine production and subsequent neutrophilic infiltration to the site of inflammation, which in part contributes to the disruption of the intestinal barrier and the development of clinical manifestations associated with the infection. On gross examination, colonic pseudomembranes with yellow colored plaque formation are typical. On microscopic examination, erosions within colonic crypts or formation of mushroom-like exudates with hemorrhage and necrosis are characteristic features.

Pathophysiology

Transmission

  • Spores of C. difficile are transmitted via the fecal-oral route to the human host.
  • Spore ingestion may be community-acquired (soil and food) or healthcare-associated (hospitals and clinics).
  • C. difficile spores are heat-, acid-, and antibiotic-resistant.

Pathogenesis

  • Both C. difficile virulence strain and host susceptibility factors are needed for the development of clinical manifestations.
  • Following ingestion, the acid-resistant spores of C. difficile are able to survive the human gastric acidity.
  • The spores germinate to the vegetative form in the small intestine and eventually colonize in the large intestine among susceptible patients (e.g. recent history of antibiotic administration with antibiotic-induced disruption of the normal GI flora). In contrast, the normal GI flora in a healthy patient prevents the growth of C. difficile (colonization resistance phenomenon), and adequate immune responses clear the infection even before clinical manifestations develop.
  • In susceptible patients, C. difficile releases 2 major virulence factors: Exotoxins A and B (TcdA and TcdB), both of which mediate the development of pseudomembranous colitis.
Exotoxins A and B are cytotoxic virulence factors that are able to glycosylate and inactivate Rho GTPases and cause colonocyte death and loss of intestinal barrier.
In the majority of individuals, the toxin production is countered by adequate host antitoxin responses.
Among susceptible patients, however, the infectious injury is extensive, resulting in diarrhea and colitis.
Following the development of clinical manifestations, host immune responses may be either adequate (leading to complete resolution of the infection) or inadequate (leading to recurrence of clinical manifestations).

Virulence Factors

  • In susceptible patients, C. difficile releases 2 major virulence factors: Exotoxins A and B (TcdA and TcdB), both of which mediate the development of pseudomembranous colitis.
  • Not all strains of C. difficile are equally virulent.[1][2]
  • The virulence of an individual strain is directly associated with the amount of toxin A and B produced.[1]
Toxin A mass is 308 kDa, whereas toxin B mass is 269 kDa.
Although both toxins may be expressed from a single promoter, each toxin has its individual set of promoters and ribosomal binding sites along the toxic genes within the toxicon.
Both toxins act synergically and both induce vascular permeability and hemorrhage by binding to specific host receptors.[3]
Both toxins have monoglucosyltransferase activity at the N-terminus. Toxins are able to glycosylate Rho GTPase (involved in actin cytoskeleton) and cause the formation of abnormal G-actin (normally F-actin). In turn, G-actin induces the development of cell rounding, which is characteristic of toxin-induced cytopathy.[4][5][6]
Toxin A, but not toxin B, is associated with luminal fluid accumulation and may be responsible for the diarrhea associated with C. difficile infection.[3]
Toxin A is thought to stimulate cytokine production by macrophages (Il-1, IL-8, leukotrienes), which may be responsible for the subsequent neutrophilic migration and inflammation.
Although toxin A has been studied more extensively than toxin B, virulence by strains with toxin B only virulence factor has been reported.[7] The mechanism by which toxin B acts is yet to be understood.
  • Other less clinically important virulence factors that have been isolated include the following:
Enterotoxic protein
High-molecular weight protein
Actin-specific ADP-ribosyl-transferase
DCT binary toxin
Fimbiae
SlpA S-layer
Cwp84 cysteine protease
Fibronectin binding protein
Cwp66

Adhesion

  • Although some C. difficle strains contain fimbriae or flagellae, the main adhesin component of the organism is thought to be exotoxin A.[1]
  • Since, C. difficile toxin A mediates the adhesion of the organism to the host intestinal wall, more virulent strains with more exotoxin A are able to adhere better than strains of reduced virulence.[8]
  • Typically, C. difficile adheres to the wall of the terminal ileum and the cecum, which justifies the development of ileocecitis in the majority of patients.[8]
  • The role of other adhesive properties of C. difficile, including hydrophobic surfaces and charge interactions with the human host, have been studied to a lesser extent.[9]

Chemotaxis

  • Host intestinal mucus serves as a chemoattractant for C. difficile.[10][11]
  • Chemotaxis is further facilitated by the organism's motility, which is mediated by flagellae.[1]

Hydrolytic Enzymes

C. difficile expresses several enzymes that help in the breakdown of host mucosal integrity and organism growth[12][13]:

  • Hyaluronidase: Major enzyme that converts hyaluronic acid from mucus glycoproteins into N-acetylglucosamine needed for nutritional growth
  • Chondroitin-4-sulphatase
  • Heparinase (weak activity)
  • Collagenase (weak activity)

Gross Pathology

On gross pathology, the following characteristic features may be present in C. difficile colitis:

  • Colonic pseudomembranes with yellow colored plaque formation
  • Areas of hemorrhage, which may be either multifocal, segmental, or diffuse
  • Hyperemic congestion
  • Marked edema formation of the intestinal wall
  • Superficial erosions and ulcer formation

Microscopic Pathology

On microscopic pathology, the following characteristic features may be present in C. difficile colitis:

  • Erosions within colonic crypts with pseudomembrane formation, which contains neutrophils, fibrin, and necrotic debris
  • Linear neutrophilic infiltration at the level of the lamina propria and within areas of necrosis
  • Necrotizing enteritis with or without hemorrhage
  • Submucosal edema
  • Inflammatory exudates (mushroom-like)

References

  1. 1.0 1.1 1.2 1.3 Borriello SP (1998). "Pathogenesis of Clostridium difficile infection". J Antimicrob Chemother. 41 Suppl C: 13–9. PMID 9630370.
  2. Delmée M, Avesani V (1990). "Virulence of ten serogroups of Clostridium difficile in hamsters". J Med Microbiol. 33 (2): 85–90. PMID 2231680.
  3. 3.0 3.1 Lyerly DM, Saum KE, MacDonald DK, Wilkins TD (1985). "Effects of Clostridium difficile toxins given intragastrically to animals". Infect Immun. 47 (2): 349–52. PMC 263173. PMID 3917975.
  4. Just I, Selzer J, von Eichel-Streiber C, Aktories K (1995). "The low molecular mass GTP-binding protein Rho is affected by toxin A from Clostridium difficile". J Clin Invest. 95 (3): 1026–31. doi:10.1172/JCI117747. PMC 441436. PMID 7883950.
  5. Just I, Selzer J, Wilm M, von Eichel-Streiber C, Mann M, Aktories K (1995). "Glucosylation of Rho proteins by Clostridium difficile toxin B." Nature. 375 (6531): 500–3. doi:10.1038/375500a0. PMID 7777059.
  6. Just I, Wilm M, Selzer J, Rex G, von Eichel-Streiber C, Mann M; et al. (1995). "The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho proteins". J Biol Chem. 270 (23): 13932–6. PMID 7775453.
  7. Lyerly DM, Barroso LA, Wilkins TD, Depitre C, Corthier G (1992). "Characterization of a toxin A-negative, toxin B-positive strain of Clostridium difficile". Infect Immun. 60 (11): 4633–9. PMC 258212. PMID 1398977.
  8. 8.0 8.1 Borriello SP, Welch AR, Barclay FE, Davies HA (1988). "Mucosal association by Clostridium difficile in the hamster gastrointestinal tract". J Med Microbiol. 25 (3): 191–6. PMID 3346902.
  9. Krishna MM, Powell NB, Borriello SP (1996). "Cell surface properties of Clostridium difficile: haemagglutination, relative hydrophobicity and charge". J Med Microbiol. 44 (2): 115–23. PMID 8642572.
  10. Dailey DC, Kaiser A, Schloemer RH (1987). "Factors influencing the phagocytosis of Clostridium difficile by human polymorphonuclear leukocytes". Infect Immun. 55 (7): 1541–6. PMC 260555. PMID 3596798.
  11. Davies HA, Borriello SP (1990). "Detection of capsule in strains of Clostridium difficile of varying virulence and toxigenicity". Microb Pathog. 9 (2): 141–6. PMID 2277588.
  12. Seddon SV, Hemingway I, Borriello SP (1990). "Hydrolytic enzyme production by Clostridium difficile and its relationship to toxin production and virulence in the hamster model". J Med Microbiol. 31 (3): 169–74. PMID 2156075.
  13. Wilson KH, Perini F (1988). "Role of competition for nutrients in suppression of Clostridium difficile by the colonic microflora". Infect Immun. 56 (10): 2610–4. PMC 259619. PMID 3417352.



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