Clostridium difficile infection pathophysiology: Difference between revisions

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{{Clostridium difficile}}
{{Siren|Clostridium difficile infection}}
{{CMG}}
{{Clostridium difficile infection}}
{{CMG}}; {{AE}} {{YD}}


== Pathophysiology ==
==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.


===Bacteriology===
==Pathophysiology==
Clostridia are motile [[bacterium|bacteria]] that are ubiquitous in nature and are especially prevalent in soil. Under the microscope after [[Gram stain]]ing, they appear as long drumsticks with a bulge located at their terminal ends. ''Clostridium difficile'' cells are [[Gram positive]]. ''Clostridium'' shows optimum growth when plated on [[blood agar]] at human body temperatures. When the environment becomes stressed, however, the bacteria produce spores that tolerate the extreme conditions that the active bacteria cannot. First described by Hall and O'Toole in 1935, "the difficult clostridium" was resistant to early attempts at isolation and grew very slowly in culture.<ref name=Hall_1935>{{cite journal | author = Hall I, O'Toole E | title = Intestinal flora in newborn infants with a description of a new pathogenic anaerobe, ''Bacillus difficilis'' | journal = Am J Dis Child | year = 1935 | volume = 49 | issue = | pages = 390 | url= }}</ref>
===Transmission===
''C. difficile'' is a commensal bacterium of the human [[intestine]] in a minority of the population. . In small numbers it does not result in disease of any significance. Antibiotics, especially those with a broad spectrum of activity, cause disruption of normal [[intestinal flora]], leading to an overgrowth of ''C. difficile''. This leads to [[pseudomembranous colitis]].
*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.


''C. difficile'' is resistant to most [[antibiotic]]s. It flourishes under these conditions. It is transmitted from person to person by the [[fecal-oral route]]. Because the organism forms heat-resistant spores, it can remain in the [[hospital]] or [[nursing home]] environment for long periods of time. It can be cultured from almost any surface in the hospital. Once spores are ingested, they pass through the stomach unscathed because of their acid-resistance. They change to their active form in the colon and multiply. It has been observed that several [[disinfectant]]s commonly used in hospitals may fail to kill the bacteria, and may actually promote spore formation.  However, disinfectants containing [[bleach]] are effective in killing the organisms<ref>{{cite news | url= http://news.bbc.co.uk/1/hi/health/4871840.stm
===Pathogenesis===
  | title=Cleaning agents 'make bug strong'
*Both ''C. difficile'' virulence strain and host susceptibility factors are needed for the development of clinical manifestations.
  | work=BBC News Online
*Following ingestion, the acid-resistant spores of ''C. difficile'' are able to survive the human gastric acidity.  
  | date=3 April 2006
  | accessdate=2007-01-11}}</ref>.


Patients are rarely infected unless the normal flora of the intestinal tract has been altered by [[antibiotic]]s. Following colonization ''C. diff'' releases two [[cytotoxin]]s, A and B:
*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.
* The cytotoxins bind to receptors on intestinal [[epithelial cell]]s.
* The cytotoxins usually result in acute inflammatory infiltrate, leading to cell [[necrosis]] and shedding. 
* A shallow [[ulcer]] results, from which serum proteins, mucus, and inflammatory cells emanate, leading to the appearance of a pseudomembrane.
* Some strains do not produce toxin.


=== Toxins ===
*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.
Pathogenic ''C. difficile'' strains produce various [[toxin]]s.  The most well-characterized are [[enterotoxin]] (''toxin A'') and [[cytotoxin]] (''toxin B'').<ref name=Sherris /> These two toxins are both responsible for the [[diarrhea]] and [[inflammation]] seen in infected patients, although their relative contributions have been debated by researchers. Another toxin, ''binary toxin'', has also been described, but its role in disease is not yet fully understood.<ref>{{cite journal |author=Barth H, Aktories K, Popoff M, Stiles B |title=Binary bacterial toxins: biochemistry, biology, and applications of common Clostridium and Bacillus proteins |journal=Microbiol Mol Biol Rev |volume=68 |issue=3 |pages=373-402, table of contents |year=2004 |pmid=15353562}}</ref>


===Role in Disease ===
::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.
With the introduction of [[broad-spectrum antibiotics]] in the latter half of the twentieth century, antibiotic-associated diarrhea became more common. [[Pseudomembranous colitis]] was first described as a complication of ''C. difficile'' [[infection]] in 1978,<ref name=Larson_1978>{{cite journal |author=Larson H, Price A, Honour P, Borriello S |title=''Clostridium difficile'' and the aetiology of pseudomembranous colitis |journal=Lancet |volume=1 |issue=8073 |pages=1063-6 |year=1978 |pmid=77366}}</ref> when a toxin was isolated from patients suffering from pseudomembranous colitis and [[Koch's postulates]] were met.


''Clostridium Difficile Infection'' (CDI), can range in severity from asymptomatic to severe and life threatening, and many deaths have been reported, especially amongst the aged. People are most often infected in [[hospital]]s, [[nursing home]]s, or institutions, although ''C. difficile'' infection in the community, outpatient setting is increasing. ''Clostridium difficile'' associated diarrhea (aka CDAD) has been linked to use of broad-spectrum antibiotics such as [[cephalosporin]]s and [[clindamycin]], though the use of quinolones is now probably the most likely culprit, which are frequently used in hospital settings. Frequency and severity of ''C. difficile'' colitis remains high and seems to be associated with increased death rates. Immunocompromised status and delayed diagnosis appear to result in elevated risk of death. Early intervention and aggressive management are key factors to recovery.
::In the majority of individuals, the toxin production is countered by adequate host antitoxin responses.


The rate of ''Clostridium difficile'' acquisition is estimated to be 13 percent in patients with hospital stays of up to two weeks and 50 percent in those with hospital stays longer than four weeks.
::Among susceptible patients, however, the infectious injury is extensive, resulting in diarrhea and colitis.


Increasing rates of community-acquired ''Clostridium difficile''-associated infection/disease (CDAD) has also been linked to the use of medication to suppress [[gastric acid]] production: [[H2-receptor antagonist]]s increased the risk twofold, and [[proton pump inhibitor]]s threefold, mainly in the elderly. It is presumed that increased gastric [[pH]], (alkalinity), leads to decreased destruction of spores.<ref name=Dial_2005>{{cite journal |author=Dial S, Delaney J, Barkun A, Suissa S |title=Use of gastric acid-suppressive agents and the risk of community-acquired ''Clostridium difficile''-associated disease |journal=[[Journal of the American Medical Association|JAMA]] |volume=294 |issue=23 |pages=2989-95 |year=2005 |pmid=16414946}}</ref>
::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.<ref name="pmid9630370">{{cite journal| author=Borriello SP| title=Pathogenesis of Clostridium difficile infection. | journal=J Antimicrob Chemother | year= 1998 | volume= 41 Suppl C | issue=  | pages= 13-9 | pmid=9630370 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9630370  }} </ref><ref name="pmid2231680">{{cite journal| author=Delmée M, Avesani V| title=Virulence of ten serogroups of Clostridium difficile in hamsters. | journal=J Med Microbiol | year= 1990 | volume= 33 | issue= 2 | pages= 85-90 | pmid=2231680 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2231680  }} </ref>
*The virulence of an individual strain is directly associated with the amount of toxin A and B produced.<ref name="pmid9630370">{{cite journal| author=Borriello SP| title=Pathogenesis of Clostridium difficile infection. | journal=J Antimicrob Chemother | year= 1998 | volume= 41 Suppl C | issue=  | pages= 13-9 | pmid=9630370 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9630370  }} </ref>
::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.<ref name="pmid3917975">{{cite journal| author=Lyerly DM, Saum KE, MacDonald DK, Wilkins TD| title=Effects of Clostridium difficile toxins given intragastrically to animals. | journal=Infect Immun | year= 1985 | volume= 47 | issue= 2 | pages= 349-52 | pmid=3917975 | doi= | pmc=PMC263173 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3917975  }} </ref>
 
::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.<ref name="pmid7883950">{{cite journal| author=Just I, Selzer J, von Eichel-Streiber C, Aktories K| title=The low molecular mass GTP-binding protein Rho is affected by toxin A from Clostridium difficile. | journal=J Clin Invest | year= 1995 | volume= 95 | issue= 3 | pages= 1026-31 | pmid=7883950 | doi=10.1172/JCI117747 | pmc=PMC441436 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7883950  }} </ref><ref name="pmid7777059">{{cite journal| author=Just I, Selzer J, Wilm M, von Eichel-Streiber C, Mann M, Aktories K| title=Glucosylation of Rho proteins by Clostridium difficile toxin B. | journal=Nature | year= 1995 | volume= 375 | issue= 6531 | pages= 500-3 | pmid=7777059 | doi=10.1038/375500a0 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7777059  }} </ref><ref name="pmid7775453">{{cite journal| author=Just I, Wilm M, Selzer J, Rex G, von Eichel-Streiber C, Mann M et al.| title=The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho proteins. | journal=J Biol Chem | year= 1995 | volume= 270 | issue= 23 | pages= 13932-6 | pmid=7775453 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7775453  }} </ref>
 
::Toxin A, but not toxin B, is associated with luminal fluid accumulation and may be responsible for the diarrhea associated with ''C. difficile'' infection.<ref name="pmid3917975">{{cite journal| author=Lyerly DM, Saum KE, MacDonald DK, Wilkins TD| title=Effects of Clostridium difficile toxins given intragastrically to animals. | journal=Infect Immun | year= 1985 | volume= 47 | issue= 2 | pages= 349-52 | pmid=3917975 | doi= | pmc=PMC263173 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3917975  }} </ref>
 
::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.<ref name="pmid1398977">{{cite journal| author=Lyerly DM, Barroso LA, Wilkins TD, Depitre C, Corthier G| title=Characterization of a toxin A-negative, toxin B-positive strain of Clostridium difficile. | journal=Infect Immun | year= 1992 | volume= 60 | issue= 11 | pages= 4633-9 | pmid=1398977 | doi= | pmc=PMC258212 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1398977  }} </ref> 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.<ref name="pmid9630370">{{cite journal| author=Borriello SP| title=Pathogenesis of Clostridium difficile infection. | journal=J Antimicrob Chemother | year= 1998 | volume= 41 Suppl C | issue=  | pages= 13-9 | pmid=9630370 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9630370  }} </ref>
 
*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.<ref name="pmid3346902">{{cite journal| author=Borriello SP, Welch AR, Barclay FE, Davies HA| title=Mucosal association by Clostridium difficile in the hamster gastrointestinal tract. | journal=J Med Microbiol | year= 1988 | volume= 25 | issue= 3 | pages= 191-6 | pmid=3346902 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3346902  }} </ref>
 
*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.<ref name="pmid3346902">{{cite journal| author=Borriello SP, Welch AR, Barclay FE, Davies HA| title=Mucosal association by Clostridium difficile in the hamster gastrointestinal tract. | journal=J Med Microbiol | year= 1988 | volume= 25 | issue= 3 | pages= 191-6 | pmid=3346902 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3346902  }} </ref>
 
*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.<ref name="pmid8642572">{{cite journal| author=Krishna MM, Powell NB, Borriello SP| title=Cell surface properties of Clostridium difficile: haemagglutination, relative hydrophobicity and charge. | journal=J Med Microbiol | year= 1996 | volume= 44 | issue= 2 | pages= 115-23 | pmid=8642572 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8642572  }} </ref>
 
====Chemotaxis====
*Host intestinal mucus serves as a chemoattractant for ''C. difficile''.<ref name="pmid3596798">{{cite journal| author=Dailey DC, Kaiser A, Schloemer RH| title=Factors influencing the phagocytosis of Clostridium difficile by human polymorphonuclear leukocytes. | journal=Infect Immun | year= 1987 | volume= 55 | issue= 7 | pages= 1541-6 | pmid=3596798 | doi= | pmc=PMC260555 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3596798  }} </ref><ref name="pmid2277588">{{cite journal| author=Davies HA, Borriello SP| title=Detection of capsule in strains of Clostridium difficile of varying virulence and toxigenicity. | journal=Microb Pathog | year= 1990 | volume= 9 | issue= 2 | pages= 141-6 | pmid=2277588 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2277588  }} </ref>
 
*Chemotaxis is further facilitated by the organism's motility, which is mediated by flagellae.<ref name="pmid9630370">{{cite journal| author=Borriello SP| title=Pathogenesis of Clostridium difficile infection. | journal=J Antimicrob Chemother | year= 1998 | volume= 41 Suppl C | issue=  | pages= 13-9 | pmid=9630370 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9630370  }} </ref>
 
====Hydrolytic Enzymes====
''C. difficile'' expresses several enzymes that help in the breakdown of host mucosal integrity and organism growth<ref name="pmid2156075">{{cite journal| author=Seddon SV, Hemingway I, Borriello SP| title=Hydrolytic enzyme production by Clostridium difficile and its relationship to toxin production and virulence in the hamster model. | journal=J Med Microbiol | year= 1990 | volume= 31 | issue= 3 | pages= 169-74 | pmid=2156075 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2156075  }} </ref><ref name="pmid3417352">{{cite journal| author=Wilson KH, Perini F| title=Role of competition for nutrients in suppression of Clostridium difficile by the colonic microflora. | journal=Infect Immun | year= 1988 | volume= 56 | issue= 10 | pages= 2610-4 | pmid=3417352 | doi= | pmc=PMC259619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3417352  }} </ref>:
*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==
==References==
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{{Reflist|2}}
[[Category:Disease]]
[[Category:Disease]]
[[Category:Gastroenterology]]
[[Category:Gastroenterology]]
[[Category:Needs overview]]
[[Category:Needs overview]]
[[Category:Infectious disease]]
 
[[Category:Bacterial diseases]]


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Latest revision as of 17:26, 18 September 2017

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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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