Active and passive immunization against Clostridium difficile diarrhea and colitis
Introduction
Clostridium difficile is a gram positive, anaerobic, spore-forming bacterium that is commonly found in the environment. The organism is transmitted by the fecal–oral route through the ingestion of resistant spores that survive passage through the stomach, ultimately residing in the colon. Antimicrobial therapy creates an ecological niche, which allows C. difficile spores to germinate in the colon. The bacterium colonizes the luminal surfaces of colonic epithelial cells and produces two large exotoxins (toxins A and B), which are principally responsible for the disease manifestations associated with this infection. C. difficile is currently the most frequent cause of nosocomial infectious diarrhea [1], [2] and is responsible for an estimated US$ 1 billion in health care costs annually in the US alone [3].
Section snippets
Incidence, risk factors and modes of transmission
The incidence of C. difficile carriage in the healthy adult population is ∼1–3%. The rate of colonization increases substantially to ∼20% with antibiotic usage [2], due to the alteration of the protective commensal flora. Up to 60% of healthy neonates and infants are colonized with C. difficile without clinical symptoms [4], [5]. The total number of C. difficile-associated diarrhea (CDAD) cases is estimated to be at least 300,000 annually in the US. The incidence can be higher in hospitals,
Clinical symptoms, diagnosis and treatment
C. difficile colonization of adults produces a spectrum of clinical symptoms ranging from asymptomatic carriage to life threatening pseudomembranous colitis. Diarrhea often appears 1–2 weeks after initiation of antibiotic therapy, which can be accompanied by modest fever and abdominal cramping. Moderate or severe colitis develops in a subset of patients and the most serious form of the infection, pseudomembranous colitis, carries the risk of intestinal perforation and death.
The diagnosis of C.
Toxin structure and mechanisms of actions
C. difficile is a non-invasive organism which possesses multiple virulence factors that aid in colonization and may promote disease. These include various adherence factors such as flagellar proteins [12], surface layer proteins [13], and a surface-exposed adhesin [14]. In addition, all pathogenic strains of C. difficile express one or two large exotoxins (A and B) and the majority expresses both toxins. Toxin A (308 kDa) and toxin B (270 kDa) exhibit 49% amino acid identity. These toxins belong
Role of toxins in disease
Studies in animals have contributed greatly to our understanding of the pathogenicity of toxins A and B. When administered orally, the purified toxins are capable of inducing the full spectrum of disease manifestations typical of C. difficile infection. Purified toxin A possesses potent enterotoxic and pro-inflammatory activity, as determined in ligated loop studies in mice, rats, hamsters and rabbits [23], [24]. Toxin A is also cytotoxic to cultured cells in low nanogram quantities. By
Vaccination with C. difficile toxoids in animal models
One approach to defining the roles of toxins A and B in the pathogenesis of C. difficile infection has been to examine the protective capacity of toxin-specific immunity in animals.
Mechanisms of protection in animal models
The ability of an antitoxin antibody preparation to convey full protection from oral C. difficile challenge in mice and hamsters indicates that antibodies are the essential effector molecules in these animal models. The oral administration of toxin-specific antibodies is capable of neutralizing the enterotoxicity and mucosal inflammation caused by the toxins presumably by intercepting the toxins in the intestinal lumen rendering them inactive. This “immune exclusion” likely models the action of
Antibody responses to toxins in humans
Many healthy adults (∼60%) have detectable serum IgG and IgA to toxins A&B [58] despite only a small population (2–3%) being colonized [59], as determined by culturing stool on selective media. It is not known if the prevailing responses in adults are a reflection of childhood exposure or sub-clinical infection(s) as adults. The ability to mount an effective immune response following exposure to C. difficile appears to impact the course of disease expression. Indeed, only a small proportion of
Immunological approaches to clinical management
Because antimicrobial therapy is the principal inciting agent for CDAD, the need for non-antibiotic approaches for the clinical management of this disease is apparent. Interventions that allow for the restoration of the commensal flora and exploit its protective effect hold the greatest promise for primary prevention and secondary prophylaxis. Active and passive immunization strategies are being developed which may yield effective alternatives to anti-microbial therapy for use in certain
Acknowledgements
We thank Thomas Monath for his critical review and helpful comments.
References (72)
- et al.
Isolation rates and toxigenic potential of Clostridium difficile isolates from various patient populations
Gastroenterology
(1981) - et al.
Epidemiology of antibiotic associated colitis isolation of Clostridium difficile from the hospital environment
Am. J. Med.
(1981) - et al.
Prospective randomized trial of metronidazole versus vancomycin for Clostridium difficile-associated diarrhea and colitis
Lancet
(1983) - et al.
Recurrence of symptoms in Clostridium difficile infection-relapse or reinfection?
J. Hosp. Infect.
(1998) - et al.
Large clostridial cytotoxins—a family of glycosyltransferases modifying small GTP-binding proteins
Trends Microbiol.
(1996) - et al.
Low pH-induced formation of ion channels by Clostridium difficile toxin B in target cells
J. Biol. Chem.
(2001) - et al.
The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho proteins
J. Biol. Chem.
(1995) - et al.
A novel cytotoxin from Clostridium difficile serogroup F is a functional hybrid between two other large clostridial cytotoxins
J. Biol. Chem.
(1999) - et al.
Clostridium difficile toxin B is an inflammatory enterotoxin in human intestine
Gastroenterology
(2003) - et al.
Prevention of clindamycin-induced colitis in hamsters by Clostridium sordellii antitoxin
Gastroenterology
(1979)
Human colonic aspirates containing immunoglobulin A antibody to Clostridium difficile toxin A inhibit toxin A-receptor binding
Gastroenterology
Hepatobiliary transport of IgA in the golden Syrian hamster (Mesocricetus auratus)
Immunol. Lett.
Clostridium difficile toxin B disrupts the barrier function of T84 monolayers
Gastroenterology
Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin
J. Pediatr.
Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea
Lancet
Clostridium difficile colitis
N. Engl. J. Med.
Nocosomial acquisition of Clostridium difficile infection
N. Eng. J. Med.
Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile
Clin. Infect. Dis.
Epidemiology of Clostridium difficile in infants
J. Infect. Dis.
Isolation of Clostridium difficile from the environment and contacts of patients with antibiotic-associated colitis
J. Infect. Dis.
Clostridium difficile colonization and diarrhea at a tertiary care hospital
Clin. Infect. Dis.
A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease
JAMA
Role of FliC and FliD flagellar proteins of Clostridium difficile in adherence and gut colonization
Infect. Immun.
Binding of Clostridium difficile surface layer proteins to gastrointestinal tissues
Infect. Immun.
Characterization of a cell surface protein of Clostridium difficile with adhesive properties
Infect. Immun.
Morphological changes in adherent cells induced by Clostridium difficile toxins
Biochem. Soc. Trans.
Toxin A of Clostridium difficile is a potent cytotoxin
J. Clin. Microbiol.
pH-induced conformational changes in Clostridium difficile toxin B
Infect. Immun.
Glucosylation of Rho proteins by Clostridium difficile toxin B
Nature
GT160-246, a toxin binding polymer for treatment of Clostridium difficile colitis
J. Antimicrob. Chemother.
Effects of Clostridium difficile toxins given intragastrically to animals
Infect. Immun.
Clostridium difficile infection in adult hamsters
Lab. Anim. Sci.
Characterization of a toxin A-negative, toxin B-positive strain of Clostridium difficile responsible for a nosocomial outbreak of Clostridium difficile-associated diarrhea
J. Clin. Microbiol.
Fatal pseudomembranous colitis associated with a variant Clostridium difficile strain not detected by toxin A immunoassay
Ann. Intern. Med.
Cited by (106)
Are Clostridium difficile toxins nephrotoxic?
2019, Medical HypothesesUse of a neutralizing antibody helps identify structural features critical for binding of Clostridium difficile toxin TcdA to the host cell surface
2017, Journal of Biological ChemistryBiodefense and Special Pathogen Vaccines
2017, Plotkin's Vaccines