The roles of host and pathogen factors and the innate immune response in the pathogenesis of Clostridium difficile infection

Abstract

Clostridium difficile (C. difficile) is the most common cause of nosocomial antibiotic-associated diarrhea and the etiologic agent of pseudomembranous colitis. The clinical manifestation of Clostridium difficile infection (CDI) is highly variable, from asymptomatic carriage, to mild self-limiting diarrhea, to the more severe pseudomembranous colitis. Furthermore, in extreme cases, colonic inflammation and tissue damage can lead to toxic megacolon, a condition requiring surgical intervention. C. difficile expresses two key virulence factors; the exotoxins, toxin A (TcdA) and toxin B (TcdB), which are glucosyltransferases that target host-cell monomeric GTPases. In addition, some hypervirulent strains produce a third toxin, binary toxin or C. difficile transferase (CDT), which may contribute to the pathogenesis of CDI. More recently, other factors such as surface layer proteins (SLPs) and flagellin have also been linked to the inflammatory responses observed in CDI. Although the adaptive immune response can influence the severity of CDI, the innate immune responses to C. difficile and its toxins play crucial roles in CDI onset, progression, and overall prognosis. Despite this, the innate immune responses in CDI have drawn relatively little attention from clinical researchers. Targeting these responses may prove useful clinically as adjuvant therapies, especially in refractory and/or recurrent CDI. This review will focus on recent advances in our understanding of how C. difficile and its toxins modulate innate immune responses that contribute to CDI pathogenesis.

Host Immune Response to Clostridium difficile Infection in Inflammatory Bowel Disease Patients

“…4,6 Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD), Ulcerative Colitis (UC), and patients after ileal pouch anal anastomosis (IPAA), is known to be an independent risk factor for CDI. 4,9,10 In this population, traditional risk factors do not have the same correlation with symptomatic infection. Proton-pump inhibitors are a less common risk 11 and in children colonization is more common over symptomatic disease.…”

“…27 Normal gut flora is needed to compete with C. difficile for nutrients and regulate transformation of bile salts, particularly taucholate, which is needed for C. difficile germination. 10,25 In its vegetative state C. difficile produces toxins which enter the cell and damage the intestinal epithelial cytoskeleton, 17,26 act as a chemoattractant for neutrophils and lead to inflammation. It is this inflammatory response, not the degree of bacterial burden, which leads to cell injury and determines the clinical severity of CDI.…”

“…Previous data show that up to 60% of older children and adults in the general population have antibodies to C. difficile toxin A and B. 10 Early studies showed toxin antibody levels do not offer initial protection against colonization 23 but are correlated with the occurrence of symptomatic disease. Kyne et al 24 found that higher levels of Toxin A IgM on day 3 and IgG on day 12 after onset of c. difficile diarrhea were associated with single-episode CDI without recurrence.…”

ProbioticSaccharomyces boulardiiCNCM I-745 prevents outbreak-associatedClostridium difficile-associated cecal inflammation in hamsters

“…Although the mechanism of its hypervirulence is not fully elucidated, this strain is fluoroquinolone resistant (12) and appears to produce more toxin A and toxin B than any other C. difficile strains (35). The binary toxin also possesses cytotoxic activity, but its role in CDI is still not well understood (48). Based on these considerations, the in vivo and in vitro effects of S.b in C. difficile ribotype 027 may be directed against toxin A, toxin B, and/or the binary toxin.…”

Secretory diarrhoea: mechanisms and emerging therapies

“…C. difficile -associated diarrhoea and colitis occurs secondary to elaborated toxins that activate epithelial inflammatory signalling pathways and recruit immune cells. 68 …”