The role of toxins in Clostridium difficile infection

Abstract

Clostridium difficile is a bacterial pathogen that is the leading cause of nosocomial antibiotic-associated diarrhea and pseudomembranous colitis worldwide. The incidence, severity, mortality and healthcare costs associated with C. difficile infection (CDI) are rising, making C. difficile a major threat to public health. Traditional treatments for CDI involve use of antibiotics such as metronidazole and vancomycin, but disease recurrence occurs in about 30% of patients, highlighting the need for new therapies. The pathogenesis of C. difficile is primarily mediated by the actions of two large clostridial glucosylating toxins, toxin A (TcdA) and toxin B (TcdB). Some strains produce a third toxin, the binary toxin C. difficile transferase, which can also contribute to C. difficile virulence and disease. These toxins act on the colonic epithelium and immune cells and induce a complex cascade of cellular events that result in fluid secretion, inflammation and tissue damage, which are the hallmark features of the disease. In this review, we summarize our current understanding of the structure and mechanism of action of the C. difficile toxins and their role in disease.

Importance of flagella in acute and chronic Pseudomonas aeruginosa infections

“…Some highly pathogenic microorganisms pursue the strategy to express a few but very effective virulence factors (Lee et al, 2016;Chandrasekaran and Lacy, 2017;Fowler et al, 2017). In contrast, the success of the opportunistic pathogen P. aeruginosa can be attributed to a highly complex virulence-regulatory network (Balasubramanian et al, 2013).…”

Advances in mass spectrometry‐based glycomics

“…Isotopic labeling with 18 O could be incorporated in the reducing end of glycans through the enzymatic digestion process. Glycan reducing end 18 O labeling (GREOL) was first reported by using an enzyme, Endo H and heavy water, resulting in a 2 Da mass difference between 18 O labeled glycans and native glycans [142].…”

“…Isotopic labeling with 18 O could be incorporated in the reducing end of glycans through the enzymatic digestion process. Glycan reducing end 18 O labeling (GREOL) was first reported by using an enzyme, Endo H and heavy water, resulting in a 2 Da mass difference between 18 O labeled glycans and native glycans [142]. Recently, Yang and coworkers also successfully incorporated 18 O to the reducing end of N-glycans using an enzyme, PNGase F, so-called PCGOL (PNGase F catalyzed glycan 18 O-labeling) [143].…”

“…Glycan reducing end 18 O labeling (GREOL) was first reported by using an enzyme, Endo H and heavy water, resulting in a 2 Da mass difference between 18 O labeled glycans and native glycans [142]. Recently, Yang and coworkers also successfully incorporated 18 O to the reducing end of N-glycans using an enzyme, PNGase F, so-called PCGOL (PNGase F catalyzed glycan 18 O-labeling) [143]. Additionally, they introduced glycan reducing end dual isotopic labeling (GREDIL) which utilizes NaBH 4 /NaBD 4 as reducing agents to prompt mass difference between labeled and native glycans by 3 Da [144].…”

Novel therapies and preventative strategies for primary and recurrent Clostridium difficile infections

“…For example, certain strains can produce TcdA and TcdB but not the binary toxin. TcdA and TcdB enter the cell by binding to specific cellular receptors found on intestinal epithelial cells . After endocytosis, acidification of the endosome leads to conformational changes of the toxin that releases the N‐terminal glucosyltransferase domain into the cytoplasm.…”