Both, toxin A and toxin B, are important inClostridium difficileinfection.

Abstract

T he bacterium Clostridium difficile is the leading cause of healthcare associated diarrhoea in the developed world and thus presents a major financial burden. The main virulence factors of C. difficile are two large toxins, A and B. Over the years there has been some debate over the respective roles and importance of these two toxins. To address this, we recently constructed stable toxin mutants of C. difficile and found that they were virulent if either toxin A or toxin B was functional. This underlined the importance of each toxin and the necessity to consider both when developing countermeasures against Clostridium difficile infection (CDI). In this article we discuss our findings in the context of previous work and outline some of the challenges which face the field as a result. IntroductionIn recent years Clostridium difficile infection (CDI) has emerged as the leading cause of healthcare associated diarrhoea in the developed world. The endospores of this Gram-positive anaerobe are widely distributed in the environment and their ingestion by hospitalised patients with a disrupted gut microflora, a common consequence of antibiotic treatment, leads to colonisation and subsequent disease. 1-3The clinical symptoms of CDI can range from asymptomatic carriage to a mild selflimiting or severe diarrhoea which may progress to the potentially fatal conditions of pseudomembranous colitis and/ or toxic megacolon. In most developed countries, the incidence of CDI continues to increase, concomitant with the emergence of so-called 'hyper-virulent' strains, responsible for increased severity of CDI and a rise in fatalities. In England and Wales, for example, where the mortality rates attributable to CDI are apparently falling, C. difficile still killed almost 4,000 people in 2009 alone. This upsurge in the incidence of CDI has placed a large financial burden on healthcare systems worldwide. 2 Toxin A and Toxin B in DiseaseTwo main virulence factors, toxin A and toxin B, have been described for C. difficile. The two encoding genes, tcdA and tcdB, respectively, form part of a well defined pathogenicity locus (PaLoc) (Fig. 1). The locus also encompasses three ancillary genes. The tcdR gene encodes an alternative sigma factor (TcdR) responsible for the transcription of tcdA and tcdB.4,5 A second gene tcdC, is suggested to encode an antisigma factor (TcdC) which represses toxin production by directly interacting with TcdR or TcdR-containing RNA polymerase. 6 The third gene, tcdE, codes for a protein (TcdE) which shares similarity to phage holin proteins, and may be involved in toxin secretion. 7 The entire PaLoc element is 19.6 kb in size and, therefore, represents an investment by the organism in terms of its continued maintenance in the genome (Fig. 1).The function of the toxins themselves has been studied extensively and their mode of action is now well understood. Both are cytotoxic and belong to the family of large clostridial toxins, capable of inactivating Rho-GTPases and leading to www.landesbioscience.com Gut Microbes...

CodY-Dependent Regulation of Sporulation in Clostridium difficile

“…difficile encodes two large toxins, TcdA and TcdB, which are essential for virulence (1)(2)(3)(4)62). Previous studies demonstrated that toxin production is controlled by the global nutritional regulatory factors CcpA and CodY in strain JIR8094 (56,63).…”

“…It is found primarily within the mammalian gastrointestinal (GI) tract, where it can cause severe, toxin-mediated GI disease (1)(2)(3)(4). C. difficile is transmitted through the fecaloral route, primarily in health care-associated settings, where it is a leading cause of nosocomial infections (5-7).…”

Clostridium difficile Extracytoplasmic Function σ Factor σ V Regulates Lysozyme Resistance and Is Necessary for Pathogenesis in the Hamster Model of Infection

“…TcdB and, to a lesser degree, TcdA are required for C. difficile pathogenesis, but not colonization, in the hamster model of C. difficile infections (7,9,10). Expression of the toxin genes is tightly regulated by a number of factors.…”

In VitroandIn VivoAntibacterial Evaluation of Cadazolid, a New Antibiotic for Treatment of Clostridium difficile Infections

“…Clinical symptoms range from asymptomatic colonization to diarrhea, severe pseudomembranous colitis, sepsis, and death. The main virulence factors of C. difficile are two high-molecular-weight toxins, the enterotoxin toxin A (TcdA) and the cytotoxin toxin B (TcdB), while the contribution of the binary toxin remains unclear (8). Toxin A and toxin B cause damage to the intestinal epithelial barrier and promote mucosal inflammation.…”