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All bacterial infections are of great concern to society. Some bacterial infections, however, seem to have periods of high drama or wider public health import. The 100 or so known species of Clostridium (from the Greek kloster or “spindle”; phylum Firmicutes) belong to a group of obligately anaerobic, gram-positive, spore-forming, rod-shaped bacteria. Of these, only a handful are pathogenic to humans. Yet this handful is known to cause many types of serious bacterial diseases, including some of the most common (eg, Clostridium perfringens food poisoning), to some of the most dramatic: Gas gangrene (clostridial myonecrosis), tetanus, and botulism are the most commonly recognized names (etiologic agents: C. perfringens, Clostridium tetani, and Clostridium botulinum, respectively) [1]. Over the years researchers have learned that the pathogenesis, indeed many of the acute observed pathologies, of these diseases are mediated predominately by secreted bacterial poisons, or protein exotoxins, of which the Clostridia are prolific producers. Some of these (the botulinum neurotoxins) represent the most poisonous agents known [2]. Bacterial toxins’ gene expression, processing, secretion, protein structures, molecular targets, biochemical activities, and especially the varied, unique biologic consequences of these toxins to our cells and to ourselves have served as mainstays of bacterial disease research for decades. Each advance in toxin research has honed understanding of the cognate infectious cycles, and many derivative medical countermeasures—especially the toxoid vaccines— are proven and marvelous success stories. Today we are up against a relatively new and potent clostridial challenger, Clostridium difficile, a cause of serious gastrointestinal tract infections and a troublesome public health risk [3, 4]. Cases of C. difficile infection (CDI) continue to increase, afflicting mostly older people receiving antibiotics for reasons unrelated to CDI. The clinical presentation of CDI can range from asymptomatic colonization to a fulminant colitis with the development of toxic megacolon [5]. Although CDI was initially recognized as a nosocomial infection, the recent rise of community-acquired CDI has been cause for alarm [6, 7]. The details of the C. difficile infectious cycle and its pathogenesis appear to be significantly more complex than, say, tetanus, botulism, or even gas gangrene. CDI arises after antibiotic administration disrupts the ecology of the healthy, normal gastrointestinal bacterial community, compromising colonization resistance and allowing for C. difficile to find an environmental “toehold” for setting up shop after spore ingestion and germination [8]. Inflammation and activities of our innate immune responses are implicated as either helping to contain the organism, assisting the organism in persistence, contributing to acute pathologies, or all of the above [9]. Any roles for acquired immunity, either in clearing the pathogen or in long-term immunity, are in the early stages of investigation. Recurrence is common after treatment, and spread to new victims via fecal-oral transmission is a torment to healthcare facilities [10]. High levels of recurrence and transmission are believed to be due to, at least in part, the robust resistance properties of its spore to both antibiotics and surface decontamination agents. So where do C. difficile toxins fit into this complicated picture? Three C. difficile exotoxins have been discovered, intensely researched, and highly suspected as potential factors contributing to CDI, perhaps key factors to virulence. However, correlates Received and accepted 21 August 2013; electronically published 27 August 2013. Correspondence: Vincent Young, Infectious Diseases Division, University of Michigan, 5220 MSRB III SPC 5640, 1150 W Medical Center Dr, Ann Arbor, MI 48109-5640 (youngvi@ umich.edu). The Journal of Infectious Diseases 2014;209:9–11 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/infdis/jit461

Overlapping Roles for Toxins in Clostridium difficile Infection