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Diarrheal disease is one of the most common diseases of humans. The causative agents of infectious diarrhea and dysentery can be viral, bacterial, or protozoal. Ideally, subjects in a volunteer study should be representative of the population in which diarrheal disease occurs. However, some enteric pathogens, such as rotavirus and enteropathogenic Escherichia coli (EPEC), cause diarrhea primarily in infants and small children. Pathogens which are transmitted almost exclusively through the ingestion of common food are believed to require a higher infective dose to produce disease than organisms capable of spreading directly from person to person. This is because food-borne pathogens have often had the opportunity to replicate to high concentrations in foods before consumption. Both volunteer studies and epidemiological data concur in assigning a low infective dose to Shigella and Campylobacter jejuni diarrhea. Evidence is particularly strong in the case of Shigella species, in which numerous volunteer studies with three different Shigella species have shown that the infective dose for shigellosis is between 10 and 500 organisms. Most of the enteric pathogens which require a very large inoculum to cause disease, such as V. cholerae and enterotoxigenic E. coli (ETEC), are extracellular pathogens whose mode of virulence involves adherence and toxin secretion. The abilities of organisms to survive passage through the normally acidic stomach is probably an important factor for determining infective dose, but other, more specific determinants such as the ability to survive and replicate within cells are likely to play significant roles as well.

Mycolactones are a family of lipophilic small molecules and virulence factors produced as secondary metabolites by Mycobacterium ulcerans and some highly related aquatic mycobacteria. This chapter describes what is known about mycolactones and their unique role in the pathogenesis of Buruli ulcer, explains their unusual biosynthetic locus, and highlights the key questions that remain to be answered. A recent report describes an abundant extracellular matrix produced by M. ulcerans that harbors vesicles that are rich in mycolactones. Mycolactones are related to antibacterial macrolides such as erythromycin and immunosuppressants such as FK506 because they all share a polyketide-derived macrolactone core. The apoptotic ability of mycolactone F is significantly less than that of the other mycolactones; a feature that may be associated with its shorter acyl side chain. All of these mycolactone-producing mycobacteria, including M. ulcerans, form a distinct lineage within a genetically more diverse assemblage of Mycobacterium marinum that have clearly evolved from a common M. marinum-like progenitor. All mycolactone-producing mycobacteria found so far have been discovered through their ability to cause disease in vertebrates, but they may be acting as “indicator” species and represent only a proportion of the mycolactones that exist in nature.