How Humans Assist Cholera
November 15, 2002
Abstract & Commentary
Synopsis: Passage through the human gastrointestinal tract enhances the infectiousness of Vibrio cholerae.
Source: Merrell DS, et al. Host-induced epidemic spread of the cholera bacterium. Nature. 2002;417:642-645.
An in vitro passaged strain of vibro cholerae (DSM-V894) was mixed with V cholerae 01 Inaba El Tor recovered from stools of Bangladeshi patients and immediately used to inoculate infant mice by gavage. The mice were subsequently sacrificed, their small intestines homogenized, and quantitative cultures performed to determine the relative infectivity of the passaged strain and of the strains freshly recovered from human stool. The latter proved to have markedly enhanced infectivity, outcompeting the passaged strain by as much as 700-fold. This enhanced infectivity was, however, lost after this strain itself was passaged in vitro.
Epidemic cholera is the consequence of contaminated water supplies. To investigate whether the competitive advantage of V cholerae freshly shed from human stool was maintained in circumstances that could account for propagation of the disease in nature, mouse infectivity experiments were repeated after incubation of such strains into pond water; the hyperinfectious state of these strains was, in fact, maintained.
Transcriptional analysis using a spotted DNA microarray found that at least 237 genes were differentially expressed, with 44 genes being induced and 193 suppressed in human-shed V cholerae. The transcriptum (ie, the complete collection of transcribed RNAs of these stool-derived isolates) was consistent with that observed with bacterial growth in an environment in which oxygen and iron are limited; Merrell and colleagues point out that these are conditions that have been demonstrated to prevail in the ricewater stools of cholera. Genes encoding a number of known virulence factors, including cholera toxin, were not differentially regulated, while expression of genes involved in chemotaxis was repressed in stool-derived V cholerae, an effect that could possibly lead to increased shedding from the gastrointestinal tract.
Comment by Stan Deresinski, MD, FACP
This remarkable set of experiments paints a fascinating picture of the genetic machinations of V cholerae that optimize its survival in very different environments.
Merrell et al suggest that ingested V cholerae that escape the acid environment of the stomach and find their way to the small intestine and then into the colon alter their gene expression so that the organism becomes "hyperinfectious." Furthermore, the organism maintains this state after shedding of these isolates in diarrheal stools into a nutrient-poor aquatic environment. In contrast, this state is lost upon exposure of the organism in nutrient-rich culture media.
Passage through the gastrointestinal tract of the human host increases the infectiousness of V cholerae and this infectiousness is maintained in environments such as pond water. Thus, as pointed out by Merrell et al, human infection enhances subsequent water-borne spread of V cholerae by lowering the dose required to establish infection in subsequent victims. The human host thus plays a key role in conditioning these organisms to ensure continued epidemic spread of cholera. In the words of Pogo: "We have met the enemy and it is us!"
Dr. Deresinski, Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor of Infectious Disease Alert.
Passage through the human gastrointestinal tract enhances the infectiousness of Vibrio cholerae.
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