Virulence factors in outbreak-strain cholera

Infection with Vibrio cholerae is an ongoing problem in many developing regions of the world. Cholera is spread by the fecal-oral route in conjunction with poor hygiene and substandard water sanitation; asymptomatic carriage in humans can allow for continuous dissemination and transmission of the organism. Mortality in cholera infection is caused by massive intestinal fluid losses. Over $200$200 cholera subtypes have been identified, although only a few toxin-producing (toxigenic) subtypes cause outbreaks.

In the small intestine, the cholera organism produces a flagella-like structure that allows it to breach the intestinal wall. Once it has invaded, the organism subsequently discontinues production of the flagellum, in order to save energy. Toxigenic cholera causes massive, often life-threatening diarrhea via the actions of the cholera toxin, a six-subunit protein (an A subunit and 5 B subunits). The B subunit binds to gangliosides on intestinal epithelial cells, causing endocytosis (Figure 1). Inside the cell, the 6 subunits dissociate, and part of the A subunit binds with a protein called ADP ribosylation factor 6 (Arf6). This, in turn, causes permanent ribosylation of a G protein, causing an intracellular adenylate cyclase to constitutively produce cyclic AMP (cAMP). cAMP is an important intracellular regulatory molecule whose production leads to ongoing losses of $\text{H}_2O$start text, H, end text, start subscript, 2, end subscript, O, $Na^+$N, a, start superscript, plus, end superscript, $Cl^-$C, l, start superscript, minus, end superscript, and $HCO^3$H, C, O, cubed via a transmembrane ion channel (CFTR).

Figure 1. Actions of Vibrio cholerae and its toxin.

Outbreak-strain cholera toxin is encoded by the CTXɸ gene, which is carried by a viral bacteriophage. The virus integrates its own genome into the bacterium, and the genes conferred provide a virulence advantage to the organism by inducing toxin production, profuse diarrhea and dissemination of the organism. CTXɸ-carrying organisms are the commonest cholera subtypes that cause large outbreaks. Other known and hypothesized methods by which V. cholerae acquires virulence factors include organism-to-organism gene transfer and acquisition of free DNA from the aquatic environment.

Cholera vaccine targets have included various virulence factors such as pili and cholera toxin itself. Currently, two oral vaccines are in use - Dukoral, which includes whole-cell killed V. cholerae plus the cholera toxin b subunit; and Shanchol, which includes only whole-cell killed V. cholerae.

Lapierre, D. (n.d.) Vibrio cholerae. Retrieved from Sharing in Health.