Cholera toxin

Cholera toxin (CT), a protein complex secreted by the bacterium Vibrio cholerae, is the principal virulence factor responsible for the diarrheal disease cholera. The toxin is an oligomeric complex composed of six protein subunits: one A subunit (CTA) and five B subunits (CTB). The B subunits bind to the GM1 ganglioside receptors on the surface of intestinal epithelial cells, facilitating the entry of the A subunit into the cell. Once inside, the A subunit activates adenylate cyclase, leading to an increase in intracellular cyclic AMP (cAMP) levels. This elevation in cAMP disrupts the ionic balance in the cells, causing an efflux of chloride ions and water into the intestinal lumen, which results in the watery diarrhea characteristic of cholera.

Structure and Function

The A subunit of cholera toxin (CTA) is responsible for the enzymatic activity of the toxin. It is initially synthesized as a single polypeptide that is cleaved into two parts, CTA1 and CTA2, linked by a disulfide bond. The CTA1 fragment is the active component that increases cAMP levels in the host cell. The B subunits (CTB) form a pentameric ring that binds to GM1 ganglioside receptors on the surface of the host cell, facilitating the internalization of the A subunit.

Mechanism of Action

Upon binding to the GM1 receptor, the cholera toxin is endocytosed and transported to the endoplasmic reticulum. Here, the disulfide bond between CTA1 and CTA2 is reduced, releasing the active CTA1 fragment into the cytosol. CTA1 then activates adenylate cyclase by ADP-ribosylation of the Gs alpha subunit, leading to an increase in cAMP levels. The elevated cAMP levels activate protein kinase A, which phosphorylates the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, causing it to open. This results in the secretion of chloride ions into the intestinal lumen. Sodium ions and water follow the chloride ions due to osmotic and electrochemical gradients, leading to diarrhea.

Clinical Significance

Cholera toxin is the primary cause of the severe diarrheal symptoms of cholera, a major public health concern in many developing countries where access to clean water and sanitation is limited. Understanding the structure and function of cholera toxin has been crucial in developing treatments and preventive measures against cholera. Oral rehydration therapy (ORT), which involves the administration of a simple solution of sugar and salts, is used to treat dehydration caused by the toxin-induced diarrhea. Vaccines targeting the B subunit of cholera toxin have also been developed to provide immunity against cholera.

Prevention and Control

Efforts to control cholera outbreaks focus on improving water quality, sanitation, and hygiene practices to prevent the spread of Vibrio cholerae. Vaccination campaigns are also employed in areas with high rates of cholera. The development of new vaccines that offer longer-lasting protection and the use of antibiotics in severe cases are ongoing areas of research.