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Team:UT-Dallas/Project/history
From 2014.igem.org
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Introduction:Cholera is a gastrointestinal disease caused by a toxin released by aquatic bacterium Vibrio cholerae. Symptoms of cholera are acute watery diarrhea and vomiting. In severe cases, patients may show signs of severe dehydration, such as sunken eyes, decreased skin turgor, muscle cramping, and decreased blood pressure. If left untreated, severe cases can result in death within a few hours. There are two serotypes of V. cholerae responsible for the global cholera pandemics: O1 and O139. O1 has two biotypes - classical and El Tor. Non-O1 and non-O139 V. cholerae infections can cause similar but with milder symptoms (1). There have been seven recorded cholera pandemics beginning in 1816 and many more outbreaks in that time. Today, cholera infects approximately 3-5 million people every year and between 100,000-120,000 of these cases are fatal (1). Although cases of cholera are rare in developed countries, it continues to be a public health concern in regions with underdeveloped water treatment practices because of its relatively high death rate and persistence in the environment.
Mechanism of Infection:Although most V. cholerae ingested dies in the acidic stomach, the survivors can quickly colonize the small intestine. The symptoms associated with V. cholerae infection are primarily caused by the cholera toxin, but there are several genes that contribute to the colonization and pathogenicity of V. cholerae. Many of the genes associated with the virulence of V. cholerae are located on a pathogenicity island believed to originate from phage (2). We chose several genes identified for their role in pathogenicity and colonization to target for our project. 
The cholera toxin is an oligomeric protein made up 6 subunits: 1 copy of subunit A (ctxA) and 5 copies of subunit B (ctxB). The 5 ctxB subunits form a ring that directly binds to the GM1 ganglioside receptors on the surface of intestinal epithelial cells, causing the cholera toxin to be endocytosed. Once inside, the disfulfide bridges in the toxin are reduced, freeing the A subunit which then activates G proteins inside the cell, causing constitutive production of cAMP. This activates chloride ion channels, causing efflux of chloride ions, followed by water, Na+, and K+ due to osmotic and electrical gradients. This produces the characteristic watery diarrhea and rapid loss of water and electrolytes (3).
Transcriptional regulator toxT:
Toxin Coregulated Pilus:
Accessory Colonization Factor:
Cholera and the beginnings of phage therapy:In the late 1800s, English chemist Ernest Hanbury Hankin traveled to India to study the cholera outbreak. He observed bactericidal activity in the water taken from the Ganges river when applied to cultures of V. cholerae. In his notes, he described the agent responsible as being able to pass through a fine porcelain filter but became inactive when boiled. He also noted that people living in regions that obtained their water from the Ganges river were not experiencing a cholera outbreak (7).
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