Case study- Cholera

 Case study Cholera

A 21- year old female working in a rural school suddenly began to pass profuse watery stools almost continuously. She soon started to vomit, her general condition declined abruptly, and she was rushed to the general hospital. On admission she was cyanotic, skin turgor was poor, blood pressure was 70/50 mm Hg and her pulse was rapid and weak. The doctor on duty diagnosed cholera .The stool sample was taken for culture and the treatment was started immediately.

Which type of lipid is a receptor for cholera toxin in the intestine?

A. GM2 Ganglioside

B.GM1 Ganglioside

C. Sphingomyelin

D. Galactocerebroside

E. Phosphatidyl Inositol

Answer- The right answer is  B–GM1 Ganglioside.

Gangliosides are kind of glycolipids. Glycolipids are compound lipids containing carbohydrates besides lipid components. Glycolipids are widely distributed in every tissue of the body, particularly in nervous tissue such as brain. They occur particularly in the outer leaflet of the plasma membrane, where they contribute to cell surface carbohydrates. The major glycolipids found in animal tissues are glycosphingolipids. They contain ceramide and one or more sugars. Galactosyl ceramide is a major glycosphingolipid of brain and other nervous tissue, found in relatively low amounts elsewhere. It contains a number of characteristic C24 fatty acids, eg, Cerebronic acid (figure-1).

Galactosyl ceramide

Figure-1- Structure of galactosylceramide (Galactocerebroside), Sphingosine is an amino alcohol, a complex of fatty acid and sphingosine is called ceramide.

Galactosylceramide can be converted to sulfogalactosylceramide (sulfatide), present in high amounts in myelin. Glucosylceramide is the predominant simple glycosphingolipid of extraneural tissues, also occurring in the brain in small amounts.

Gangliosides are complex glycosphingolipids derived from glucosylceramide that contain in addition one or more molecules of a sialic acid. Neuraminic acid (NeuAc)is the sialic acid found in human tissues. Gangliosides are also present in nervous tissues in high concentration. They appear to have receptor and other functions. The simplest ganglioside found in tissues is GM3, which contains ceramide, one molecule of glucose, one molecule of galactose, and one molecule of NeuAc. In the shorthand nomenclature used, G represents ganglioside; M is a monosialo-containing species; and the subscript 3 is a number assigned on the basis of chromatographic migration. GM1 a more complex ganglioside derived from GM3, is of considerable biologic interest, as it is known to be the receptor in human intestine for cholera toxin (figure-2).Other gangliosides can contain anywhere from one to five molecules of sialic acid, giving rise to di-, trisialogangliosides, etc. Gangliosides also serve as receptors for circulating hormones and thereby influence various biochemical processes in the cells.

GM1

Figure-2- GM1 ganglioside, a monosialo ganglioside, the receptor in human intestine for cholera toxin

Case discussion

In the present case, the patient is suffering from cholera. Cholera is an acute diarrheal disease that can, in a matter of hours, result in profound, rapidly progressive dehydration and death. Cholera is caused by the bacteria, Vibrio cholerae. Infection occurs upon consumption of contaminated food, often seafood, or water. Cholera is rare except in areas where sanitation is inadequate. Patients present with watery diarrhea and vomiting, usually with no fever.

Cholera is a toxin-mediated disease. Its characteristic watery diarrhea is due to the action of cholera toxin, a potent protein enterotoxin elaborated by the organism after it colonizes the small intestine. The cholera toxin, choleragen, is a protein composed of two functional units a B subunit  and A subunit, The B pentamer binds to GM1 ganglioside, a glycolipid on the surface of epithelial cells that serves as the toxin receptor and makes possible the delivery of the A subunit to its cytosolic target. The A subunit catalyzes the covalent modification of Gs protein. The result is the intracellular accumulation of high levels of cyclic AMP (figure-3).

These events lead to the accumulation of sodium chloride in the intestinal lumen. Since water moves passively to maintain osmolality, isotonic fluid accumulates in the lumen. Watery diarrhea results, when the volume of the fluid exceeds the capacity of the rest of the gut to reabsorb it. Unless the wasted fluid and electrolytes are adequately replaced, shock (due to profound dehydration) and acidosis (due to loss of bicarbonate) follow. Identifying the bacteria in a stool sample confirms the diagnosis. Replacing lost fluids and giving antibiotics effectively treats the infection.

Pathogenesis of cholera toxin

Figure-3-Normally Na+ is absorbed from the intestinal lumen through Na+/H+ exchange system. In the infected cells- B subunit of cholera toxin binds to GM1 Ganglioside and A subunit brings about covalent modification of Gs protein. As a result there is accumulation of c -AMP.  There is constant activation of protein kinase a enzyme. PKA opens the chloride channel but inhibits Na+/H+ exchange. In these events there is accumulation of Na+ and Clin the lumen. Water moves out as an osmotic effect causing diarrhea.

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