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Cholera - Causes and Pathogenesis
Last reviewed: 04.07.2025
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Causes of cholera
The cause of cholera is Vibrio cholerae, which belongs to the genus Vibrio of the family Vibrionaceae.
The cholera vibrio is represented by two biovars, similar in morphological and tinctorial properties (the cholera biovar and the El Tor biovar).
The causative agents of cholera are vibrios of serogroups 01 and 0139 of the species Vibrio cholerae, which belongs to the genus Vibrio, family Vibrionaceae. Within the species Vibrio cholerae, two main biovars are distinguished - biovar cholerae classic, discovered by R. Koch in 1883, and biovar El Tor, isolated in 1906 in Egypt at the El Tor quarantine station by F. and E. Gotshlich.
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Cultural properties
Vibrios are facultative anaerobes, but prefer aerobic growth conditions, so they form a film on the surface of the liquid nutrient medium. The optimum growth temperature is 37 °C at a pH of 8.5-9.0. For optimum growth, microorganisms require the presence of 0.5% sodium chloride in the medium. The accumulation medium is 1% alkaline peptone water, on which they form a film within 6-8 hours. Cholera vibrios are unpretentious and can grow on simple media. The elective medium is TCBS (thiosulfate citrate sucrose-bile agar). Alkaline agar and tryptone soy agar (TSA) are used for subculturing.
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Biochemical properties
The causative agents of cholera are biochemically active and oxidase-positive, have proteolytic and saccharolytic properties: produce indole, lysine decarboxylase, liquefy gelatin in a funnel-shaped form, do not produce hydrogen sulfide. Ferment glucose, mannose, sucrose, lactose (slowly), starch, do not ferment rhamnose, arabinose, dulcitol, inositol, inulin. Have nitrate reductase activity.
Cholera vibrios differ in their sensitivity to bacteriophages. The classic cholera vibrio is lysed by bacteriophages of group IV according to Mukerjee, and the El Tor biovar vibrio is lysed by bacteriophages of group V. Differentiation among cholera pathogens is carried out by biochemical properties, by the ability to hemolyze ram erythrocytes, agglutinate chicken erythrocytes, and by sensitivity to polymyxin and bacteriophages. Biovar El Tor is resistant to polymyxin, agglutinates chicken erythrocytes and hemolyzes ram erythrocytes, has a positive Voges-Proskauer reaction and hexamine test. V. cholerae 0139 belongs to the El Tor biovar according to phenotypic characteristics.
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Antigenic structure
Cholera vibrios have O- and H-antigens. Depending on the structure of the O-antigen, more than 150 serogroups are distinguished, among which the causative agents of cholera are serogroups 01 and 0139. Within serogroup 01, depending on the combination of A-, B- and C-subunits, there is a division into serovars: Ogawa (AB), Inaba (AC) and Hikoshima (ABC). Vibrios of serogroup 0139 are agglutinated only by serum 0139. The H-antigen is a generic antigen.
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Attitude to environmental factors
The causative agents of cholera are sensitive to UV, drying, disinfectants (except quaternary amines), acidic pH values, and heating. The causative agents of cholera, especially the El Tor biovar, are capable of existing in water in symbiosis with hydrobionts and algae; under unfavorable conditions, they can transform into an uncultivated form. These properties allow us to classify cholera as an anthroposapronosis infection.
Pathogenicity factors
The V. cholerae genome consists of two circular chromosomes: large and small. All genes necessary for life and the implementation of the pathogenic principle are localized on the large chromosome. The small chromosome contains an integron that captures and expresses antibiotic resistance cassettes.
The main pathogenicity factor is cholera enterotoxin (CT). The gene mediating the synthesis of this toxin is localized in the toxigenicity cassette located on the genome of the filamentous bacteriophage CTX. In addition to the enterotoxin gene, the zot and ace genes are located on the same cassette. The product of the zot gene is a toxin (zonula occludens toxin), and the ace gene determines the synthesis of an additional enterotoxin (accessory cholerae enterotoxin). Both of these toxins participate in increasing the permeability of the intestinal wall. The phage genome also contains the ser-adhesin gene and the RS2 sequence encoding phage replication and its integration into the chromosome.
The receptor for the CTX phage is the toxin-regulated pili (Ter). They are type 4 pili, which, in addition to being receptors for the CTX phage, are necessary for colonization of the microvilli of the small intestine, and also participate in the formation of biofilm, in particular on the surface of the shell of aquatic organisms.
Ter are expressed in a coordinated manner with the CT gene. The large chromosome also contains the pap gene, which determines the synthesis of neuraminidase, which facilitates the implementation of the toxin action, and the hap gene, which determines the synthesis of soluble hemallutinin protease, which plays an important role in the removal of the pathogen from the intestine into the external environment as a result of its destructive action on the receptors of the intestinal epithelium associated with vibrios.
Colonization of the small intestine by toxin-regulated pili creates a platform for the action of cholera enterotoxin, which is a protein with a molecular weight of 84,000D, consisting of 1 subunit A and 5 subunits B. Subunit A consists of two polypeptide chains A1 and A2, linked together by disulfide bridges. In the B subunit complex, five identical polypeptides are linked to each other by a non-covalent bond in the form of a ring. The B-subunit complex is responsible for binding the entire toxin molecule to the cellular receptor - monosialic ganglioside GM1, which is very rich in epithelial cells of the small intestinal mucosa. In order for the subunit complex to interact with GM1, sialic acid must be cleaved from it, which is carried out by the enzyme neuraminidase, which facilitates the implementation of the toxin's action. Subunit complex B after attachment to 5 gangliosides on the intestinal epithelial membrane changes its configuration so that it allows A1 to detach from the A1B5 complex and penetrate the cell. Having penetrated the cell, the A1 peptide activates adenylate cyclase. This occurs as a result of the interaction of AI with NAD, resulting in the formation of ADP-ribose, which is transferred to the GTP-binding protein of the regulatory subunit of adenylate cyclase. As a result, the functionally necessary hydrolysis of GTP is inhibited, leading to the accumulation of GTP in the regulatory subunit of adenylate cyclase, determining the active state of the enzyme, and as a consequence - increased synthesis of c-AMP. Under the influence of c-AMP in the intestine, active ion transport changes. In the crypt area, epithelial cells intensively release Cl- ions, and in the villi area, the absorption of Na+ and Cl- is hampered, which forms the osmotic basis for the release of water into the intestinal lumen.
Cholera vibrios survive well at low temperatures; they survive in ice for up to 1 month, in sea water - up to 47 days, in river water - from 3-5 days to several weeks, in soil - from 8 days to 3 months, in feces - up to 3 days, on raw vegetables - 2-4 days. on fruits - 1-2 days. Cholera vibrios die in 5 minutes at 80 °C, instantly at 100 °C; they are highly sensitive to acids, drying and direct sunlight, under the influence ofChloramine and other disinfectants die within 5-15 minutes, persist well and for a long time and even multiply in open water bodies and waste waters rich in organic matter.
Pathogenesis of cholera
The entry point for infection is the digestive tract. The disease develops only when the pathogens overcome the gastric barrier (usually this is observed during the period of basal secretion, when the pH of the gastric contents is close to 7), reach the small intestine, where they begin to intensively multiply and secrete exotoxin. Enterotoxin or choleragen determines the occurrence of the main manifestations of cholera. Cholera syndrome is associated with the presence of two substances in this vibrio: protein enterotoxin - choleragen (exotoxin) and neuraminidase. Choleragen binds to a specificenterocyte receptor - ganglioside. Under the action of neuraminidase, a specific receptor is formed from gangliosides. The cholera-specific receptor complex activates adenylate cyclase, which initiates the synthesis of cAMP. Adenosine triphosphate regulates the secretion of water and electrolytes from the cell into the intestinal lumen by means of an ion pump. As a result, the mucous membrane of the small intestine begins to secrete a huge amount of isotonic fluid, which does not have time to be absorbed in the large intestine - isotonic diarrhea develops. With 1 liter of feces, the body loses 5 g of sodium chloride. 4 g of sodium bicarbonate, 1 g of potassium chloride. The addition of vomiting increases the volume of fluid lost.
As a result, the plasma volume decreases, the volume of circulating blood decreases and it thickens. The fluid is redistributed from the interstitial to the intravascular space. Hemodynamic disorders and microcirculation disorders occur, which result in dehydration shock and acute renal failure. Metabolic acidosis develops, which is accompanied by convulsions. Hypokalemia causes arrhythmia, hypotension, changes in the myocardium and intestinal atony.