Cholera: causes and pathogenesis
Last reviewed: 23.04.2024
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Causes of Cholera
The cause of cholera - Vibrio cholerae belongs to the genus Vibrio of the family Vibrionaceae.
The cholera vibrio is represented by two biovars, similar in morphological and tinctorial properties (the biology of the cholera proper and the El Tor biologist).
The causative agents of cholera are the vibrios of serogroups 01 and 0139 of the species Vibrio cholerae, which belongs to the genus Vibrio, the family Vibrionaceae. Inside the species Vibrio cholerae distinguish two main biovars - biovar cholerae classic, discovered by R. Koch in 1883, and biovar El Tor, isolated in 1906 in Egypt in the quarantine station El Tor F. And E. Gottshlichami.
Culture properties
Vibrios are facultative anaerobes, but they prefer aerobic growth conditions, so a film forms on the surface of the liquid nutrient medium. The optimum growth temperature is 37 ° C at pH 8.5-9.0. For optimal 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 for 6-8 hours. Cholera vibrios are unpretentious and can grow on simple media. The selective medium is TCBS medium (thiosulfate citrate sucrose-containing agar). Alkaline agar and tryptone-soy agar (TCA) are used for subculturing.
Biochemical properties
Cholera pathogens are biochemically active and oxidase-positive, have proteolytic and saccharolytic properties: they produce indole, lysine decarboxylase. Liquefied in funnel-shaped form gelatin, do not produce hydrogen sulphide. Ferment glucose, mannose, sucrose, lactose (slowly), starch, do not ferment rhamnose, arabiose, dulcite, inositol, inulin. Have nitrate reductase activity.
Cholerae vibrios differ in sensitivity to bacteriophages. The classic cholera vibrio is lysed by group IV bacteriophages by Mukerjee, and the vibrio of the biovar El Tor is bacteriophages of group V. Differentiation among the pathogens of cholera is carried out according to biochemical properties, by the ability to hemolyze erythrocytes of a ram, agglutinate chicken red blood cells, and also by sensitivity to polymyxin against bacteriophages. Biovar El Tor is resistant to polymyxin, agglutinates chicken red blood cells and hemolysates erythrocytes of ram, has a positive reaction of Foges-Proskauer and a hexamine test. V. Cholerae 0139 on phenotypic signs refers to the biologist El Tor.
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Antigenic structure
Cholera vibrios possess O- and H-antigens. Depending on the structure of the O-antigen, more than 150 serogroups are distinguished, among them the serogroups 01 and 0139 are the causative agents of the cholera. Within the serogroup 01, depending on the combination of the A-, B- and C-subunits, a subdivision into serovars occurs: Ogawa (AB), Inaba AC) and Gikoshima (ABC). Serum 0139 vibrios are agglutinated only by serum 0139. H-antigen is a common antigen.
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Attitude to environmental factors
Cholera pathogens are sensitive to UV, drying, disinfectants (with the exception of quaternary amines), acidic pH values, heating. The causative agents of cholera, especially the biologist El Tor, are able to exist in water in symbiosis with hydrobionts, algae, under unfavorable conditions, can pass into a noncultivated form. These properties allow attribution of cholera to anthroposapronous infections.
Pathogenicity factors
The V. Cholerae genome consists of two circular chromosomes: large and small. All genes necessary for vital activity and the realization of the pathogenic origin are localized on a large chromosome. A small chromosome contains an integrin that captures and expresses antibiotic resistance cassettes.
The main factor of pathogenicity is cholera enterotoxin (CT). The gene mediating the synthesis of this toxin is localized in the toxigen cassette located on the genome of the filamentous bacteriophage CTX. In addition to the enterotoxin gene, zot and ace genes are on the same cassette. The product of the zot gene is toxin, (zonula occludens toxin), and the gene determines the synthesis of additional enterotoxin (accessory cholerae enterotoxin). Both these toxins are involved in increasing the permeability of the intestinal wall. The genome of the phage also contains the ser-adhesin gene and the RS2 sequence, which codes for phage replication and its integration into the chromosome.
The receptor for phage CTX is toxin-regulating pilings (Ter). They are Type 4 pili which, in addition to being receptors for CTX phage, are necessary for the colonization of small intestinal microvilli, and also participate in the formation of biofilms, in particular on the surface of the carbiontte shell.
Ter is coordinately expressed with the CT gene. On the large chromosome there is also the pope gene, which determines the synthesis of neuraminidase, which contributes to the effect of toxin, and the hap gene, which determines the synthesis of soluble hemal- tonin proteinase, which plays an important role in excreting the causative agent from the intestine to the external environment as a result of its destructive effect on the intestinal epithelial receptors associated with vibrios.
Colonization of the small intestine, carried out by toxin-regulated pilils, creates a springboard for the action of cholera enterotoxin, which is a protein with a molecular weight of 84000D, consisting of 1 subunit of A and 5 subunits of B. Subunit A consists of two polypeptide chains A1 and A2 interconnected by disulfide bridges. In the subunit complex B, 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 molecule of the toxin to the cellular receptor - monosial 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 neuraminidase enzyme, which facilitates the action of the toxin. Subunit complex B after attachment to the 5 gangliosides on the membrane of the intestinal epithelium changes its configuration so that A1 can detach from the A1B5 complex and enter the cell. Penetrating into the cell, A1 peptide activates the adenylate cyclase. This occurs as a result of the interaction of AI with NAD, which results in the formation of ADP-ribose, which is transferred to the GTP-binding protein of the regulatory subunit of adenylate cyclase. As a result, there is an inhibition of the functionally necessary hydrolysis of GTP, resulting in the accumulation of GTP in the regulatory subunit of adenylate cyclase, determining the active state of the enzyme, and as a consequence - enhancing the synthesis of c-AMP. Under the influence of C-AMP in the intestine, the active transport of ions changes. In the crypt region of epithelial cells, C1- ions are strongly isolated, and in the villus region, absorption of Na + and Cl- is difficult, which is the osmotic basis for isolating water into the intestine.
Cholera vibrios survive well at low temperature; in the ice persist up to 1 month. In sea water - up to 47 days, in river water - from 3-5 days to several weeks, in the soil - from 8 days to 3 months, in feces - up to 3 days, on raw vegetables - 2-4 days. On fruit - 1-2 days. Cholera vibrios at 80 ° C die after 5 minutes, at 100 ° C - instantly; highly sensitive to acids, drying and the action of direct sunlight, killed by chloramine and other disinfectants after 5-15 minutes, remain well and long and even reproduce in open water and sewage, rich in organic substances.
Pathogenesis of cholera
The gateway to infection is the digestive tract. The disease develops only when the pathogens cross the gastric barrier (usually it is observed in the period of basal secretion, when the pH of the gastric contents is close to 7), reach the small intestine, where they begin to multiply extensively and release exotoxin. Enterotoxin or cholerogen determines the occurrence of the main manifestations of cholera. Cholera syndrome is associated with the presence in this vibrio of two substances: protein enterotoxin - cholerogen (exotoxin) and neuraminidase. Cholerogen binds to a specific receptor of enterocytes - ganglioside. Under the influence of neuraminidase, a specific receptor is formed from the gangliosides. The complex of the cholerogen-specific receptor activates adenylate cyclase, which initiates the synthesis of cAMP. Adenosine triphosphate regulates through the ion pump the secretion of water and electrolytes from the cell to the lumen of the intestine. As a result, the mucosa of the small intestine begins to secrete a huge amount of isotonic fluid that does not have time to be absorbed in the large intestine, isotonic diarrhea develops. With 1 liter of stool, the body loses 5 g of sodium chloride. 4 g of sodium hydrogencarbonate, 1 g of potassium chloride. The addition of vomiting increases the volume of fluid lost.
As a result, the volume of plasma decreases, the volume of circulating blood decreases and it thickens. The fluid is redistributed from the interstitial to the intravascular space. There are hemodynamic disorders, disorders of microcirculation, 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 atony of the intestine.