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5 x 3 micrometers) *Facultative anaerobes *Fermentative *Require salt for growth (V. cholerae can grow on most media without added salt) *Susceptible to stomach acids *Strains subdivided into 140 serogroups (O cell wall antigens) *Serogroup O1 subdivided into serotypes (Inaba, Ogawa, and Hikojima) and biotypes (Classic and El Tor---classified based on certain enzymes produced) Epidemiology: *Serotype O1 responsible for major pandemics with significant mortality in developing countries *Serotype O139 can cause similar diseases *Organism found in estuarine and marine environments worldwide *associated with chitinous shellfish *organisms can multiple freely in water *bacterial levels in contaminated waters increase during the warm months *spread by consumption of contaminated food or water *Direct person-person spread is rare b/c the infectious does is so high (more than 108 organisms) because most organisms are killed by stomach acids Virulence Factors: 1) Cholera Toxin (CTX) encoded for by bacteriophage CTXΦ *two subuints: ctxA (A1 and A2 portion connected by a disulfide bond) and ctxB (5 identical B subunits assembled to form a pentamer) *the bacteriophage binds to the toxin-coregulated pilus (tcp) and moves into the bacterial cell, where it becomes integrated into the V. cholerae genome *toxin finishes assembly in the periplasm and is then released into the gut lumen *binds to its receptor: the GM1 ganglioside on the luminal surface of the gut epithelial cells *several B subunits must bind to GM1 gangliosides to assure tigh attachment of the toxin *the entire cholera toxin is endocytosed in caveolae in a clathrin-independent fashion *caveloin addresses the vesicle to the trans-Golgi network--> vesicle fuses with outer cisternae *pH of the Golgi causes separation of A from B subunits—B pentamers remain in Golgi with no further action *A subunit contains KDEL sequence → transported to cis-Golgi (COPI-dependent)--> pinched off into a vesicle that is moved to the RER--> fuses to get inside RER → A subunit reduced by disulfide isomerase → A1 enters cytoplasm via sec61 → avoids ubiquitnylation (has very few lysine residues) → activates ARF by enzymatic transfer of myristic acid to one of the amino acid R groups in ARF (the ARF refolds) and by ARF binding to GTP → A1-ARF complex moves exits Golgi and enters baolateral membrane of the cell → A1 subunit binds to the alpha subunit of the heterotrimeric G protein → A1 subunit catalyzes the hydrolysis/transfer of ADP-ribose from NAD to the alpha subunit (releasing nicontinamide) → this subunit now blocks the alpha subunit from hydrolyzing GTP (it's permamently activated) → activated G-alpha subunit activates adenylate cyclase, which cleaves ATP to produce cAMP (potent intracellular messenger) → cAMP diffuses throughout cell: 4 molecules bind to the regulatory subunit of protein kinase A, which allows the catalytic subunit to drift away and phosphorylate target proteins like CFTR at the expense of ATP → Ser813 of CFTR phosphorylated → chloride transported out of cell into extracellular fluid → sodium ions also are ejected out of the cell by the Na+/K+-ATPase into the lumen ---> water follows salt out of the cells *Cholera toxin causes the crypt cells of the epithelium to secrete chloride ions (with Na+ and water following) *In the presence of the toxin, the cells lining the villus are blocked from resorbing sodium and chloride as they normally do *Cholera toxin causes the goblet cells of the epithelium to secrete abnormally large amounts of
mucin into the gut lumen 2) Toxin co-regulated pilus * binding site for CTXΦ *mediates adherence to intestinal mucosal cells *nonadherent strains are unable to establish infection *encoded by the tcp gene complexing 3) Chemotaxis Protein *adhesion factor *encoded for by the cep genes 4) Accessory Cholera Enterotoxin *increases intestinal fluid secretion 5) Zonlua Occludens Toxin *Increases intestinal permeability by loosening the tight junctions of the small intestine 6) Neuraminidase *modifies cell surface to increase GM1 binding sites for cholera toxin Clinical Summary: begins as an abrupt onset of watery diarrhea and vomiting and can progress to severe dehydration, metabolic acidosis and hypokalemia, and hypolemic shock *Most exposed have aymptomatic infections or self-limited diarrhea *Some develop severe, rapidly fatal diarrhea -incubation period 2-3 days after ingestion of V. cholerae cells -abrupt onset of watery diarrhea and vomiting -“rice-water” stools -severe fluid and electrolyte loss can lead to dehydration, painful muscle cramps, metabolic acidosis (due to bicarbonate loss), cardiac arrhythmia, and renal failure -mortality is 60% in untreated patients; less than 1% if rehydration started promptly Immunological Response: -mostly non-inflammatory infection; toxin is causing illness, not the foreign cells themselves -usually no gross changes to intestinal epithelia or small bowel, but upregulated expression of some cytokines (NOT from primary reading, from a Nature paper) <http://www.nature.com/nrmicro/journal/v7/n10/box/nrmicro2204_BX1.html> Diagnosis: -microscopic examination of stool is generally nonproductive because the organism is diluted in the large volume of watery diarrhea -also, the organisms cannot be differentiated from other enteric organisms -culture should be performed early in the course of disease with fresh stool specimens maintained in a neutral to alkaline pH (because Virbio organisms survive poorly in an acidic or dry environment) -special selective agar for Vibrios can be used to recover them from specimens with a mixture of organisms -----thiosulfate citrate bile salts sucrose (TCBS) agar; alkaline peptone broth (an enrichment broth, pH 8.6) -isolates can be serotyped using polyvalent antisera For clinical diagnosis, history is important: recent consumption of shellfish? Recent visit to an endemic area? (Or are you in an endemic area?) Treatment: -Must treat promptly with fluid and electrolyte replacement (before the massive fluid loss leads to hypovolemic shock) -Oral Rehydration Solution (ORS) is preferred -IV fluid replacement can be used if the patient is unable to drink the fluids ( e.g, our case, the Haiti case study) -antibiotic therapy can reduce toxin production and can help to eliminate the organism more rapidly
(although of secondary value) -Azithromycin is the drug of choice for children and adults -Resistance to previously recommended drugs such as ciprofloxacin, furazolidone, and trimethoprim-sulfamethoxazole) has emerged, rendering them uneffective Public Health Aspects of Cholera: *People infected with V. cholerae can shed bacteria for the first few days of acute illness and represent important sources of new infections *Long-term carriage of V. cholerae does not occur, but vibrios are free-living in estuarine and marine reservoirs *Only improvements in sanitation can lead to effective control of cholera* *A variety of vaccines have been developed, but non have provided long-term immunity *One oral vaccine conferred immunity for 62% of trial participants at one year and showed some evidence for herd immunity, but multiple doses are required and protection fades 2-3 years after immunization *No vaccine for O139 strains *Because the infectious does of organisms is high, antibiotic prophylaxis is generally unneccesary in people who use appropriate hygiene
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