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Cholera: Mechanism of Infection, History and Treatment Kathleen E. Page

Cholera: Mechanism of Infection, History and Treatment

byKathleen E. Page

College of Medicine Class of 2007Medical University of South CarolinaMolecular Basis of Medicine Treatise

Abstract

The bacterium Vibrio cholerae causes the diarrheal disease known as cholera. Thisgram-negative bacterium produces an endotoxin which locks a G protein into theconfiguration promoting constant cAMP formation. Cyclic AMP elevation causesinhibition of sodium and chloride into intestinal cells thereby causing them to releasewater, resulting in the massive diarrhea that characterizes the illness. Cholera symptoms

vary with the percentage of body fluid loss. Treating cholera mainly involves ofreplacing the fluids lost to diarrhea. The illness spreads via the fecal-oral route and canbe passed by ingesting either contaminated food or water. Vaccines are available, buttravelers from developed countries are said to be at low risk of contracting the disease.

Page, Kathleen E. Cholera: Mechanism of Infection, History and Treatment. South Carolina Journal of MolecularMedicine (SCJ MM) 5:26-29; 2004.

Authors Addresses:[email protected]

The manuscript has been seen and approved by the author and the editor.

The term cholera designates the severediarrheal disease caused by thebacterium Vibrio cholerae. Thebacteriums name originates from theGreek words meaning flow of bile. V.cholerae is a gram-negative flagellatedbacillus that colonizes the intestinallumen. The bacteria do not invade theintestinal epithelia. Instead, theendotoxin they produce, designated

cholera toxin (CT), invades these cellsand causes the disastrous symptoms.Cholera spreads via the fecal-oral routeand proves to have more devastatingconsequences in areas lacking propersanitation of water and human waste.Italian scientist Filippo Pacini firstdescribed cholera during an 1854

outbreak in Florence. He performedautopsies of cholera patients andmicroscopically examined histologicalsections of the intestinal mucosa. Hediscovered a comma-shaped bacillus andpublished a paper the same year entitled"Microscopical observations andpathological deductions on cholera."Pacini supported the germ theory andinsisted that cholera was contagious.

Until the 1965 acknowledgement ofPacinis earlier discovery by theinternational committee onnomenclature, Robert Koch had beencredited with discovering the bacteriumthat caused cholera. During the 1883epidemic in Egypt, he discovered abacillus present in the intestinal lumen of

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patients who had died of cholera but notother causes. He followed the epidemicto India, and in 1884 finally isolated thebacillus in pure culture. He, like Pacini,noted the bent shape of the bacillus.1

Also important to the elucidation ofcholeras causative organism is the workof John Snow. At medical conferencesin 1849 and 1853 he had argued thatdiseases such as cholera spread viadrinking water rather than air. His ideasreceived few supporters. During the1854 cholera epidemic in London,however, he probed his water-bornetheory further. Through methodicalepidemiological investigation, Snow

eventually determined the primarysource of contamination to be the BroadStreet pump. Upon the removal of itshandle, the number of new cases ofcholera fell dramatically, and thendisappeared. Investigation of the pumprevealed that a sewer pipe passed withina few feet of the well. The pipe hadgradually leaked its raw sewage into thedrinking water supply.2

Vibrio cholerae can be subdivided into

serogroups based upon antigens on itssomatic surface. The serogroups O1 andO139 comprise the pathogenic strains.The O1 serogroup can be further dividedinto three serotypes according to somaticantigens and then into two biotypesaccording to specific phenotypes.Ogawa (somatic antigens A and C),Inaba (A and B), and Hikojima (A, Band C) designate the serotypes. El Torand classic designate the biotypes. TheO1 El Tor biotype predominates in mostcurrent infections.3 Serogroups O1 andO139 prove pathogenic due to theirproduction of an enterotoxin thatpromotes the secretion of fluids andelectrolytes into the intestinal lumen,resulting in diarrhea once the amount

overcomes the bodys resorptivemechanisms.This cholera toxin contains two Asubunits and five B subunits. The Bsubunits allow binding to a ganglioside

(GM1) receptor on the intestinalepithelial cells. The B pentamer mustbind to five corresponding GM1receptors. This binding occurs on cellsurface areas termed lipid rafts, due toconcentration of specific lipids.Membrane cholesterol is critical to theseinteractions and endocytosis of the Asubunits. In an experiment removingcholesterol from epithelial membranes,researchers found that its presence

facilitates the CT-GM1 complexformation and endocytosis.4 Anotherexperiment proved that the lipid raftshelp anchor the toxin to the membranefor endocytosis of the A subunits. Theyhelp traffic the toxin into the cell, and tothe basolateral surface, where it acts.5Once internalized, the A subunitsproteolytically cleave into A1 and A2peptides. The A1 peptide ADP-ribosylates a GTP-binding protein,

thereby preventing its inactivation. Thealways active G protein causes adenylatecyclase to continue forming cAMP.This increase in intracellular cAMPblocks absorption of sodium andchloride by microvilli and promotes thesecretion of water from the intestinalcrypt cells to preserve osmotic balance.6This water secretion causes the waterydiarrhea with electrolyte concentrationsisotonic to plasma. The fluid loss occursin the duodenum and upper jejunum,with the ileum less affected. The colonis less sensitive to the toxin, and istherefore still able to absorb some fluid.The large volume, however, overwhelmsthe colons absorptive capacity.7

Symptoms of cholera begin following a24- to 48-hour incubation period.

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Patients experience a sudden onset ofhigh volume watery diarrhea that is oftenfollowed by vomiting. Abdominalcramps may accompany thesesymptoms. The diarrhea has a

characteristic rice water appearance.Its volume in severe manifestations ofthe disease can exceed 250 mL/kg in thefirst twenty-four hours. Adults typicallypresent as afebrile, while children mayhave a fever. Other clinical signscorrespond to the patients degree ofdehydration on presentation. With afluid loss of 3-5% of the body weight,the patient complains of excessive thirst.With a 5-8% loss, the patient

experiences hypotension, tachycardia,weakness, fatigue, and dry mucousmembranes. With greater than a 10%loss, the patients urine output decreasessignificantly; the eyes appear glassy andsunken; fontanelles in infants appearsunken; the pulse becomes weak,thready or absent; the skin appearswrinkled; the patient seems excessivelysleepy or may lapse into a coma.5

Treatment of cholera proves fairly

simple: patients must be rehydrated toavoid hypovolemic shock and death.This process occurs in two phases,primary rehydration and maintenance.Patients who can tolerate oralrehydration solution (ORS) shouldreceive it, while severely dehydratedpatients can receive Lactated Ringerssolution or saline IV. Achieving normalhydration status should take less thanfour hours, with the rate for severelydehydrated patients approaching 50-100mL/kg/hour. Upon attainment of normalhydration status, the patient mustcontinue to receive oral ORS or IV fluidtherapy until the diarrhea abates.Treatment guidelines recommend a ratein adults of 500-1000 mL/hour of oralrehydration solution to maintain normal

hydration status. Antibiotics can beuseful in treatment of the infection, butthey are not curative. Tetracycline,ciprofloxacin and erythromycin canshorten the duration and volume of fluid

loss, but the disease still must run itscourse. Drug resistance becomes aconcern in areas with endemic cholera. 5Treatment with appropriate fluids saveslives of patients, and with no treatment25-50% of typical cases are fatal.8

Cholera infection requires a relativelyhigh infectious dose of the bacteria. In awater vehicle, the infectious dose is 103to 106 organisms, while a food vehiclerequires only 102 to 104 organisms. This

high dose results from the bacteriassusceptibility to the acidity of thestomach. The risk of cholera infectionincreases in those persons who useantacids, histamine receptor blockers,and proton pump inhibitors as thesedrugs decrease gastric acidity. The samerisk applies to patients with chronicgastritis due to H. pylori infection orthose who have had a gastrectomy.Persons with type O blood also have an

increased risk of infection, and thissusceptibility is not fully understood.5Equally important to the treatment ofcholera is the prevention of futureinfections. Since cholera spreads via thefecal-oral route, creating or maintaininga potable water supply is critical duringan epidemic. Boiling and chlorination ofwater can help kill the bacteria in watersupplies. Proper disposal and/orsterilization of infectious waste, properhygiene in food preparation, and cookingfoods to high enough temperatures alsohelp to attenuate the epidemic. Infectionwith the O1 serogroup seems to conveyimmunity against future infection withthe same strain of bacteria, however thisdoes not hold true for the O139serogroup. Vaccines can help limit

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epidemics in endemic areas where poorsanitation seems difficult to overcome.Theoral route of vaccination seems mosteffective. The WC/rBS vaccine consistsof killed, whole cell V. cholerae as well

as the purified recombinant B subunit ofthe cholera toxin. This particularvaccine offers less protection against theEl Tor biotype. Another oral vaccine,CVD 103-HgR, uses live, attenuatedcholera bacteria. So far, this vaccineseems to be well tolerated and extremelyimmunogenic. New vaccines are beingtested against El Tor and O139.Vaccination is no longer required forinternational travelers, as the risk of an

international traveler from a developedcountry contracting cholera is so small(1 case in 500,000 travelers).5,9Cholera causes disease in many thirdworld countries lacking proper sanitationmethods, but it is relatively easy to treat.Nonetheless, further investigation intovaccine possibilities would no doubt aidin preventing these infections. Furtherunderstanding of the role of lipid rafts inthe mechanism of disease may one day

help in development of drugs orvaccines. The more pressing issue,however, is adequate funding andmanpower to control the present cholerapandemics in Asia and Central America.

References

1 Frerichs, Ralph R.http://www.ph.ucla.edu/epi/snow/firstdiscoveredcholera.html. Dateaccessed: October 28, 2003.

2 Frerichs, Ralph R.http://www.ph.ucla.edu/epi/snow/uab_snow.htm. Date accessed:October 28, 2003.

3http://www.cdc.gov/ncidod/dbmd/dis

easeinfo/cholera/ch5.pdf. Dateaccessed: October 28, 2003.

4 Wolf, A.A., Fujinaga, Y., and Lencer,W.I. (2002). Uncouplingof the

cholera toxin-G(M1) gangliosidereceptor complex from endocytosis,retrograde Golgi trafficking, anddownstream signal transduction bydepletion of membrane cholesterol.J. Biol. Chem. 277, 1624916256.

5 Lencer, W. I. 2001. Microbes, andmicrobial toxins. Paradigms formicrobial-mucosal toxins. V.Cholera: invasion of theintestinalepithelial barrier by a stably folded

protein toxin. Am. J . Physiol.Gastrointest. Liver Physiol.280:G781-G786.

6 Torgersen, M. L., G. Skretting, B. vanDeurs, and K. Sandvig. 2001.Internalization of choleratoxin bydifferent endocytic mechanisms. J .Cell Sci. 114:3737-3747.

7 Handa, Sajeev.http://www.imedicine.com/wc.dll?emedclass~displayTopic~&BookId=6

&Topic=351&id=1026&accttype=P.Date accessed: October23, 2003.8

http://www.cdc.gov/ncidod/dbmd/diseaseinfo/cholera_t.htm. Dateaccessed: November 17,2003.

9 Mandell: Principles and Practice ofInfectious Diseases, 5thed.,Copyright 2000 ChurchillLivingstone, Inc.

Editor: Maurizio Del Poeta, MDSelective 2003: Lipid-mediated InfectiousDiseases

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