5. Paradigms of Gastrointestinal Infections – V. cholerae - colonization of the surface of the

enterocytes with production of an exotoxin (enterotoxin) that causes secretory diarrhea. No damage to

the enterocytes and little inflammatory response.

Reading and Case Studies – Text Chapter 16, Reading Assignment (6) and Mr. V, p. 527-528, and

Case 20 in Reading Assignment (7).

A. Microbiology - V. cholerae – Gram negative curved (comma shaped) rod with a single polar

flagellum.

B. Pathogenesis of V. cholerae

1. The motile bacteria move to the surface of the enterocyte, attach and colonize:

VIRULENCE FACTORS

a. Flagella – allow the bacteria to move through the intestinal mucus to reach the

the surface of the enterocyte.

b. Attachment via colonization factors – Toxin coregulated pilus (TCP)

2. Production of Cholera Toxin (CT). The gene for CT is encoded on a bacteriophage

which is integrated into the bacterial chromosome. CT is an A-B exotoxin

(enterotoxin) which acts locally in the small intestine to cause the symptoms of the

disease.

CT:

a. 5 B subunits (bind to GM1 ganglioside on the enterocyte surface), 1 A subunit

diffuses into the cell cytoplasm through a pore created by the 5 B subunits.

As it diffuses in, A is nicked into A1 and A2 subunits.

b. The A-1 subunit ADP ribosylates the Gs (stimulatory) membrane-bound

regulatory protein of adenylate cyclase –“locking it on”. The increased

adenylate cyclase causes increased levels of cAMP which accumulate along

the cell membrane causing active secretion of electrolytes into the lumen of

the small intestine.

3. The virulence factors of V. cholerae are coordinately regulated by a two component

regulatory system. This system is different in that there is a single transmembranous

protein (ToxR) that acts as both the sensor (senses environmental signals) and the

regulator protein (binds to the promoter region of V. cholerae virulence genes, leading

to increased expression of CT and TCP.) Exact environmental signals not fully

understood.

C. Epidemiology (Read the “Cholera Lesson”)

1. Ecology – grows naturally in marine environments worldwide. Can associate with

phytoplankton and chitinous shellfish.

2. Transmission – asymptomatic or symptomatic individuals contaminate water or food.

Large numbers must be ingested to cause disease. Smaller infectious dose if stomach

acid is compromised (antacids, acid- supressing medication, after gastric surgery).

3. Serogroups Associated with Disease:

1. O1 serogroup – historically caused periodic pandemics; two biotypes –

“Classical and El Tor”.

2. O 139- the first non-O1 serogroup associated with epidemic disease.

3. Other non-O1 strains present in the Gulf of Mexico – disease is associated with

consumption of raw oysters. (See Case Studies, above)

D. The Disease Cholera- Asymptomatic colonization to mild diarrhea, to severe rapidly fatal

diarrhea “ rice water” stools – up to one liter/hour. Severe fluid and electrolyte loss leads to

dehydration, shock, and death (60% of the time) if untreated.

E. Treatment and Prevention

1. Oral (or intravenous) rehydration therapy

2. Separate sewage and drinking water systems, disinfection of drinking water and food;

hygiene measures.

3. Killed vaccine – no longer recommended by WHO because of its limited protective

efficacy- provided limited protection against O1 infections and no protection against O

139 infections.