Cholera

Of all enteric pathogens, Vibrio cholerae is responsible for the most rapidly fatal diarrheal disease in humans.1 Although cholera is rare in developed countries, it remains a major cause of diarrheal morbidity and mortality in many parts of the developing world.2 However, with the occurrence of both natural (e.g. earthquakes) and human-generated calamities (such as ethnic wars), the spreading of cholera infection in refugee camps, where sanitary conditions resemble those in cholera endemic areas, represents a significant threat worldwide. Vibrios (from the Greek for 'comma') are single, short, curved Gram-negative rods, with a single, long, polar flagellum that allows for the organism's characteristic motility.

Viral Pathways Water

Figure 10.1 Enterocyte intracellular signaling leading to intestinal secretion. Four main pathways seem to be involved in the intestinal secretion of water and electrolytes: cAMP, cGMP, Ca and the cytoskeleton. These pathways are activated by several enteric pathogens, either directly or through the elaboration of enterotoxic products. CT, cholera toxin; LT, heat-labile enterotoxin; TDH, thermostable direct hemolysin; C.D., Clostridium difficile; EAST1, enteroaggregative Escherichia coli heat stable toxin 1; STa, heat stable toxin a; AC, adenylate cyclase; GC, guanylate cyclase; CM, calmodulin; PKC, protein kinase C; ZOT, Zonula Occludens Toxin; EGF-r, epidermal growth factor receptor; ECM, extracellular matrix.

Figure 10.1 Enterocyte intracellular signaling leading to intestinal secretion. Four main pathways seem to be involved in the intestinal secretion of water and electrolytes: cAMP, cGMP, Ca and the cytoskeleton. These pathways are activated by several enteric pathogens, either directly or through the elaboration of enterotoxic products. CT, cholera toxin; LT, heat-labile enterotoxin; TDH, thermostable direct hemolysin; C.D., Clostridium difficile; EAST1, enteroaggregative Escherichia coli heat stable toxin 1; STa, heat stable toxin a; AC, adenylate cyclase; GC, guanylate cyclase; CM, calmodulin; PKC, protein kinase C; ZOT, Zonula Occludens Toxin; EGF-r, epidermal growth factor receptor; ECM, extracellular matrix.

Table 10.1 Percentage of identified bacterial pathogens in symptomatic patients from industrialized and developing countries

Agent

Industrialized countries (%)

Developing countries (%)

Vibrio cholerae

<1

0-3

Non-O1 Vibrio species

?

Salmonella

3-7

4-6

Shigella

1 -3

5-9

Campylobacter

6-8

7-9

Yersinia

1-2

?

Escherichia coli

2-5

14-17

Clostridium difficile

?

?

Aeromonas, Plesiomonas,

and Edwardsiella

0-2

4-5

Vibrio cholerae 01 is transmitted by the fecal-oral route and is spread through contaminated food and water, with a period of incubation of a few hours to 5 days. The vast majority of subjects infected remain asymptomatic or experience mild disease with watery stools, rare nausea or vomiting, and no significant dehydration. Stools are classically described as 'rice water' due to the presence of mucus in clear stools. In cholera gravis, profuse watery diarrhea and vomiting lead to massive fluid and electrolyte loss that can occur at a rate of 1 litre/h, and can reach a total volume loss of 100% of body weight. Vibrios can be easily identified from the stool by Gram stain.

Cholera has been a recognized human plague for over two millennia. The study of this disease has spanned from ancient Greece, and the Roman Empire, to the famous John Snow's tracing of an outbreak to a water pump in Broad Street, London, in 1854. Thirty years later Robert Koch proposed that the agent responsible for cholera produced 'a special poison' acting on the intestinal epithelium and that the symptoms of cholera could be 'regarded essentially as a poisoning'. Considerable time elapsed before the existence of this hypothesized toxin was demonstrated in 1959. Ten years later, cholera toxin (CT) was purified to homogeneity. It was only recently, however, that we learned that vibrios produce a variety of other extracellular products that enable these microorganisms to activate different intracellular signaling in the host mammalian cells, all leading to diarrhea. One of the most intriguing new toxins discovered in V. cholerae is zonula occludens toxin (Zot),3 an enterotoxin that increases the intestinal permeability by interacting with a mammalian cell receptor, with subsequent activation of intra-cellular signaling leading to the disassembly of the intercellular tight junctions (Figure 10.2).

The introduction of oral rehydration solutions (ORS) decreased the mortality from this illness from over 50% to less than 1%. The use of antibiotics has limited indications, but has been demonstrated to reduce the volume and duration of diarrhea by half and reduce the duration of excretion to one day. Tetracycline (500 mg/dose, given four times per day) is the most widely used antibiotic, but large outbreaks of tetracycline-resis-tant organisms have been reported. Furazolidone (1.25mg/kg four times per day), trimethoprim

(TMP, 5mg/kg twice per day), sulfamethoxazole (SMX, 25mg/kg twice per day), and erythromycin (10mg/kg three times per day) have been suggested for children.

Both killed whole-cell and live attenuated cholera vaccines have been proposed as a preventive intervention for cholera.3 A large double-blind field trial of the killed vaccine showed 85% efficacy for a period of 4-6 months, dropping to 50% over 3 years of follow-up.4 A locally produced killed vaccine in Vietnam provided a 66% protection against El Tor cholera during an outbreak occurring 8-10 months after vaccination.5 A genetically engineered attenuated cholera vaccine (CVD 103-HgR), obtained by deleting the active subunit of cholera toxin (see below) from a V cholerae O1 classic biotype, was well tolerated when administered to volunteers. This vaccine elicited a high level of protection (82-100%) against homologous challenge with a strain of the same biotype.6 Protection across biotypes was also observed, albeit to a lesser extent,7 lasting for at least 6 months after a single oral dose.8 Live attenuated V. cholerae O139 vaccines have been developed, with promising preliminary results.9,10

Non-01 Vibrio species

V. parahaemolyticus, V. fluvialis, V. mimicus, V. hollisae, V furnissii and V vulnificus cause sporadic cases of gastroenteritis, and are present in coastal and estuarine areas throughout the world.11 Virtually all cases of non-O1 Vibrio infections in the USA are associated with eating raw shellfish,12 and the gastroenteritis can range from a mild illness to profuse, watery diarrhea comparable to that seen in epidemic cholera. Diarrhea, abdominal cramps and fever are the most common symptoms, with nausea, vomiting and bloody stools occurring less frequently.11 As with V. cholerae O1, the mainstay of therapy for diarrheal disease is oral rehydration. In cases of septicemia (which typically occur in immuno-compromised patients), supportive care and correction of shock are essential interventions associated with the antibiotic treatment (tetracy-cline). In countries such as the USA non-O1 infections can be prevented by not eating raw or under-cooked seafood, particularly during the warm months.

Zonula Occludens Toxin

Figure 10.2 Proposed zonula occludens toxin (Zot) intracellular signaling leading to the opening of intestinal tight junctions. Zot interacts with a specific surface receptor (1) whose distribution within the intestine varies. The protein is then internalized and activates phospholipase C (2) that hydrolyzes phosphatidyl inositol (PPI) (3) to release inositol 1,4,5-tris phosphate (IP3) and diacylglycerol (DAG) (4). Protein kinase Ca (PKCa) is then activated (5), either directly (via DAG) (4) or through the release of intracellular Ca++ (via IP3) (4a). PKCa catalyzes the phosphorylation of target protein(s), with subsequent polymerization of soluble G actin in F actin (7). This polymerization causes the rearrangement of the filaments of actin and the subsequent displacement of proteins (including ZO1) from the junctional complex (8). As a result, intestinal tight junctions become looser.

Figure 10.2 Proposed zonula occludens toxin (Zot) intracellular signaling leading to the opening of intestinal tight junctions. Zot interacts with a specific surface receptor (1) whose distribution within the intestine varies. The protein is then internalized and activates phospholipase C (2) that hydrolyzes phosphatidyl inositol (PPI) (3) to release inositol 1,4,5-tris phosphate (IP3) and diacylglycerol (DAG) (4). Protein kinase Ca (PKCa) is then activated (5), either directly (via DAG) (4) or through the release of intracellular Ca++ (via IP3) (4a). PKCa catalyzes the phosphorylation of target protein(s), with subsequent polymerization of soluble G actin in F actin (7). This polymerization causes the rearrangement of the filaments of actin and the subsequent displacement of proteins (including ZO1) from the junctional complex (8). As a result, intestinal tight junctions become looser.

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  • Belladonna Mugwort
    How big is an enterocyte?
    7 years ago

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