What type of pathogen is cholera

The motility of the vibrios may affect virulence by enabling them to penetrate the mucus layer. They also produce mucinolytic enzymes, neuraminidase, and proteases.

The growing cholera vibrios elaborate the cholera enterotoxin CT or choleragen , a polymeric protein M r 84, consisting of two major domains or regions. The A region M r 28, , responsible for biologic activity of the enterotoxin, is linked by noncovalent interactions with the B region M r 56, , which is composed of five identical noncovalently associated peptide chains of M r 11, The B region, also known as choleragenoid, binds the toxin to its receptors on host cell membranes.

It is also the immunologically dominant portion of the holotoxin. The structural genes that encode the synthesis of CT reside on a transposon-like element in the V cholerae chromosome, in contrast to those for the heat-labile enterotoxins LTs of E coli Ch. The amino acid sequences of these structurally, functionally, and immunologically related enterotoxins are very similar.

Their differences account for the differences in physicochemical behavior and the antigenic distinctions that have been noted. There are at least two antigenically related but distinct forms of cholera enterotoxin, called CT-1 and CT Vibrio cholerae exports its enterotoxin, whereas the E coli LTs occur primarily in the periplasmic space. This may account for the reported differences in severity of the diarrheas caused by these organisms.

Vibrio cholerae attachment and colonization in experimental rabbits. The events are assumed to be similar in human cholera. A Scanning electron microscopy during early infection. Curved vibrios adhering to epithelial surface. Synthesis of CT and other virulence-associated factors such as toxin-coregulated pili are believed to be regulated by a transcriptional activator, Tox R, a transmembrane DNA-binding protein. The molecular events in these diarrheal diseases involve an interaction between the enterotoxins and intestinal epithelial cell membranes Fig.

The toxins bind through region B to a glycolipid, the G M1 ganglioside, which is practically ubiquitous in eukaryotic cell membranes. With diphtheria toxin, however, the substrate is elongation factor 2 and the result is cessation of host cell protein synthesis. The subsequent cAMP-mediated cascade of events has not yet been delineated, but the final effect is hypersecretion of chloride and bicarbonate followed by water, resulting in the characteristic isotonic voluminous cholera stool.

In hospitalized patients, this can result in losses of 20 L or more of fluid per day. The stool of an actively purging, severely ill cholera patient can resemble rice water—the supernatant of boiled rice. Perhaps by production of CT, the cholera vibrios thus ensure their survival by increasing the likelihood of finding another human host. Recent evidence suggests that prostaglandins may also play a role in the secretory effects of cholera enterotoxin.

Recent studies in volunteers using genetically-engineered Tox — strains of V cholerae have revealed that the vibrios have putative mechanisms in addition to CT for causing milder diarrheal disease. These include Zot for Zonula occludens toxin and Ace for accessory cholera enterotoxin , and perhaps others, but their role has not been established conclusively.

Certainly CT is the major virulence factor and the act of colonization of the small bowel may itself elicit an altered host response e. Mechanism of action of cholera enterotoxin. Cholera toxin approaches target cell surface. B subunits bind to oligosaccharide of G M1 ganglioside. Conformational alteration of holotoxin occurs, allowing the presentation of the A subunit to cell surface.

Comparison of activities of cholera enterotoxin CT with pertussis toxin PT. Various animal models have been used to investigate pathogenic mechanisms, virulence, and immunity. Ten-day-old suckling rabbits develop a fulminating diarrheal disease after intraintestinal inoculation with virulent V cholerae or CT. Adult rabbits are relatively resistant to colonization by cholera vibrios; however, they do respond, with characteristic out pouring of fluid, to the intraluminal inoculation of live vibrios or enterotoxin in surgically isolated ileal loops.

Suckling mice are susceptible to intragastric inoculation of vibrios and to orally administered toxin. Adult conventional mice are also susceptible to orally administered toxin, but resist colonization except in isolated intestinal loops. Interestingly, however, germ-free mice can be colonized for months with cholera vibrios. They rarely show adverse effects, although they are susceptible to cholera enterotoxin.

Dogs have been used experimentally, although they are relatively refractory and require enormous inocula to elicit choleraic manifestations. Chinchillas also are susceptible to diarrhea following intraintestinal inoculation with moderate numbers of cholera vibrios.

Infections initiated by extraintestinal routes of inoculation e. The intraperitoneal infection in mice has been used to assay the protective effect of conventional killed vibrio vaccines no longer widely used.

Various animals, including humans, rabbits, and guinea pigs, also respond to intradermal inoculation of relatively minute amounts of CT with a characteristic delayed maximum response at 24 hours , sustained visible up to 1 week or more , erythematous, edematous induration associated with a localized alteration of vascular permeability.

In laboratory animals, this response can be measured after injecting a protein-binding dye, such as trypan blue, that extravasates to produce a zone of bluing at the site of intracutaneous inoculation of toxin. This observation has been exploited in the assay of CT and its antibody and in the detection of other enterotoxins.

In addition, because of the broad spectrum of activity of CT on cells and tissues that it never contacts in nature, various in vitro systems can be used to assay the enterotoxin and its antibody.

In each, the toxin causes a characteristically delayed, but sustained, activation of adenylate cyclase and increased production of cAMP, and it may cause additional, readily recognizable, morphologic alterations of certain cultured cell lines. The cells most widely used for this purpose are Chinese hamster ovary CHO cells, which elongate in response to picogram doses of the toxin, and mouse Y-l adrenal tumor cells, which round up. Cholera toxin has become an extremely valuable experimental probe to identify other cAMP-mediated responses.

It also activates adenylate cyclase in pigeon erythrocytes, a procedure that was used by D. Michael Gill to define its mode of action. These assays and models also have been applied in the study of an expanding number of CT-related and unrelated enterotoxins. These include the LTs of E coli , which are structurally and immunologically similar to it and are effective in any model that is responsive to CT.

The family of small molecular weight heat-stable enterotoxins ST of E coli , which activate guanylate cyclase, and which are rapidly active in the infant mouse and certain other intestinal models, are clearly unrelated to CT.

CT-related enterotoxins have been reported from certain nonagglutinable non-O group I Vibrio strains and a Salmonella enterotoxin was shown to be related immunologically to CT. CT-like factors from Shigella and V parahaemolyticus have thus far been demonstrated only in sensitive cell culture systems.

Other enterotoxins and enterocytotoxins, which elicit cytotoxic effects on intestinal epithelial cells, also have been described from Escherichia , Klebsiella , Enterobacter , Citrobacter , Aeromonas , Pseudomonas , Shigella , V parahaemolyticus , Campylobacter , Yersinia enterocolitica , Bacillus cereus , Clostridium perfringens , C difficile , and staphylococci.

Escherichia coli , some vibrio strains, and some other enteric bacteria produce cytotoxins that, like Shiga toxin of Shigella dysenteriae, act on Vero African green monkey kidney cells in vitro.

These toxins have been called Shiga-like toxins, Shiga toxin-like toxins, Vero toxins, and Vero cytotoxins. The classic staphylococcal enterotoxins perhaps should more properly be called neurotoxins, as they seem to affect the central nervous system rather than the gut directly to cause fluid secretion or histopathologic effects.

Infection with cholera vibrios results in a spectrum of responses. These range from no observed manifestations except perhaps a serologic response the most common to acute purging, which must be treated by hospitalization and fluid replacement therapy; this is the classic response. The reasons for these differences are not entirely clear, although it is known that individuals differ in gastric acidity and that hypochlorhydric individuals are most prone to cholera.

Whether individuals differ in the availability of intestinal receptors for cholera vibrios or for their toxin has not been established. Prior immunologic experience of subjects at risk is certainly a major factor. For example, in heavily endemic regions such as Bangladesh, the attack rate is relatively low among adults in comparison with children.

In neoepidemic areas, cholera is more frequent among the working adult population. Resistance is related to the presence of circulating antibody and, perhaps more importantly, local immunoglobulin A IgA antibody against the cholera bacteria or the cholera enterotoxin or both.

Intestinal IgA antibody can prevent attachment of the vibrios to the mucosal surface and neutralize or prevent binding of the cholera enterotoxin. For reasons that are not clear, individuals of blood group O are slightly more susceptible to cholera. Breastfeeding is highly recommended as a means of increasing immunity of infants to this and other diarrheal disease agents.

Recovery from cholera probably depends on two factors: elimination of the vibrios by antibiotics or the patient's own immune response, and regeneration of the poisoned intestinal epithelial cells. Treatment with a single mg dose of doxycycline has been recommended.

As studies in volunteers demonstrated conclusively, the disease is an immunizing process. Patients who have recovered from cholera are solidly immune for at least 3 years. Cholera vaccines consisting of killed cholera bacteria administered parenterally have been used since the turn of the century.

However, recent controlled field studies indicate that little, if any, effective immunity is induced in immunologically virgin populations by such vaccines, although they do stimulate preexisting immunity in the adult population in heavily endemic regions.

Controlled studies have likewise shown that a cholera toxoid administered parenterally was ineffective in preventing cholera. Probably the natural disease should be simulated to induce truly effective immunity although a parenterally administered conjugate vaccine consisting of the polysaccharide of the vibrio LPS covalently linked to cholera toxin has given promising results in preliminary studies.

Studies in volunteers have shown that orally administered, chemically mutagenized or genetically engineered mutants which do not produce CT or produce only its B subunit protein can induce immunity against subsequent challenge. However, most of these candidate vaccines also produce unacceptable side effects—primarily mild to moderate diarrhea. This strain has minimal reactogenicity but does not colonize well and therefore has to be given in higher doses. Field studies with this strain are in progress.

Combined preparations of bacterial somatic antigen and toxin antigen have been reported to act synergistically in stimulating immunity in laboratory animals; that is, the combined protective effect is closer to the product than to the sum of the individual protective effects. However, a large field study evaluating such nonviable oral vaccines in Bangladesh revealed that neither the whole-cell bacterin nor the killed vibrios supplemented with the B-subunit protein of the cholera enterotoxin induced sufficient long term protection, especially in children, to justify their recommendation for public health use.

No clear-cut advantage of the inclusion of the B-subunit was demonstrated. In any case, even if these vaccines were effective, the requirement for large and repeated doses would make them too expensive for use in the developing areas that are usually afflicted with epidemic cholera. Moreover, they were clearly less effective in children—the primary target population in heavily endemic areas.

Neither the killed whole cell vaccine nor strain CVDHgR could be expected to protect against the new O serovar. Humans apparently are the only natural host for the cholera vibrios. Cholera is acquired by the ingestion of water or food contaminated with the feces of an infected individual. Previously, the disease swept the world in six great pandemics and later receded into its ancestral home in the Indo-Pakistani subcontinent.

In , the El Tor biotype a subset distinguished by physiologic characteristics of V cholerae , not previously implicated in widespread epidemics, emerged from the Celebes now Sulawesi , causing the seventh great cholera pandemic. In the course of their migration, the El Tor biotype cholera vibrios virtually replaced V cholerae of the classic biotype that formerly was responsible for the annual cholera epidemics in India and East Pakistan now Bangladesh.

The pandemic that began in is now heavily seeded in Southeast Asia and in Africa. It has also invaded Europe, North America, and Japan, where the outbreaks have been relatively restricted and self-limited because of more highly developed sanitation.

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What are the steps in identifying the pathogen that causes a specific disease? Cholera is most likely to occur and spread in places with inadequate water treatment, poor sanitation, and inadequate hygiene. Cholera bacteria can also live in the environment in brackish rivers and coastal waters.

Shellfish eaten raw have been a source of infection. Rarely, people in the U. A person can get cholera by drinking water or eating food contaminated with cholera bacteria. In an epidemic, the source of the contamination is usually the feces of an infected person that contaminates water or food. The disease can spread rapidly in areas with inadequate treatment of sewage and drinking water. The infection is not likely to spread directly from one person to another; therefore, casual contact with an infected person is not a risk factor for becoming ill.

Cholera infection is often mild or without symptoms, but can be severe. It usually takes days for symptoms to appear after a person ingests cholera bacteria, but the time can range from a few hours to 5 days. Persons living in places with unsafe drinking water, poor sanitation, and inadequate hygiene are at the highest risk for cholera. If you think you or a member of your family might have cholera, seek medical attention immediately.

Dehydration can be rapid so fluid replacement is essential. If you have oral rehydration solution ORS , start taking it immediately; it can save a life.

Continue to drink ORS at home and while traveling to get medical treatment. If an infant has watery diarrhea, continue breastfeeding.

All isolates should be sent to CDC via state health department laboratories for cholera toxin-testing and subtyping. Cholera - Vibrio cholerae infection.

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