Table of contents :

Homo-restricted^ref. > 139 O Ag serotypes grouped into 6 serogroups. Alkalophiles (pH 7÷9). Not invasive : just in gut lumen or adhesed to gut lining epithelium.

• Group 1  = Vibrio cholerae O1 (properly said cholera vibrio; almost always fall into the Heiberg I fermentation pattern (sucrose and mannose but not arabinose)).

Proteomics : virulence factors : sensing its changing environment is key when making the transition from an aquatic lifestyle to one more suited to a human host. An inverse correlation between motility and virulence gene expression has been reported, with the NADH:ubiquinone oxidoreductase system which powers motility by generating a sodium-motive force, playing a pivotal role. Bile inhibits activity of the transcription factor ToxT, a protein responsible for direct activation of numerous virulence gene promoters.Components of an acid-tolerance response system and quorum sensing also have a role in regulation of virulence gene expression. V. cholerae O139 O-antigen polysaccharide is essential for Ca²⁺-dependent biofilm development in seawater => impact of estuarine ion flux on the microbial ecology of the estuary
• hemagglutinin

The presence or absence of hemolysis in V. cholerae does not necessarily distinguish pathogenic strains of the organism from nonpathogenic ones. The classical biotype of the cholera bacillus is nonhemolytic and certainly can cause overt cholera. Hemolysis can be found in the El Tor biotype and, historically, this has been used to distinguish the biotypes. Strains of El Tor that do not produce hemolysis have been reported, and some strains of both O1 and O139 V. cholerae which are not hemolytic initially can be hemolytic after serial passage through rabbit ideal loops. The usefulness of hemolysis as a virulence factor is unclear, since nonhemolytic strains produce fluid accumulation in the rabbit gut, and hemolytic strains do not necessarily produce a secretory response^ref
• accessory colonization factor (acf)
• mucinase or hemagglutinin protease (hap) that degrades different types of protein including fibronectin, lactoferrin and cholera toxin itself, contributing to detachment rather than attachment. Possibly the vibrios would need to detach from cells that are being sloughed off of the mucosa in order to reattach to newly formed mucosal cells.
• neuraminidase degrades plasma membraner gangliosides in small bowel enterocytes to the monosialosyl form, creating the GM₁ ganglioside.
• Vibrio cholerae acquired genetic elements in such a sequence : regulatory factors => TCP bacteriophage insertion site => TCP bacteriophage genome, that encodes for a protein (TCP) which is both a type IV fimbria and the receptor for a second bacteriophage (CTXf) => CTXf genome, whose ctxAB operon encodes the AB₅ cholera enterotoxin (CT / CTx) / choleragen. The GM₁ ganglioside on jejunum enterocytes and M cells acts as a receptor for the p11.6^B subunits (a.k.a. choleragenoid). The p29^A subunit divides itself (through disulfide bond reduction) into p5.5^A2 and p23.5^A1 fragments : the latter catalyzes ADP-ribosylation on a Arg residue (glycosidic bond) in Ga_s subunits (helped by c-ARF), causing irreversible activation of adenylyl cyclase. This results in excessive secretion of Na⁺ and Cl^- by enterocytes, which, recalling H₂O for osmotic gradient, cause lavish diarrhea. CT also induces secretion of VIP from neurons in the myoenteric plexus, which in turns further stimulates secretions in enterocytes. LD₅₀ = 20 pg in humans. After Koch thought he had established Vibrio cholerae as the cause of cholera a sceptical colleague drank a culture without ill effect : if drinking water is kept free of the V cholerae infected with the phage all is well, just as phage and bacterium live harmlessly together in zooplankton infested coastal waters of the Pacific
• toxin coregulated pili (Tcp) (a colonization factor) : the ctx operon and the tcp operon are part of a regulon, the expression of which is controlled by the same environmental signals. The proteins involved in control of this regulon expression have been identified as ToxR, ToxS and ToxT. It is expressed before cholera toxin
• zonula occludens toxin (Zot)
• accessory cholera enterotoxin (Ace)
• a single protein required for efficient intestinal colonization mediates attachment to both zooplankton and human epithelial cells by binding to a sugar present on both surfaces^ref
Serovars according to O antigens :
• Ogawa (A and B Ags)
• Inaba (A and C Ags)
• Hikojima (A, B and C Ags : relatively rare)
Biovars :
• cholerae (classical; produce CT-1) : sensitive to group IV phage and bacteriophage IV labile when outside host => only direct transmission; considered extinct, reappeared in Bangladesh in 1982; cases:carriers ratio 1:2-4.
• eltor (isolated in El Tor quarantine station for pilgrims in the Sinai peninsula) : most strains produce CT-2 but the Gulf Coast strains produce CT-1. Resistant to bacteriophage IV and polymixin B. They produce an hemagglutinin (for chicken RBCs) and an hemolysin (for goat or sheep RBCs in Greig test : however, during the most recent pandemic, most (except for the recent isolates from Texas and Louisiana) don't express it); cases:carriers  ratio 1:30-100; longer latency and less severe infections (paracholera). More stable when outside host => also indirect transmission. The presence or absence of hemolysis in V. cholerae does not necessarily distinguish pathogenic strains of the organism from nonpathogenic ones. The classical biotype of the cholera bacillus is nonhemolytic and certainly can cause overt cholera. Hemolysis can be found in the El Tor biotype and, historically, this has been used to distinguish the biotypes. Strains of El Tor that do not produce hemolysis have been reported, and some strains of both O1 and O139 V. cholerae which are not hemolytic initially can be hemolytic after serial passage through rabbit ideal loops. The usefulness of hemolysis as a virulence factor is unclear, since nonhemolytic strains produce fluid accumulation in the rabbit gut, and hemolytic strains do not necessarily produce a secretory response^ref
Epidemiology : estuarine environments. Cholera was originally an endemic disease localized within the delta region of the River Ganges. As the Indian trade with Western European countries increased from 1817, cholera spread all over the world, bringing as many as 6 pandemics before 1923. No other pandemic of such classical cholera has
ever broken out since.
• 1817-1823 : first pandemic by classical biovar
• 1829-1851 : second pandemic by classical biovar
• 1852-1859 : third pandemic by classical biovar
• 1854 : before acceptance of the "germ theory" John Snow stopped an epidemic in Soho, London by the simple expedient of removing the handle of the "Broad Street pump" (a contaminated water supply)
• 1863-1879 : forth pandemic by classical biovar
• 1881-1896 : fifth pandemic by classical biovar
• 1883 : first isolation of the "Kommabacillus" by Robert Koch
• 1899-1923 : sixth pandemic by classical biovar
• 1961 : seventh pandemic begun in Sulawesi (Celebes), Indonesia and is still acting, sustained by eltor biovar. Because humans are the only reservoirs, survival of the cholera vibrios during interepidemic periods probably depends on a relatively constant availability of low-level undiagnosed cases and transiently infected, asymptomatic individuals. Long-term carriers have been reported but are extremely rare. The classic case occurred in the Philippines, where "cholera Dolores" harbored cholera vibrios in her gall-bladder for 12 years : no secondary cases had been associated with her well-marked strain. Recent studies, however, have suggested that cholera vibrios can persist for some time in shellfish, algae or plankton in coastal regions of infected areas and it has been claimed that they can exist in a "viable but nonculturable state". It has spread to
• neighboring Southeast Asia
• Japan^ref has reported secondary cases : although cholera cases in Japan used to be restricted to returnees from cholera-endemic areas, infections among people who never experienced overseas travel have increased noticeably in recent years. With cholera being endemic in the country, there was an outbreak in Arida City, Wakayama Prefecture in 1977, of which the source of infection was ascribed to a returnee from the Philippines. Another outbreak occurred in 1978, presumably due to consumption of lobsters of Indonesian origin served at a wedding parlor at Ikenohata, Tokyo. In 1989, there was an outbreak, which began in Nagoya, involving patients living in 7 different prefectures, and, in 1991, another outbreak occurred in Tokyo Metropolis. As an imported incident worth special mention, many cholera patients appeared among travelers to Bali Island in 1995. Cases of cholera infection exploded in as many as 37 different prefectures involving 296 cases^ref. Cholera cases in 1996 numbered 62, comprising 49 (79%t) imported cases and 13 (21%) domestic cases without history of overseas travel; the total number of cases was markedly less than that of 1995 (377). The difference may be attributed to the markedly decreased number of cases (3) of Bali returnees. Cholera cases numbered 101 in 1997. Out of these cases, 36 -- with no history of overseas travel -- were living in 17 different prefectures^ref accounting for 36% of the total number of cases in 1997. The largest number of cases was found in August 1997, and the next largest in July 1997, showing an incidence pattern similar to that of Vibrio parahaemolyticus food poisoning^ref. On the other hand, the imported cases numbered largest, at 16, in April 1997. This was due to outbreaks involving 11 patients in 2 groups of sightseeing tours to Thailand. The ages of the patients without history of overseas travel ranged from 13 to 86 years (average 60 years), of which those aged over 60 years accounted for about 51%. The ages of the patients who had history of overseas travel ranged from 6 to 72 years (average 46 years), and those > 60 years accounted for only about 17%. The cases without history of overseas travel were mostly older people, but no case was found among their family members. 34 strains of Vibrio cholerae O1 isolated from cases with no history of overseas travel in 1997 were analyzed for phage type, drug sensitivity, and genotype by pulsed-field gel electrophoresis (PFGE) after digestion with NotI restriction enzyme. Identical, or very similar, patterns were obtained with all strains. The patterns were identical to those of the strains prevailing recently in Southeast Asia, and different from those of the strains responsible for the past domestic outbreaks. It was difficult to identify the route of infection from these analytical results. V. cholerae O139 was 1st isolated from a traveler to India in Saitama Prefecture in April 1993 and from a Nepalese visitor to Nagano Prefecture in July of the same year^ref. These cases both developed severe cholera symptoms, but the case in Tochigi Prefecture in October 1993, returning from India, showed only mild diarrhea. The other 4 cases reported during February to April 1994 were infected in Thailand. V. cholerae O139 was isolated from 2 cases returning from the Indian subcontinent in August 1993 and also from other 2 cases returning from India and China in October 1994. There were no reports of cases of V. cholerae O139 infection for some time following the above-mentioned cases, but, in September 1997, infection was found in a returnee (a 24-year-old male) from Nepal
• Singapore : in 1993, 12 persons were infected with cholera after eating inadequately cooked mussels harvested near a sewage discharge site. The 1999 Singapore outbreak affected at least 8 individuals at a wedding reception and was related to a banana flavored drink in which contaminated ice was used. There have been imported cases of V. cholerae infection in 2000 and 2002. In May 2004 an 89-year-old man died, among 9 people infected, and authorities are trying to trace the source of the disease
• Indian Subcontinent
• Near East
• Africa
• Malawi recorded its 1st case of infection in 1973 with about 35 000 infections and since then the epidemic has been claiming a lot of lives in the country. In 1998/99 cholera attacked 3000 people, while 2000 lives were lost in 2001/02. In 2004, the country registered about 12 040 cases of cholera.
• Guinea Bissau : 26,000 cases and > 400 deaths in 2005
• Angola has largely been spared cholera outbreaks since 1995. That may have lessened the population's immunity and helps explain the rapid spread of the disease since the first case was reported on 13 Feb 2006, recording 554 deaths and 12 052 cases in just over 2 months
• Tanzania : the last severe outbreak recorded in 1997, when more than 1100 people were taken ill by the disease and at least 124 died in Zanzibar, which has a population of 1 million
• Ghana : no case in 2005
• Northern Europe
• North America
• USA : in 1978, an outbreak of about 12 cases in Louisiana : in that outbreak, sewage was infected, and infected shellfish apparently were involved. Interestingly, the hemolytic vibrio strain implicated was identical to one that caused an unexplained isolated case in Texas in 1973. WHO recorded about 124,000 in 2002, and 3,800 deaths. In USA shell fish is usually implicated in autochthonous cases (most often Gulf Coast) :
• no cases were reported during 1911 to 1965; 136 during 1965 to 1991 (3 fatal) - 93 of these locally-acquired. 26 (9 imported, 0 fatal) in 1991; 103 (100 imported, 1 fatal) in 1992 - including 64 from California and 75 passengers
• on an airline flight from South America; 22 (19 imported) during 1993 (including one infection by V. cholerae O139 from India); 47 (45 imported - 2 V. cholerae 0139) in 1994; 23 (imported, nonfatal) in 1995; 4 (0 fatal) in 1996; 3 first half of 1997.
• 6 cases (imported) of V. cholerae O139 infection were reported during 1992 to 1994.
In the USA, epidemic cholera has not occurred during the past 100 years. Although small outbreaks have been identified, most cases have been sporadic. During 1996-2005, a total of 64 cases of toxigenic V. cholerae O1 were reported to CDC from USA states and territories. In 35 (55%) cases, cholera infection was acquired during foreign travel. For the remaining 29 (45%) cases, infection was acquired in the USA. 7 (24%) of these 29 cases were attributed to consumption of Gulf Coast seafood (such as crabs, shrimp, or oysters); 22 (76%) others could not be attributed to consumption of Gulf Coast seafood. Among the 22 cases not associated with either foreign travel or Gulf Coast seafood, 13 were associated with consumption of seafood from areas other than the Gulf Coast, and 9 exposures were undetermined. 13 of the cases occurred in states outside of the Gulf Coast, 8 occurred in USA territories (7 in Guam and 1 in the Mariana Islands), and 1 case occurred in Louisiana. 7 of the 11 USA cholera cases in 2005 were reported during Oct-Dec 2005, after Hurricanes Katrina and Rita. In addition to the 2 Louisiana cases described in this report, 2 cases occurred in Guam, and 3 others were attributed to foreign travel. The number and sources of these 7 cases are consistent with reports of cholera in previous years^ref. No evidence suggests increased risk for cholera among Gulf Coast residents or consumers of Gulf Coast seafood after the hurricanes. Illness in the 2 Louisiana residents was attributed to shellfish that was not prepared or handled properly, perhaps because of difficult living conditions after the hurricanes. Boiling shellfish for > 10 minutes is recommended to render the V. cholerae organism nonviable and then placing the shellfish into clean serving dishes to prevent recontamination^ref (Wachsmuth IK, Blake PA, Olsvik O, eds. Vibrio cholerae and cholera: molecular to global perspectives. Washington, DC: American Society for Microbiology, 1994)^ref.
• South America (since 1991)
There are about 110,000 to 200,000 cholera cases worldwide each year. Around 5,000 deaths are reported annually. Mozambique as a whole has reported up to 45,000 cases in a single year.
Outbreaks of many infectious diseases, including cholera, malaria and dengue, vary over characteristic periods > 1 year. Evidence that climate variability drives these interannual cycles has been highly controversial, chiefly because it is difficult to isolate the contribution of environmental forcing while taking into account nonlinear epidemiological dynamics generated by mechanisms such as host immunity. A critical interplay of environmental forcing, specifically climate variability, and temporary immunity explains the interannual disease cycles present in a four-decade cholera time series from Matlab, Bangladesh.The transmission rate, the key epidemiological parameter affected by extrinsic forcing, over time for the predominant strain (El Tor) have been reconstructed with a nonlinear population model that permits a contributing effect of intrinsic immunity. Transmission shows clear interannual variability with a strong correspondence to climate patterns at long periods (over 7 years, for monsoon rains and Brahmaputra river discharge) and at shorter periods (under 7 years, for flood extent in Bangladesh, sea surface temperatures in the Bay of Bengal and the El Niño-Southern Oscillation). The importance of the interplay between extrinsic and intrinsic factors in determining disease dynamics is illustrated during refractory periods, when population susceptibility levels are low as the result of immunity and the size of cholera outbreaks only weakly reflects climate forcing^ref.
Transmission :
• orofaecal route after ingestion of > 10¹¹ vibrios (> 10⁴ in individuals with hypochlorhydria or gastroresecated) via feces- or vomitus-contaminated water, raw or under-cooked seafood
• in general, overall disinfection of a residence after discovery of a case of  V. cholerae infection is unnecessary.  The possibility that contaminated food or water remains in the home, however, and this ought to be considered.  Because the organism has a high ID₅₀, spread is not usually from fomites or person-to-person.  Adequate and potable water availability is the most important factor in preventing the spread of cholera
=> (epidemic or Asiatic) cholera : most infections are subclinical, but < 10% infected persons, after an incubation period ranging from 6 hrs. up to 5 days, experience sudden and explosive diarrhea (first fecal, then watery ("rice water" stools) and mucous-flecked due to vibrio aggregates), nausea and vomiting and prostration leading rapidly to fluid and electrolyte depletion (up to 100 motions/die, loss of up to 10% of body H₂O; 5 mg => loss of 1÷6 L H₂O/die ; 25 mg => up to 25 L H₂O/die) => gastrocnemius cramps, dry and cold skin, rarely fever, nausea and vomiting and abdominal pain. It lasts from 12 hrs. up to 7 days. Because the stool can contain 10^7-9 viable vibrios / mL (in asymtomatic individuals < 10⁵ / g stools), such a patient could shed 2^.10¹² vibrios per day into the environment. If untreated, 50-60 % undergo hypovolemic shock (choleric facies), acute tubular necrosis => acute renal failure; if untreated death occurs within 2 hrs - few days.
=> immunoproliferative small intestinal disease (IPSID)
Therapy :
• fluid and electrolyte replacement : Ringer's lactate initially for severe cases, then oral rehydration salts (ORS : Na⁺Cl^- 3.5 g, K⁺Cl^- 1.5 g, Na⁺HCO₃^- 2.5 g (or trisodium citrate 2.9 g) and Glc 20.0 g dissolved in 1 L of water)
• antidiarrhoic drugs
• CFTR inhibitors
• antibacterials : tetracycline 500 mg po qid for 3 days or furazolidone 400 mg daily for 3 days or a single dose of 300 mg doxycycline. They halve lasting of diarrhoea. Single-dose azithromycin was effective in the treatment of severe cholera in adults. The lack of efficacy of ciprofloxacin (each given in a single 1-g dose of 2 500-mg tablets) may result from its diminished activity against V. cholerae O1 strains currently circulating in Bangladesh^ref.
Secretory IgA, as well as IgG and IgM in serum exudate, can be detected in the intestinal mucosa of immune individuals : they bring about protective immunity by immobilizing vibrio flagella and blocking attachment to the intestinal epithelium.
Prevention :
• many villagers rely on rivers, lakes, and ponds for household water - especially because many drilled wells have become contaminated with arsenic.
• boiling is the most effective way to purify water, but in some countries wood for fuel is scarce.
• folding a sari cloth (the traditional cotton garment worn by women in India and Bangladesh) to give > 4 (ideally 8) layers filters out virtually all the bacteria. The bacteria are tiny and would on their own be impossible to strain out with a simple filter. But they hang onto the egg-cases and mouths of Copepoda (copepods : microscopic crustaceans a thousand times larger than the bacteria). A rise in water temperature results in a plankton bloomwhichauses a growth spurt of copepods, each of which can carry up to 10,000 cholera bacteria. Old, cheap sari cloth makes a better filter than new, expensive cloth : the threads become smushy and loose, as a result the pore size becomes even smaller.
• when germicidal rate for Vibrio Cholerae of El-Tor biotype in the 5 different kinds of water bodies reach to 100% in 5 minutes, concentrations of chlorine compound disinfectant, indophor, chlorine dioxide and glutaraldehyde are 25.0-250.0 mg/L, 100.0-250.0 mg/L, 10.0-25.0 mg/L and 100-500 mg/L, respectively. Concentrations of disinfectants needed to disinfected waste water are higher than that to disinfect natural water^ref.
• killed injectable, oral and transgenic, or attenuated vaccines. It is unlikely that cholera could ever be eliminated by the use of vaccines, but that they could reduce the number of cases among high-risk populations.
It is considered by CDC as a category B biological weapon.
• Group 2 = atypical or non-toxigenic Vibrio cholerae O1
=> asymptomatic
• Group 3 = Vibrio cholerae non-O1 (a.k.a. non-cholera vibrio (NCV) or non-agglutinating vibrio (NAV)).
• if CT⁺ => cholera
• Vibrio cholerae O139 (Bengal : capsulated; arose in October 1992 in India and Bangladesh probably from horizontal transfer of CTXf; it may become the cause of the 8^th great pandemic of cholera)
• if NAG-ST⁺ => dysentery
• Vibrio cholerae non-O1/non-O139
• Vibrio cholerae 569B

• Pfeiffer's phenomenon : the lysis of Vibrio cholerae when injected into the peritoneal cavity of an immunized guinea pig; the term is also used to describe the in vitro lysis of cholera vibrios or other bacteria when incubated with specific antibody and complement.

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