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Vibrio cholerae

Vibrio cholerae is a Gram-negative, comma-shaped bacterium. Some strains of V. cholerae cause the disease cholera. V. cholerae is a facultative anaerobic organism[1] and has a flagellum at one cell pole. V. cholerae was first isolated as the cause of cholera by Italian anatomist Filippo Pacini in 1854,[2] but his discovery was not widely known until Robert Koch, working independently 30 years later, publicized the knowledge and the means of fighting the disease.[3][4]

Pathogenesis[edit]

V. cholerae pathogenicity genes code for proteins directly or indirectly involved in the virulence of the bacteria. During infection, V. cholerae secretes cholera toxin, a protein that causes profuse, watery diarrhea. Colonization of the small intestine also requires the toxin coregulated pilus (TCP), a thin, flexible, filamentous appendage on the surface of bacterial cells. Vibrio cholerae can cause syndromes ranging from asymptomatic to cholera gravis.[4] In endemic areas, 75% of cases are asymptomatic, 20% are mild to moderate, and 2-5% are severe forms like cholera gravis.[4] Symptoms include abrupt onset of watery diarrhea (a grey and cloudy liquid), occasional vomiting and abdominal cramps.[1][4] Dehydration ensues with symptoms and signs such as thirst, dry mucous membranes, decreased skin turgor, sunken eyes, hypotension, weak or absent radial pulse, tachycardia, tachypnea, hoarse voice, oliguria, cramps, renal failure, seizures, somnolence, coma and death.[1] Death due to dehydration can occur in a few hours to days in untreated children. The disease is also particularly dangerous for pregnant women and their fetus during late pregnancy, as it may cause premature labor and fetal death.[4][5][6] In cases of cholera gravis involving severe dehydration, up to 60% of patients can die; however, less than 1% of cases treated with rehydration therapy are fatal. The disease typically lasts from 4–6 days.[4][7] Worldwide, diarrhoeal disease, caused by cholera and many other pathogens, is the second leading cause of death for children under the age of 5 and at least 120,000 deaths are estimated to be caused by cholera each year.[8][9] In 2002, the WHO deemed that the case fatality ratio for cholera was about 3.95%.[4]

Colonization of the small intestine[edit]

There are several characteristics of pathogenic V. cholerae that are important determinants of the colonization process. These include adhesins, neuraminidase, motility, chemotaxis and toxin production. If the bacteria are able to survive the gastric secretions and low pH of the stomach, they are well adapted to survival in the small intestine. V. cholerae is resistant to bile salts and can penetrate the mucus layer of the small intestine, possibly aided by secretion of neuraminidase and proteases (mucinases).[10] The flagellum facilitates chemotactic-directed movement toward the preferred colonization site within the intestine,[11] and also contributes to biofilm formation within the environment.[12] V. cholerae strains defective for motility are less virulent than motile strains.[13] Specific adherence of V. cholerae to the intestinal mucosa is probably mediated by long filamentous fimbriae that form bundles at the poles of the cells. These fimbriae have been termed Tcp pili (for toxin coregulated pili), because expression of these pili genes is coregulated with expression of the cholera toxin genes.[10] Genetic analysis of Vibrio Pathogenicity Island indicates that it was recently acquired by V. cholera by horizontal gene transfer.[14] Not much is known about the interaction of Tcp pili with host cells, and the host cell receptor for these fimbriae has not been identified.[10]

Genome[edit]

V. cholerae has two circular chromosomes, together totalling 4 million base pairs of DNA sequence and 3,885 predicted genes.[15] The genes for cholera toxin are carried by CTXphi (CTXφ), a temperate bacteriophage inserted into the V. cholerae genome. CTXφ can transmit cholera toxin genes from one V. cholerae strain to another, one form of horizontal gene transfer. The genes for toxin coregulated pilus are coded by the VPI pathogenicity island (VPIφ). The entire genome of the virulent strain V. cholerae El Tor N16961 has been sequenced,[1] and contains two circular chromosomes.[4] Chromosome 1 has 2,961,149 base pairs with 2,770 open reading frames (ORF’s) and chromosome 2 has 1,072,315 base pairs, 1,115 ORF’s. It is the larger first chromosome that contains the crucial genes for toxicity, regulation of toxicity and important cellular functions, such as transcription and translation.[1]

The second chromosome is determined to be different from a plasmid or megaplasmid due to the inclusion of housekeeping and other essential genes in the genome, including essential genes for metabolism, heat-shock proteins and 16S rRNA genes, which are ribosomal sub-unit genes used to track evolutionary relationships between bacteria. Also relevant in determining if the replicon is a chromosome is whether it represents a significant percentage of the genome, and chromosome 2 is 40% by size of the entire genome. And, unlike plasmids, chromosomes are not self-transmissible.[4] However it is believed that the second chromosome may have once been a megaplasmid because it contains some genes that are usually found on plasmids.[1]

V. cholerae contains a genomic island of pathogenicity and is lysogenized with phage DNA. That means that the genes of a virus were integrated into the bacterial genome and made the bacteria pathogenic.15 The molecular pathway involved in expression of virulence is discussed in the pathology and current research sections below.

Bacteriophage CTXφ[edit]

CTXφ (also called CTXphi) is a filamentous phage that contains the genes for cholera toxin. Infectious CTXφ particles are produced when V. cholerae infects humans. Phage particles are secreted from bacterial cells without lysis. When CTXφ infects V. cholerae cells, it integrates into specific sites on either chromosome. These sites often contain tandem arrays of integrated CTXφ prophage...[16] V. cholerae enterotoxin is a product of ctx genes. ctxA encodes the A subunit of the toxin, and ctxB encodes the B subunit. The assembled toxin has a 1A: 5B proportion. The components are assembled in the periplasm after translation. Any extra B subunits can be excreted by the cell, but A must be attached to 5B in order to exit the cell. Intact A subunit is not enzymatically active, but must be nicked to produce fragments A1 and A2 which are linked by a disulfide bond. Once the cholera toxin has bound to the GM1 receptor on host cells, the A1 subunit is released from the toxin by reduction of the disulfide bond that links it to A2, and enters the cell by an unknown translocation mechanism. One hypothesis is that the 5 B subunits form a pore in the host cell membrane through which the A1 unit passes.[10] In addition to the ctxA and ctxB genes encoding cholera toxin, CTXφ contains eight genes involved in phage reproduction, packaging, secretion, integration, and regulation. The CTXφ genome is 6.9 kb long.[16]

Vibrio pathogenicity island[edit]

The Vibrio pathogenicity island (VPI) contains genes primarily involved in the production of toxin coregulated pilus (TCP). It is a large genetic element (~40 kb) flanked by two repetitive regions (att-like sites), resembling a phage genome in structure. The VPI contains two gene clusters, the TCP cluster and the ACF cluster, along with several other genes. The acf cluster is composed of 4 genes: acfABCD. The tcp cluster is composed of 15 genes: tcpABCDEFHIJPQRST and regulatory gene toxT.

Genetic Organization and Regulation of Virulence Factors in Vibrio cholerae[edit]

In Vibrio cholerae, the production of virulence factors is regulated at several levels. Regulation of genes at the transcriptional level, especially the genes for toxin production and fimbrial synthesis, has been studied in the greatest detail. Transcription of the ctxAB operon is regulated by a number of environmental signals, including temperature, pH, osmolarity, and certain amino acids. Several other V. cholerae genes are coregulated in the same manner including the tcp operon, which is concerned with fimbrial synthesis and assembly. Thus 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. ToxR is a transmembranous protein with about two-thirds of its amino terminal part exposed to the cytoplasm. ToxR dimers, but not ToxR monomers, will bind to the operator region of ctxAB operon and activate its transcription. ToxS is a periplasmic protein. It is thought that ToxS can respond to environmental signals, change conformation, and somehow influence dimerization of ToxR which activities transcription of the operon. ToxR and ToxS appear to form a standard two-component regulatory system with ToxS functioning as a sensor protein that phosphorylates and thus converts ToxR to its active DNA binding form. ToxT is a cytoplasmic protein that is a transcriptional activator of the tcp operon. Expression of ToxT is activated by ToxR, while ToxT, in turn, activates transcription of tcp genes for synthesis of tcp pili. Thus, the ToxR protein is a regulatory protein which functions as an inducer in a system of positive control. Tox R is thought to interact with ToxS in order to sense some change in the environment and transmit a molecular signal to the chromosome which induces the transcription of genes for attachment (pili formation) and toxin production. It is reasonable to expect that the environmental conditions that exist in the GI tract (i.e., 37o temperature, low pH, high osmolarity, etc.), as opposed to conditions in the extraintestinal (aquatic) environment of the vibrios, are those that are necessary to induce formation of the virulence factors necessary to infect. However, there is conflicting experimental evidence in this regard, which leads to speculation of the ecological function of the toxin during human infection.[10]

Ecology and epidemiology[edit]

The main reservoirs of V. cholerae are people and aquatic sources such as brackish water and estuaries, often in association with copepods or other zooplankton, shellfish, and aquatic plants.

Cholera infections are most commonly acquired from drinking water in which V. cholerae is found naturally or into which it has been introduced from the feces of an infected person. Other common vehicles include contaminated fish and shellfish, produce, or leftover cooked grains that have not been properly reheated. Transmission from person to person, even to health care workers during epidemics, is rarely documented. V. cholerae thrives in a water ecology, particularly surface water. The primary connection between humans and pathogenic strains is through water, particularly in economically reduced areas that don't have good water purification systems.[9]

Non-pathogenic strains are also present in water ecologies. It is thought that it is the wide variety of strains of pathogenic and non-pathogenic strains that co-exist in aquatic environments that allow for so many genetic varieties. Gene transfer is fairly common amongst bacteria and recombination of different V. cholerae genes can lead to new virulent strains.[17]

Diversity and evolution[edit]

Two serogroups of V. cholerae, O1 and O139, cause outbreaks of cholera. O1 causes the majority of outbreaks, while O139 – first identified in Bangladesh in 1992 – is confined to South-East Asia. Many other serogroups of V. cholerae, with or without the cholera toxin gene (including the nontoxigenic strains of the O1 and O139 serogroups), can cause a cholera-like illness. Only toxigenic strains of serogroups O1 and O139 have caused widespread epidemics.

V. cholerae O1 has 2 biotypes, classical and El Tor, and each biotype has 2 distinct serotypes, Inaba and Ogawa. The symptoms of infection are indistinguishable, although more people infected with the El Tor biotype remain asymptomatic or have only a mild illness. In recent years, infections with the classical biotype of V. cholerae O1 have become rare and are limited to parts of Bangladesh and India.[18] Recently, new variant strains have been detected in several parts of Asia and Africa. Observations suggest that these strains cause more severe cholera with higher case fatality rates. Vibrio cholerae is indigenous to the aquatic environment, and serotype non-O1 strains are readily isolated from coastal waters. However, in comparison with intensive studies of the O1 group, relatively little effort has been made to analyze the population structure and molecular evolution of non-O1 V. cholerae. In this study, high-resolution genomic DNA fingerprinting, amplified fragment length polymorphism (AFLP), was used to characterize the temporal and spatial genetic diversity of 67 V. cholerae strains isolated from Chesapeake Bay during April through July 1998, at four different sampling sites. Isolation of V. cholerae during the winter months (January through March) was unsuccessful, as observed in earlier studies.[19] AFLP fingerprints subjected to similarity analysis yielded a grouping of isolates into three large clusters, reflecting time of the year when the strains were isolated. April and May isolates were closely related, while July isolates were genetically diverse and did not cluster with the isolates obtained earlier in the year. The results suggest that the population structure of V. cholerae undergoes a shift in genotype that is linked to changes in environmental conditions. From January to July, the water temperature increased from 3 °C to 27.5 °C, bacterial direct counts increased nearly an order of magnitude, and the chlorophyll aconcentration tripled (or even quadrupled at some sites). No correlation was observed between genetic similarity among isolates and geographical source of isolation, since isolates found at a single sampling site were genetically diverse and genetically identical isolates were found at several of the sampling sites. Thus, V. cholerae populations may be transported by surface currents throughout the entire Bay, or, more likely, similar environmental conditions may be selected for a specific genotype. The dynamic nature of the population structure of this bacterial species in Chesapeake Bay provides new insight into the ecology and molecular evolution of V. cholerae in the natural environment.

Gallery[edit]

See also[edit]

References[edit]

  1. ^ a b c d e f "Laboratory Methods for the Diagnosis of Vibrio cholerae". Centre for Disease Control. Retrieved 29 October 2013. 
  2. ^ See:
  3. ^ Bentivoglio, M; Pacini, P (1995). "Filippo Pacini: A determined observer". Brain Research Bulletin 38 (2): 161–5. doi:10.1016/0361-9230(95)00083-Q. PMID 7583342. 
  4. ^ a b c d e f g h i Howard-Jones, N (1984). "Robert Koch and the cholera vibrio: a centenary". BMJ 288 (6414): 379–81. doi:10.1136/bmj.288.6414.379. PMC 1444283. PMID 6419937. 
  5. ^ Davis, B (February 2003). "Filamentous phages linked to virulence of Vibrio cholerae". Current Opinion in Microbiology 6 (1): 35–42. doi:10.1016/S1369-5274(02)00005-X. PMID 12615217. 
  6. ^ Boyd, EF; Waldor, MK (Jun 2002). "Evolutionary and functional analyses of variants of the toxin-coregulated pilus protein TcpA from toxigenic Vibrio cholerae non-O1/non-O139 serogroup isolates.". Microbiology (Reading, England) 148 (Pt 6): 1655–66. PMID 12055286. 
  7. ^ Miller, Melissa B.; Skorupski, Karen; Lenz, Derrick H.; Taylor, Ronald K.; Bassler, Bonnie L. (August 2002). "Parallel Quorum Sensing Systems Converge to Regulate Virulence in Vibrio cholerae". Cell 110 (3): 303–314. doi:10.1016/S0092-8674(02)00829-2. 
  8. ^ Nielsen, Alex Toftgaard; Dolganov, Nadia A.; Otto, Glen; Miller, Michael C.; Wu, Cheng Yen; Schoolnik, Gary K. (2006). "RpoS Controls the Vibrio cholerae Mucosal Escape Response". PLoS Pathogens 2 (10): e109. doi:10.1371/journal.ppat.0020109. 
  9. ^ a b Faruque, SM; Albert, MJ; Mekalanos, JJ (Dec 1998). "Epidemiology, genetics, and ecology of toxigenic Vibrio cholerae.". Microbiology and molecular biology reviews : MMBR 62 (4): 1301–14. PMC 98947. PMID 9841673. 
  10. ^ a b c d e Todar, Kenneth. “Todar's Online Textbook of Bacteriology”. Textbook of Bacteriology. 8 De. 2014. http://www.textbookofbacteriology.net
  11. ^ Camilli, A. and J. J. Mekalanos (1995). "Use of recombinase gene fusions to identify Vibrio cholerae genes induced during infection." Mol Microbiol 18(4): 671-683.
  12. ^ Watnick, P. I. and R. Kolter (1999). "Steps in the development of a Vibrio cholerae El Tor biofilm." Mol Microbiol 34(3): 586-595.
  13. ^ Guentzel, M. N. and L. J. Berry (1975). "Motility as a virulence factor for Vibrio cholerae." Infect Immun 11(5): 890-897.
  14. ^ Faruque, Shah M. et al. “Examination of Diverse Toxin-Coregulated Pilus-Positive Vibrio Cholerae Strains Fails To Demonstrate Evidence for Vibrio Pathogenicity Island Phage .” Infection and Immunity 71.6 (2003): 2993–2999. PMC. Web. 8 Dec. 2014
  15. ^ Fraser, Claire M.; Heidelberg, John F.; Eisen, Jonathan A.; Nelson, William C.; Clayton, Rebecca A.; Gwinn, Michelle L.; Dodson, Robert J.; Haft, Daniel H. et al. (2000). "DNA sequence of both chromosomes of the cholera pathogen Vibrio cholerae". Nature 406 (6795): 477–83. doi:10.1038/35020000. PMID 10952301. 
  16. ^ a b McLeod, S. M.; Kimsey, H. H.; Davis, B. M.; Waldor, M. K. (2005). "CTXφ and Vibrio cholerae: exploring a newly recognized type of phage-host cell relationship". Molecular Microbiology 57: 347–356. doi:10.1111/j.1365-2958.04676.x (inactive 2014-01-31). PMID 15978069. 
  17. ^ Faruque, SM; Nair, GB (2002). "Molecular ecology of toxigenic Vibrio cholerae.". Microbiology and immunology 46 (2): 59–66. doi:10.1111/j.1348-0421.2002.tb02659.x. PMID 11939579. 
  18. ^ Siddique, A.K.; Baqui, A.H.; Eusof, A.; Haider, K.; Hossain, M.A.; Bashir, I.; Zaman, K. (1991). "Survival of classic cholera in Bangladesh". The Lancet 337 (8750): 1125–1127. doi:10.1016/0140-6736(91)92789-5. 
  19. ^ Kaper, J; Lockman, H; Colwell, RR; Joseph, SW (Jan 1979). "Ecology, serology, and enterotoxin production of Vibrio cholerae in Chesapeake Bay.". Applied and environmental microbiology 37 (1): 91–103. PMC 243406. PMID 367273. 

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