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Bacteria
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Cholera remains a major problem in Third World countries and in any area where water supplies are contaminated with domestic sewage. Incidence of the disease increased about 20-fold between 1938 and 1988. The disease is caused by Vibrio cholerae, a curved Gram-negative rod that adheres to the mucosa within four to six hours. The cholera toxin of especially virulent strains (V. cholerae 01 or 0139) is an A-B subunit toxin (see E. coli toxins, above) that stimulates adenylate cyclase production which increases intracellular levels of cAMP. in turn, cAMP initiates secretion of both water and ions from the gut epithelial cells. It is the loss of water and salt that causes the shock characteristic of the disease. Ten to fifteen percent of those infected may die. Treatment is to restore water and electrolyte balance. The patient is made to consume sufficient balanced salt solution to replace the lost water and salt. Endemic infections occur in areas with poor sewage and water treatment facilities. Transmission occurs by contamination of food and water by the diarrheal feces. Between the epidemics the organisms probably survive as harmless parasites of copepods and other animals living in rivers, ponds and estuaries. It is probable that the organism came originally from rivers in northern India.
Serotonin as an Intestinal Secretagogue
Published in T.S. Gaginella, J.J. Galligan, SEROTONIN and GASTROINTESTINAL FUNCTION, 2020
In mice, ketanserin and tropisetron reduced cholera-toxin-induced intestinal fluid accumulation.159 Both ketanserin and tropisetron only partially inhibited choleratoxin-induced fluid secretion in the rat jejunum in vivo. The combination of ketanserin and tropisetron completely abolished choleraic secretion, indicating the involvement of 5-HT2 and 5-HT3 receptors in the mediation of the secretory response to cholera toxin.35 Cholera toxin enhanced mucosal cAMP levels by about 70% in this study. The combination of ketanserin plus tropisetron, which totally abolished the secretory effect, failed to influence elevated cAMP levels. Because stimulation of the adenylate cyclase in enterochromaffin cells results in 5-HT release from these cells,9,10,29 the elevated cAMP levels may indicate that cholera toxin causes serotonin release from enterochromaffin cells via this mechanism.35 The effect of tropisetron was partly confirmed in a conscious rat model.160
The Electrical Properties of Cells
Published in Richard C. Niemtzow, Transmembrane Potentials and Characteristics of Immune and Tumor Cell, 2020
Consider the effect of cholera toxin on intestinal epithelial cells. Cholera toxin has a specific receptor on the cell surface which, after interaction with the toxin, alters the protein conformation to produce an internal enzymatic site which, by several steps, leads to enhanced production of cyclic adenosine monophosphate (cAMP). Either one of the intervening steps, or the cAMP itself, promotes the release of Ca+ + from intracellular stores, producing an elevated cytosolic level of Ca+ +. The combination of the two events produces a generalized increase in cellular activity and protein synthesis which, in the particular case of the intestinal cells, leads to the synthesis and incorporation of additional chloride conductance units in the cell membrane. The increased chloride conductance leads to a dramatic alteration in membrane potential (and, incidentally, to an enormous loss of cellular chloride and other electrolytes). Additionally, the increased intracellular Ca++ activates a K+ conductance pathway. Thus, both conductance events are the result of a circuitous chain of events all related to the receptor activation which eventually leads to an alteration in membrane potential of conductance. (For a more thorough treatment, see Reference 13 or 15.)
MlrA, a MerR family regulator in Vibrio cholerae, senses the anaerobic signal in the small intestine of the host to promote bacterial intestinal colonization
Published in Gut Microbes, 2022
Jialin Wu, Yutao Liu, Wendi Li, Fan Li, Ruiying Liu, Hao Sun, Jingliang Qin, Xiaohui Feng, Di Huang, Bin Liu
V. cholerae has a complex life cycle involving transitions between various aquatic environments, such as surface seawater, and the human small intestine.4V. cholerae can survive in aquatic environments year-round.5 In the host, V. cholerae preferentially colonizes the epithelium of the distal small intestine.6 Once it enters the small intestine, V. cholerae mainly produces two major virulence factors: the cholera toxin (CT) encoded by ctxAB on the lysogenic CTXΦ bacteriophage, which directly causes diarrhea,7 and the toxin-coregulated pilus (TCP), which is required for bacterial attachment to enterocytes and intestinal colonization.8 TCP belongs to the type-4 Pilli family,9 and has been identified as a critical colonization factor for V. cholerae in both animal models and humans.10 TCP is a polymer of repeating subunits of the major pilin protein, TcpA,11 which is encoded by tcpA.12 In V. cholerae, the regulation of TCP biosynthesis is complex and orchestrated, forming an elaborate regulatory network. The TCP operon is mainly activated by the AraC/XylS-family transcriptional regulator, ToxT,13 which is regulated by TcpP and ToxR.14 Recently, TCP was also found to be regulated by other regulators, including Fur,15 HapR,16 AhpAB,17 CRP18 and CarR.19 However, the regulatory mechanisms underlying TCP have not been fully elucidated.
Mucosal and systemic immune responses to Vibrio cholerae infection and oral cholera vaccines (OCVs) in humans: a systematic review
Published in Expert Review of Clinical Immunology, 2022
Akshayata Naidu, Sajitha Lulu S
Nevertheless, it is important to note that there is strong evidence to suggest that natural infection to V. cholerae elicits a broad inflammatory response which is not elicited after immunization with WC and rBs-WC vaccines [15,16]. The cholera toxin, which is known to trigger an inflammatory response, as a functional entity has not been used in currently licensed vaccines because of the risk of reactogenicity. But reports suggest that in mice [76] and in in vitro study [77] mutated toxins (mmCT and dmLT (an analogue)) are capable of inducing key mediators of inflammation to generate a protective response against the pathogen (without compromising on the safety). With positive mounting evidence, the adjuvant-like potential of these derived toxins needs further clinical investigation for use in the future OCVs. On the other hand, there is also an increasing trend toward research on the live attenuated vaccines in recent years (Figure 5 & Figure 6), whether such broad and diverse responses are triggered by live attenuated vaccines (with disabled enzymatic function of the toxin) or not is not known and needs further studies.
Update on CVD 103-HgR single-dose, live oral cholera vaccine
Published in Expert Review of Vaccines, 2022
James McCarty, Lisa Bedell, Paul-Andre De Lame, David Cassie, Michael Lock, Sean Bennett, Douglas Haney
There are more than 200 serogroups of V. cholerae but only two, O1 and O139, secrete cholera toxin and cause disease [1,3]. The serogroup O1 is subdivided into classical and El Tor biotypes, both of which can be further divided into two cross-reacting serotypes, Ogawa and Inaba. El Tor (O1 serogroup) currently accounts for almost all worldwide cases of cholera, whereas serogroup O139 is rarely isolated. The cholera toxin produced during infection consists of one toxin A subunit and five toxin B subunits. The B subunits mediate binding and uptake of the toxin into intestinal epithelial cells [1]. Once endocytosed, the A and B subunits dissociate, and the A subunit activates adenylate cyclase, which increases intracellular levels of cyclic adenosine monophosphate (cAMP). This results in reduced sodium absorption, increased chloride secretion, and a net flow of water, potassium, and bicarbonate into the bowel lumen [1,5].