Regulatory Networks Controlling Vibrio cholerae Virulence Gene Expression

Abstract

Cholera, a severe disease caused by Vibrio cholerae bacteria, has had a central role in the history of infectious disease research. The cholera studies of John Snow and Robert Koch, among many others, largely gave birth to modern epidemiology and microbiology. Despite its long history as a research target, cholera continues to afflict approximately 5 million people each year and remains an important public health problem in many areas of the globe. Here we review the current knowledge of the complex regulatory network used by V. cholerae to control expression of its virulence determinants. FEATURES OF VIBRIO CHOLERAE PATHOGENICITYCholera, which is characterized by voluminous watery diarrhea, is produced when the gram-negative curved bacillus V. cholerae colonizes the upper small intestine of its human host. V. cholerae is found throughout the world in coastal areas, most often associated with aquatic fauna such as copepods and shellfish, and is transmitted to humans by contaminated food or water. Since 1817, seven cholera pandemics have been recorded, with the most recent, ongoing pandemic having begun in 1961. Although more than 200 different serogroups have been isolated from the environment, the O1 serogroup of V. cholerae was responsible for all seven pandemics. However, beginning in 1992, O139 serogroup strains were found to cause outbreaks of cholera as well; O139 V. cholerae is sometimes referred to as the eighth cholera pandemic strain.V. cholerae O1 exist in two biotypes: classical and El Tor. Classical V. cholerae was responsible for the first six cholera pandemics, whereas the seventh pandemic has been caused by El Tor V. cholerae. The two V. cholerae biotypes differ considerably. El Tor strains generally cause a milder form of cholera than that caused by classical strains and apparently evolved as better survivors in the aquatic environment; currently, El Tor strains are predominant everywhere in the world that V. cholerae O1 can be found. V. cholerae O139 likely arose by seroconversion of O1 El Tor strains (8, 72). In addition, there are subtle differences in the way that El Tor strains and classical strains regulate expression of key virulence factors, as will be discussed below.The clinical aspects of cholera are primarily induced by the activity of cholera toxin (CT), a bipartite toxin that consists of a single active A subunit and five B subunits that bind the toxin to the GM 1 ganglioside on the surface of the intestinal epithelium. Once inside epithelial cells, a proteolytically derived fragment of the CT-A subunit, CT-A 1 , ADP-ribosylates G ␣ s protein, resulting in constitutive cyclic AMP production. This leads to massive secretion of chloride and water into the lumen of the intestine. Cholera patients can lose up to 20 liters of fluid within a 24-h period, resulting in rapid dehydration, and Ͼ50% of cholera patients die without treatment. However, if patients are rehydrated orally and/or intravenously, mortality rates decrease to ϳ1%.Aside from CT, the other major V. cholerae virulence fac...

Facile and Rapid Detection of Vibrio cholerae by Multiplex PCR Based on ompU, ctxA, and toxR Genes

“…The existence of toxR gene is significant as a regulating agent for expression and function of several other genes, which are on turn responsible for the pathogenecity of V. cholerae (9,26,27). Furthermore, toxR gene does not horizontally get transferred from pathogenic strains to non-pathogenic ones (28); hence, it is specific to vibrionacea.…”

“…OmpU is the most significant outer membrane protein; it can adhere to intestinal epithelium, allowing the bacteria to colonize (7). ToxR is an transcription activating factor that positively regulates expression of several virulent genes, including ctx and toxin co-regulated pilus (TCP) genes and accessory colonization factor (ACF) genes (5,8,9). Early identification of this microorganism is essential for each health care community to alleviate the mortality rate.…”

Potential Emergence of Multi-quorum Sensing Inhibitor Resistant (MQSIR) Bacteria

“…The V. cholerae QSSs eventually lead to the expression of a transcription factor ToxT, initiating the cholera toxin and cholera toxin corelated pilus expression, otherwise repressed by HapR, with the help of quorum regulatory sRNA 1-4 (Qrr1-4) that induce AphA expression and suppress HapR expression [56,57]. Subsequently, AphA excites the TcpP/H DNA binding protein to elicit the expression of ToxT [58,59].…”

Vibrio cholerae anaerobic induction of virulence gene expression is controlled by thiol-based switches of virulence regulator AphB

“…V. cholerae resides in aquatic environments between epidemics, and human infection normally starts with the ingestion of contaminated food or water. Vibrio cells surviving passage through the acidic gastric environment enter the small intestine, where they must produce an array of virulence factors including cholera toxin (CT) and the toxin co-regulated pilus (TCP) that are transcriptionally regulated by multiple systems (1). The primary, direct transcriptional activator of virulence genes is ToxT, whose transcription is regulated by the ToxRS and TcpPH proteins.…”