Spatiotemporal Regulation of Vibrio Exotoxins by Hlyu and Other Transcriptional Regulators
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toxins Review Spatiotemporal Regulation of Vibrio Exotoxins by HlyU and Other Transcriptional Regulators Byoung Sik Kim Department of Food Science and Engineering, ELTEC College of Engineering, Ewha Womans University, Seoul 03760, Korea; [email protected] Received: 8 August 2020; Accepted: 19 August 2020; Published: 22 August 2020 Abstract: After invading a host, bacterial pathogens secrete diverse protein toxins to disrupt host defense systems. To ensure successful infection, however, pathogens must precisely regulate the expression of those exotoxins because uncontrolled toxin production squanders energy. Furthermore, inappropriate toxin secretion can trigger host immune responses that are detrimental to the invading pathogens. Therefore, bacterial pathogens use diverse transcriptional regulators to accurately regulate multiple exotoxin genes based on spatiotemporal conditions. This review covers three major exotoxins in pathogenic Vibrio species and their transcriptional regulation systems. When Vibrio encounters a host, genes encoding cytolysin/hemolysin, multifunctional-autoprocessing repeats-in-toxin (MARTX) toxin, and secreted phospholipases are coordinately regulated by the transcriptional regulator HlyU. At the same time, however, they are distinctly controlled by a variety of other transcriptional regulators. How this coordinated but distinct regulation of exotoxins makes Vibrio species successful pathogens? In addition, anti-virulence strategies that target the coordinating master regulator HlyU and related future research directions are discussed. Keywords: exotoxin; transcriptional regulation; hemolysin; cytolysin; MARTX toxin; secreted phospholipase; HlyU; Vibrio species Key Contribution: During infection, major exotoxin genes in pathogenic Vibrio species are coordinately but distinctly regulated by HlyU and other transcriptional regulators for spatiotemporal expression. 1. Introduction The genus Vibrio is composed of various bacterial species that are metabolically versatile. They are commonly found in a wide range of marine environments [1,2]. Although some live as commensals or symbionts in crustaceans, shellfish, squid, or fish, several pathogenic species cause infectious diseases in marine animals. For instance, Vibrio harveyi causes luminescent vibriosis in shrimp, V. alginolyticus causes canker in croakers, V. vulnificus causes hemorrhagic disease in aquaculture eels, V. crassostreae causes hemocyte lysis in oysters, and V. anguillarum causes erythema and necrotic lesions in Pacific and Atlantic salmon [3–8]. More important, certain Vibrio species are human pathogens that cause various diseases in immune-compromised individuals [9]. People who consume raw or undercooked seafood can get infected by Vibrio species via the intestinal tract. Another route for Vibrio infection is an open wound submersed in contaminated seawater. Depending on the invading species and the health status of patients, symptoms can range from abdominal pain or diarrhea to bacteremia, sepsis, or even death. Well-known examples of human-infecting Vibrio species include V. cholerae, V. vulnificus, V. parahaemolyticus, and V. alginolyticus [9]. Toxins 2020, 12, 544; doi:10.3390/toxins12090544 www.mdpi.com/journal/toxins Toxins 2020, 12, 544 2 of 22 ToxinsVibrio 2020, species12, x FORcause PEER REVIEW disease in humans and animals by producing diverse virulence factors.2 of Some23 virulence factors promote the proliferation of invading Vibrio in the host and protect them from the Vibrio species cause disease in humans and animals by producing diverse virulence factors. host defense systems. For example, V. cholerae expresses a toxin-coregulated pilus that enables the Some virulence factors promote the proliferation of invading Vibrio in the host and protect them from pathogens to aggregate and adhere to gut epithelial cells, facilitating microcolony formation for initial the host defense systems. For example, V. cholerae expresses a toxin-coregulated pilus that enables the colonization [10–12]. V. vulnificus has evolved many iron scavenging systems and shows extraordinarily pathogens to aggregate and adhere to gut epithelial cells, facilitating microcolony formation for initial rapidcolonization growth in [10–12]. high iron V. sera vulnificus [13]. Indeed, has multipleevolved genesmany encoding iron scavenging biosynthetic systems enzymes, and transporters, shows andextraordinarily utilization components rapid growth for in siderophores high iron sera have [13]. been Indeed, characterized multiple asgenes important encoding virulence biosynthetic genes in thisenzymes, pathogen transporters, [14–17]. Capsular and utilization polysaccharide components is another for siderophores essential virulence have been factor characterized for V. vulnificus as becauseimportant the virulence encapsulated genes strain in this can pathogen resist macrophage-mediated [14–17]. Capsular polysaccharide phagocytosis is another [18,19]. essential The ability tovirulence use host-specific factor for carbohydrates V. vulnificus because is another the encapsulated crucial trait forstrain pathogens can resist because macrophage-mediated invading bacteria competephagocytosis with the [18,19]. host andThe residual ability commensalsto use host-specific for nutrients carbohydrates [20]. Consistent is another with this,crucialVibrio traitmutants for thatpathogens are unable because to use invading sialic acids, bacter a distalia compete end carbohydrate with the host found and residual in hostmucins, commensals showed for colonizationnutrients defects[20]. Consistent in mouse with infection this, Vibrio experiments mutants [ 21that,22 are].Reduced unable to virulenceuse sialic acids, was also a distal observed end carbohydrate in V. vulnificus whenfound a in specific host mucins, transcriptional showed colonization regulator for defects the sialic in mouse acid infection utilization experiments system was [21,22]. mutated Reduced [23, 24]. Thisvirulence latter result was also emphasizes observed in that V. vulnificus virulence when factors a specific mustbe transcriptional accurately regulated regulator atfor the thetranscription sialic acid levelutilization to enable system successful was mutated pathogenesis. [23,24]. This latter result emphasizes that virulence factors must be accuratelyAnother regulated kind of at the virulence transcription factor level in to bacterial enable successful pathogens pathogenesis. is secreted protein toxins, or exotoxins.Another Unlike kind of the virulence above-mentioned factor in bacterial virulence pathogens factors, is secreted exotoxins protein are inherentlytoxins, or exotoxins. destructive andUnlike affect the theabove-mentioned integrity of hostvirulence cells factors, and tissuesexotoxins through are inherently their enzymatic destructive functionsand affect [the25, 26]. Inintegrity pathogenic of hostVibrio cellsspecies, and tissues especially throughV. cholerae,their enzymatic V. vulnificus functions, and [25,26].V. anguillarum In pathogenic, the following Vibrio species, especially V. cholerae, V. vulnificus, and V. anguillarum, the following exotoxins and their exotoxins and their transcriptional regulation mechanisms have been substantially characterized: transcriptional regulation mechanisms have been substantially characterized: cytolysin/hemolysin, cytolysin/hemolysin, multifunctional-autoprocessing repeats-in-toxin (MARTX) toxin, secreted multifunctional-autoprocessing repeats-in-toxin (MARTX) toxin, secreted phospholipase, and phospholipase, and vibriolysins (Figure1a–d) [ 27–39]. Because the inactivation of any of these toxins vibriolysins (Figure 1a-d) [27–39]. Because the inactivation of any of these toxins in V. vulnificus in V. vulnificus significantly compromises its virulence [36,40–42], it is speculated that homologous significantly compromises its virulence [36,40–42], it is speculated that homologous exotoxins in exotoxinsother pathogenic in other pathogenicVibrio speciesVibrio couldspecies contribute could to contribute their virulence to their and virulence disease progression. and disease progression.Notably, Notably,the transcriptionalthe transcriptional regulatorregulator HlyU has HlyU been has found been to foundbind to to the bind regulatory to the regulatory region of regionall these of all theseexotoxin exotoxin genes genes and control and control their expres theirsion, expression, except for except the vibriolysin for the vibriolysin genes [32,33,35,36,43]. genes [32,33 Diverse,35,36, 43]. Diversetranscriptional transcriptional regulators regulators other than other HlyU than HlyUalso alsocontrol control exotoxin exotoxin expression expression by byconveying conveying environmentalenvironmental cues. cues. FigureFigure 1. 1.Major Major exotoxins exotoxins produced produced by pathogenicby pathogenicVibrio Vibriospecies. species. (a) After (a) secretionAfter secretion from the from bacterium, the cytolysinbacterium,/hemolysin cytolysin/hemolysin is activated byis activated processing by ofproce thessing pro-region. of the pro-region. The resulting The active resulting toxin active then toxin binds to thethen target binds cell to membrane, the target andcell sevenmembrane, monomers and seven are assembled monomers to formare assembled a pre-pore to intermediate. form a pre-pore During thisintermediate. assembly, pre-stems During this are assembly, extended, pre-stems tightly gathered, are extended, and inserted tightly gathered, into the membrane, and inserted establishing into the a membrane, establishing