Decreased Potency of the
            <i>Vibrio cholerae</i>
            Sheathed Flagellum To Trigger Host Innate Immunity

Yoon, Sang Sun; Mekalanos, John J.

doi:10.1128/iai.00736-07

Cited by 37 publications

(52 citation statements)

References 50 publications

(48 reference statements)

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“…Bacterial flagellin proteins, including all five V. cholerae flagellins, are known to stimulate production of proinflammatory cytokines by activation of TLR5 (10,11,18). We therefore compared the relative abundance of transcripts for several cytokines in tissue homogenates from rabbits infected with Peru-NT or Peru-NTΔflaABCDE and from mock-infected rabbits.…”

Section: Peru-nt and Peru-ntδflaabcde Differ In Their Stimulation Ofmentioning

confidence: 99%

Reactogenicity of live-attenuated Vibrio cholerae vaccines is dependent on flagellins

Rui

Ritchie

Bronson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Cholera is a severe diarrheal disease caused by the motile Gramnegative rod Vibrio cholerae. Live-attenuated V. cholerae vaccines harboring deletions of the genes encoding cholera toxin have great promise for reducing the global burden of cholera. However, development of live vaccines has been hampered by the tendency of such strains to induce noncholeric reactogenic diarrhea in human subjects. The molecular bases of reactogenicity are unknown, but it has been speculated that reactogenic diarrhea is a response to V. cholerae's flagellum and/or the motility that it enables. Here, we used an infant rabbit model of reactogenicity to determine what V. cholerae factors trigger this response. We found that V. cholerae ctx mutants that produced flagellins induced diarrhea, regardless of whether the proteins were assembled into a flagellum or whether the flagellum was functional. In contrast, ∼90% of rabbits infected with V. cholerae lacking all five flagellin-encoding genes did not develop diarrhea. Thus, flagellin production, independent of flagellum assembly or motility, is sufficient for reactogenicity. The intestinal colonization and intraintestinal localization of the nonreactogenic flagellin-deficient strain were indistinguishable from those of a flagellated motile strain; however, the flagellin-deficient strain stimulated fewer mRNA transcripts coding for proinflammatory cytokines in the intestine. Thus, reactogenic diarrhea may be a consequence of an innate host inflammatory response to V. cholerae flagellins. Our results suggest a simple genetic blueprint for engineering defined nonreactogenic live-attenuated V. cholerae vaccine strains.animal model | cholera | innate immunity | diarrhea

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Section: Peru-nt and Peru-ntδflaabcde Differ In Their Stimulation Ofmentioning

confidence: 99%

Reactogenicity of live-attenuated Vibrio cholerae vaccines is dependent on flagellins

Rui

Ritchie

Bronson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…The flagellar sheath of V. cholerae has been widely studied; however, its origin and function are not completely understood. It has recently been proposed that the flagellar sheath of V. cholerae functions as a means to evade host immune responses (36). The sheath was also shown to protect the filament from dissociation when exposed to high temperatures and low pH, conditions that easily dissociate the nonsheathed flagellum of Salmonella enterica serovar Typhimurium (36).…”

mentioning

confidence: 99%

“…It has recently been proposed that the flagellar sheath of V. cholerae functions as a means to evade host immune responses (36). The sheath was also shown to protect the filament from dissociation when exposed to high temperatures and low pH, conditions that easily dissociate the nonsheathed flagellum of Salmonella enterica serovar Typhimurium (36). Furthermore, the flagellum is also thought to have adhesive properties, which would allow it to function as an attachment factor (1,9,14,29).…”

mentioning

confidence: 99%

Characterization of Two Outer Membrane Proteins, FlgO and FlgP, That Influence Vibrio cholerae Motility

et al. 2009

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FlgO is an outer membrane protein that localizes throughout the membrane and not at the flagellar pole. Although FlgO and FlgP do not specifically localize to the flagellum, they are required for flagellar stability. Due to the nature of these motility defects, we established that the flagellum is not sufficient for adherence; rather, motility is the essential factor required for attachment and thus colonization by V. cholerae O1 of the classical biotype. This study reveals a novel mechanism for which the outer membrane proteins FlgO and FlgP function in motility to mediate flagellar stability and influence attachment and colonization.The causative agent of the infectious diarrheal disease cholera is the bacterium Vibrio cholerae. This enteric pathogen naturally inhabits an aquatic environment and is motile by the action of a single polar flagellum. The mechanism of pathogenesis by which V. cholerae causes disease is a stepwise and cyclic process. First, contaminated food or water is ingested; then, the bacteria pass through the stomach. After withstanding that acidic environment, the bacteria enter the lumen of the intestine and attach to the intestinal epithelium of the human host. Once the bacteria establish an initial attachment, the bacteria begin to express the toxin-coregulated pilus, which facilitates bacterium-bacterium interactions and the formation of microcolonies. Subsequently, an enterotoxin, cholera toxin, is expressed and secreted by the bacteria, which through a cascade of events leads to profuse, watery diarrhea. Eventually, the bacteria are shed from the host and are dispersed back into the environment, thus renewing the cycle.Although the later stages of the disease, which include the production of toxin-coregulated pilus and cholera toxin, are well characterized, little is known about the initial stages of pathogenesis. The attachment factor GbpA has been shown to bind chitin, an abundant substance found in the environment that is a polymer of N-acetylglucosamine (GlcNAc) carbohydrate subunits (17). GbpA is also involved in the initial attachment of V. cholerae to epithelial cells, which have exposed GlcNAc moieties on their surfaces. In the absence of gbpA, only a 50% reduction in attachment is observed, suggesting that there may be additional factors that are involved in initiating attachment to the intestinal epithelium.Colonization requires a functional flagellum; therefore, motility is a crucial virulence factor of V. cholerae (9, 12). The flagellum functions to propel the cell through its environment. In the host, the flagellum functions as a means to gain access to the microvilli of the epithelial cells by facilitating the penetration of the intestinal mucus layer, an action that is important for colonization (1,4,14). The flagellum is composed of a base, a hook, and a filament. The flagellar apparatus is assembled in an ordered cascade of events. The genes necessary for motility and chemotaxis are found distributed among six regions on the large chromosome of V. cholerae (regions I t...

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“…H. pylori). It is hypothesized that the sheath acts as a protective covering that shields the antigenic flagellins from recognition by the host's immune response (Yoon and Mekalanos 2008). The mechanism whereby the OM is extended to cover the filament during V. cholerae flagellar synthesis rather than the filament protruding through the OM as in other bacterial flagella is not understood.…”

Section: Fig 2 Flagellar Motor Complexmentioning

confidence: 99%

Vibrio cholerae Flagellar Synthesis and Virulence

Anastasia¹,

Karl²

2012

Cholera

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Decreased Potency of the Vibrio cholerae Sheathed Flagellum To Trigger Host Innate Immunity

Cited by 37 publications

References 50 publications

Reactogenicity of live-attenuated Vibrio cholerae vaccines is dependent on flagellins

Reactogenicity of live-attenuated Vibrio cholerae vaccines is dependent on flagellins

Characterization of Two Outer Membrane Proteins, FlgO and FlgP, That Influence Vibrio cholerae Motility

Vibrio cholerae Flagellar Synthesis and Virulence

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