pH-Dependent Conformational Change of Gastric Mucin Leads to Sol-Gel Transition

Cao, Xingxiang; Bansil, Rama; Bhaskar, K. Ramakrishnan; Turner, Bradley S.; LaMont, J. Thomas; Niu, Niu; Afdhal, Nezam H.

doi:10.1016/s0006-3495(99)77288-7

Cited by 207 publications

(240 citation statements)

References 34 publications

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“…Mucins have short hydrophobic domains (lipid-coated, nonglycosylated, cysteine-rich domains) interspersed between long glycosylated regions (5,32). The negatively charged glycosylated domains likely repel each other, but the hydrophobic domains may cause mucins to self-condense and/ or bundle together (33)(34)(35). To test this, we added 1% vol/vol of a nonionic detergent, (nonylphenoxy)polyethylene oxide, to the same mucus samples and again characterized the pore size.…”

Section: Cvm Mucins Are Condensed And/or Bundled Into Thick Cables Viamentioning

confidence: 99%

Nanoparticles reveal that human cervicovaginal mucus is riddled with pores larger than viruses

Lai

Wang²,

Hida³

et al. 2009

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

333

343

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The mechanisms by which mucus helps prevent viruses from infecting mucosal surfaces are not well understood. We engineered non-mucoadhesive nanoparticles of various sizes and used them as probes to determine the spacing between mucin fibers (pore sizes) in fresh undiluted human cervicovaginal mucus (CVM) obtained from volunteers with healthy vaginal microflora. We found that most pores in CVM have diameters significantly larger than human viruses (average pore size 340 ± 70 nm; range approximately 50–1800 nm). This mesh structure is substantially more open than the 15–100-nm spacing expected assuming mucus consists primarily of a random array of individual mucin fibers. Addition of a nonionic detergent to CVM caused the average pore size to decrease to 130 ± 50 nm. This suggests hydrophobic interactions between lipid-coated “naked” protein regions on mucins normally cause mucin fibers to self-condense and/or bundle with other fibers, creating mucin “cables” at least three times thicker than individual mucin fibers. Although the native mesh structure is not tight enough to trap most viruses, we found that herpes simplex virus (approximately 180 nm) was strongly trapped in CVM, moving at least 8,000-fold slower than non-mucoadhesive 200-nm nanoparticles. This work provides an accurate measurement of the pore structure of fresh, hydrated ex vivo CVM and demonstrates that mucoadhesion, rather than steric obstruction, may be a critical protective mechanism against a major sexually transmitted virus and perhaps other viruses.

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Section: Cvm Mucins Are Condensed And/or Bundled Into Thick Cables Viamentioning

confidence: 99%

Nanoparticles reveal that human cervicovaginal mucus is riddled with pores larger than viruses

Lai

Wang²,

Hida³

et al. 2009

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

333

343

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“…PGM was obtained from pig stomachs and purified by Sepharose CL-2B column chromatography and density gradient ultracentrifugation as described in ref. 27. Samples for rheology were prepared to the appropriate pH using an artificial gastric juice preparation as previously described (55) (but modified to include only hydrochloric acid without additional salts, and in some samples, urea) and left to equilibrate for 48 h before study.…”

Section: Discussionmentioning

confidence: 99%

“…Although previous studies have examined the motility of H. pylori and other bacteria in fluids with varying viscosity (21-25), we are not aware of any experimental studies that indicate the ability of a flagellated prokaryote to swim through a gel with GЈ( ) Ͼ GЈЈ( ). It has been shown however, that gastric mucin, the glycoprotein content of mucus primarily responsible for its viscoelastic response, undergoes a reversible pH-dependent sol-gel transition from a viscous polymer solution to a soft gel as pH is lowered below pH Ϸ 4, and vice versa as the pH is raised (26,27). This feature of mucin is believed to play a crucial role in its protective function in the stomach in that by forming a gel at low pH, it forms a viscoelastic barrier protecting the lining of the stomach from damage by its own acidic secretions and other insults (28).…”

mentioning

confidence: 99%

Helicobacter pylori moves through mucus by reducing mucin viscoelasticity

Celli

Turner

Afdhal

et al. 2009

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

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378

326

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The ulcer-causing gastric pathogen Helicobacter pylori is the only bacterium known to colonize the harsh acidic environment of the human stomach. H. pylori survives in acidic conditions by producing urease, which catalyzes hydrolysis of urea to yield ammonia thus elevating the pH of its environment. However, the manner in which H. pylori is able to swim through the viscoelastic mucus gel that coats the stomach wall remains poorly understood. Previous rheology studies on gastric mucin, the key viscoelastic component of gastric mucus, indicate that the rheology of this material is pH dependent, transitioning from a viscous solution at neutral pH to a gel in acidic conditions. Bulk rheology measurements on porcine gastric mucin (PGM) show that pH elevation by H. pylori induces a dramatic decrease in viscoelastic moduli. Microscopy studies of the motility of H. pylori in gastric mucin at acidic and neutral pH in the absence of urea show that the bacteria swim freely at high pH, and are strongly constrained at low pH. By using two-photon fluorescence microscopy to image the bacterial motility in an initially low pH mucin gel with urea present we show that the gain of translational motility by bacteria is directly correlated with a rise in pH indicated by 2 ,7 -Bis-(2-Carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF), a pH sensitive fluorescent dye. This study indicates that the helicoidal-shaped H. pylori does not bore its way through the mucus gel like a screw through a cork as has previously been suggested, but instead achieves motility by altering the rheological properties of its environment.H. pylori ͉ bacterial motility ͉ rheology ͉ pH ͉ gelation

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“…Shear thinning behavior, Figure 5. Stress sweep data for (A) pH 2 PGM (gel), 15 mg/mL, and (B) pH 6 PGM (sol), plotted as G′ (9) and G′′ (b) versus the amplitude of the applied oscillatory shear stress at a constant frequency of ω ) 0.5 rad/s. In the pH 2 sample, as stress is increased beyond the linear regime, the gel yields and begins to flow just above 10 Pa.…”

Section: Figure 2 Creep Compliance J(t) ) γ(T)/σ0 Versus Time For mentioning

confidence: 99%

Rheology of Gastric Mucin Exhibits a pH-Dependent Sol−Gel Transition

et al. 2007

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Gastric mucin, a high molecular weight glycoprotein, is responsible for providing the gel-forming properties and protective function of the gastric mucus layer. Bulk rheology measurements in the linear viscoelastic regime show that gastric mucin undergoes a pH-dependent sol-gel transition from a viscoelastic solution at neutral pH to a soft viscoelastic gel in acidic conditions, with the transition occurring near pH 4. In addition to pH-dependent gelation behavior in this system, further rheological studies under nonlinear deformations reveal shear thinning and an apparent yield stress in this material which are also highly influenced by pH.

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pH-Dependent Conformational Change of Gastric Mucin Leads to Sol-Gel Transition

Cited by 207 publications

References 34 publications

Nanoparticles reveal that human cervicovaginal mucus is riddled with pores larger than viruses

Nanoparticles reveal that human cervicovaginal mucus is riddled with pores larger than viruses

Helicobacter pylori moves through mucus by reducing mucin viscoelasticity

Rheology of Gastric Mucin Exhibits a pH-Dependent Sol−Gel Transition

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