Na+-dependent pH Regulation by the Amitochondriate Protozoan Parasite Giardia intestinalis

Biagini, Giancarlo A.; Knodler, Leigh A.; Saliba, Kevin J.; Kirk, Kiaran; Edwards, Michael R.

doi:10.1074/jbc.m102728200

Cited by 10 publications

(6 citation statements)

References 39 publications

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“…Heat-treatment also led to inactivation of L. johnsonii La1 supernatant inhibitory properties (Figure 2A ). Additionally, in a pH range similar to the ones experienced by G. duodenalis in vivo (Biagini et al, 2001 ), a strong pH influence on the inhibitory activity was noticed, with the highest inhibition occurring at pH 6.2 (Figure 2B ).…”

Section: Resultssupporting

confidence: 65%

Deconjugated Bile Salts Produced by Extracellular Bile-Salt Hydrolase-Like Activities from the Probiotic Lactobacillus johnsonii La1 Inhibit Giardia duodenalis In vitro Growth

et al. 2016

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Giardiasis, currently considered a neglected disease, is caused by the intestinal protozoan parasite Giardia duodenalis and is widely spread in human as well as domestic and wild animals. The lack of appropriate medications and the spread of resistant parasite strains urgently call for the development of novel therapeutic strategies. Host microbiota or certain probiotic strains have the capacity to provide some protection against giardiasis. By combining biological and biochemical approaches, we have been able to decipher a molecular mechanism used by the probiotic strain Lactobacillus johnsonii La1 to prevent Giardia growth in vitro. We provide evidence that the supernatant of this strain contains active principle(s) not directly toxic to Giardia but able to convert non-toxic components of bile into components highly toxic to Giardia. By using bile acid profiling, these components were identified as deconjugated bile-salts. A bacterial bile-salt-hydrolase of commercial origin was able to mimic the properties of the supernatant. Mass spectrometric analysis of the bacterial supernatant identified two of the three bile-salt-hydrolases encoded in the genome of this probiotic strain. These observations document a possible mechanism by which L. johnsonii La1, by secreting, or releasing BSH-like activity(ies) in the vicinity of replicating Giardia in an environment where bile is present and abundant, can fight this parasite. This discovery has both fundamental and applied outcomes to fight giardiasis, based on local delivery of deconjugated bile salts, enzyme deconjugation of bile components, or natural or recombinant probiotic strains that secrete or release such deconjugating activities in a compartment where both bile salts and Giardia are present.

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Section: Resultssupporting

confidence: 65%

Deconjugated Bile Salts Produced by Extracellular Bile-Salt Hydrolase-Like Activities from the Probiotic Lactobacillus johnsonii La1 Inhibit Giardia duodenalis In vitro Growth

et al. 2016

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“…Further, 106-r is the only line in which a set of V-type ATPases and a MATE-like transporter are up-regulated. Like other protists, G. duodenalis may utilize V-type ATPases at the plasma membrane to regulate cytosolic pH (Biagini et al, 2001a). Increased transcription of dynein and kinesin-related proteins in 106-r is consistent with the recycling of such ATPases via microtubule-dependent transport of ATPase-rich vesicles, evidenced in higher eukaryotes (Breton and Brown, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Increased transcription of dynein and kinesin-related proteins in 106-r is consistent with the recycling of such ATPases via microtubule-dependent transport of ATPase-rich vesicles, evidenced in higher eukaryotes (Breton and Brown, 2013). Active proton efflux, coupled to a sodium:proton exchanger (up-regulated in 106-r and WB-r; Biagini et al, 2001a), may decrease the cytosolic sodium concentration sufficiently to drive Mtz efflux via the MATE transporter, which is a sodium-coupled multidrug efflux pump (Du et al, 2015). Indeed, although MATE transporters are generally associated with extruding cationic compounds, the possibility of Mtz efflux through these channels is supported by experiments in H. pylori demonstrating increased Mtz sensitivity MATE-knockout lines (van Amsterdam et al, 2005; Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Transcriptomics Indicates Active and Passive Metronidazole Resistance Mechanisms in Three Seminal Giardia Lines

et al. 2017

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Giardia duodenalis is an intestinal parasite that causes 200–300 million episodes of diarrhoea annually. Metronidazole (Mtz) is a front-line anti-giardial, but treatment failure is common and clinical resistance has been demonstrated. Mtz is thought to be activated within the parasite by oxidoreductase enzymes, and to kill by causing oxidative damage. In G. duodenalis, Mtz resistance involves active and passive mechanisms. Relatively low activity of iron-sulfur binding proteins, namely pyruvate:ferredoxin oxidoreductase (PFOR), ferredoxins, and nitroreductase-1, enable resistant cells to passively avoid Mtz activation. Additionally, low expression of oxygen-detoxification enzymes can allow passive (non-enzymatic) Mtz detoxification via futile redox cycling. In contrast, active resistance mechanisms include complete enzymatic detoxification of the pro-drug by nitroreductase-2 and enhanced repair of oxidized biomolecules via thioredoxin-dependent antioxidant enzymes. Molecular resistance mechanisms may be largely founded on reversible transcriptional changes, as some resistant lines revert to drug sensitivity during drug-free culture in vitro, or passage through the life cycle. To comprehensively characterize these changes, we undertook strand-specific RNA sequencing of three laboratory-derived Mtz-resistant lines, 106-2ID10, 713-M3, and WB-M3, and compared transcription relative to their susceptible parents. Common up-regulated genes encoded variant-specific surface proteins (VSPs), a high cysteine membrane protein, calcium and zinc channels, a Mad-2 cell cycle regulator and a putative fatty acid α-oxidase. Down-regulated genes included nitroreductase-1, putative chromate and quinone reductases, and numerous genes that act proximal to PFOR. Transcriptional changes in 106-2ID10 diverged from those in 713-r and WB-r (r ≤ 0.2), which were more similar to each other (r = 0.47). In 106-2ID10, a nonsense mutation in nitroreductase-1 transcripts could enhance passive resistance whereas increased transcription of nitroreductase-2, and a MATE transmembrane pump system, suggest active drug detoxification and efflux, respectively. By contrast, transcriptional changes in 713-M3 and WB-M3 indicated a higher oxidative stress load, attributed to Mtz- and oxygen-derived radicals, respectively. Quantitative comparisons of orthologous gene transcription between Mtz-resistant G. duodenalis and Trichomonas vaginalis, a closely related parasite, revealed changes in transcripts encoding peroxidases, heat shock proteins, and FMN-binding oxidoreductases, as prominent correlates of resistance. This work provides deep insight into Mtz-resistant G. duodenalis, and illuminates resistance-associated features across parasitic species.

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“…The larger surface/volume of smaller cells size may allow them to better regulate their intracellular pH, because the maintenance of intracelular pH is presumed to be controlled by surface-associated ion-exchange processes (e.g. Gatti & Christen 1985, Boron 1986, Biagini et al 2001. At high pH levels, smaller cells thus have a relatively larger surface area and hence a larger potential for maintaining a stable intracellular pH.…”

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confidence: 99%

Effect of pH on growth and domoic acid production by potentially toxic diatoms of the genera Pseudo-nitzschia and Nitzschia

Lundholm¹,

Hansen²,

Kotaki³

2004

Mar. Ecol. Prog. Ser.

160

122

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The effect of elevated pH on growth and on production of the neurotoxin domoic acid was studied in selected diatoms belonging to the genera Pseudo-nitzschia and Nitzschia. Growth of most of the 11 species studied stopped at pH values of 8.7 to 9.1. However, for P. delicatissima and N. navis-varingica the pH limit for growth was higher, 9.3 and 9.7 to 9.8, respectively. A compilation of all available data on the pH limits for growth of marine planktonic diatoms suggests that species from ponds and rock pools all have higher limits than coastal and oceanic species. Taking only coastal and oceanic species into account, the data suggest that smaller species have a higher upper pH limit for growth than larger species. Elevated pH induced production of domoic acid in P. multiseries in amounts comparable to those detected previously under silicate and phosphate limitation. As Pseudo-nitzschia species are found in high concentrations in nutrient-enriched areas, high pH and hence induction of the production of domoic acid would be expected during blooms. These results may help to understand when and why Pseudo-nitzschia species produce domoic acid in the field.KEY WORDS: Cell volume · Diatom · Domoic acid · Growth rate · pH · Phytoplankton · Pseudonitzschia · Toxin production Resale or republication not permitted without written consent of the publisherMar Ecol Prog Ser 273: [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] 2004 Pseudo-nitzschia spp. blooms are often found in coastal areas enriched by nutrient-rich freshwater runoff (Smith et al. 1990, Horner & Postel 1993, Dortch et al. 1997, Scholin et al. 2000, Odebrecht et al. 2001 or in upwelling areas (Abrantes & Moita 1999, Trainer et al. 2000, Villac & Tenenbaum 2001. A positive relationship between increasing eutrophication of coastal waters and the abundance of Pseudo-nitzschia spp. was found in present and historical data from the coast of Louisiana and Texas (Dortch et al. 1997, Parsons et al. 2002. Hence, nutrient enrichment may result in increased densities of phytoplankton organisms such as Pseudo-nitzschia spp.In seawater, pH has generally been recognised as being very stable (pH ≈ 8.2), as it is buffered by the carbonate system. However, uptake of dissolved inorganic carbon (DIC) during photosynthesis by high densities of phytoplankton may actually cause an increase in pH, and thus high pH values (around pH 9) have been recorded in natural environments during algal blooms (Hinga 1992, Macedo et al. 2001. For instance, in Narrangansett Bay, USA, 18% of the samples had pH values above 8.7 (Hinga 2002). Similarly, during the development of a bloom of the haptophyte Phaeocystis spp. in the North Sea, Brussard et al. (1996) found an increase in pH from 7.9 to 8.7. In fjords and coastal lagoons, pH values can attain even higher levels, and pH values up to around 10 may then be found during bloom periods (e.g. Marshall & Orr 1948, Macedo et al. 2001, Hansen 2002. The only study that we have been able to find in which pH, growth of potentially t...

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Na+-dependent pH Regulation by the Amitochondriate Protozoan Parasite Giardia intestinalis

Cited by 10 publications

References 39 publications

Deconjugated Bile Salts Produced by Extracellular Bile-Salt Hydrolase-Like Activities from the Probiotic Lactobacillus johnsonii La1 Inhibit Giardia duodenalis In vitro Growth

Deconjugated Bile Salts Produced by Extracellular Bile-Salt Hydrolase-Like Activities from the Probiotic Lactobacillus johnsonii La1 Inhibit Giardia duodenalis In vitro Growth

Transcriptomics Indicates Active and Passive Metronidazole Resistance Mechanisms in Three Seminal Giardia Lines

Effect of pH on growth and domoic acid production by potentially toxic diatoms of the genera Pseudo-nitzschia and Nitzschia

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