GM1 ganglioside-independent intoxication by Cholera toxin.
Cholera toxin (CT) enters and intoxicates host cells after binding cell surface receptors via its B subunit (CTB). We have recently shown that in addition to the previously described binding partner ganglioside GM1, CTB binds to fucosylated proteins. Using flow cytometric analysis of primary human j...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2018-02-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1006862 |
| _version_ | 1818905245167648768 |
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| author | Jakob Cervin Amberlyn M Wands Anna Casselbrant Han Wu Soumya Krishnamurthy Aleksander Cvjetkovic Johanna Estelius Benjamin Dedic Anirudh Sethi Kerri-Lee Wallom Rebecca Riise Malin Bäckström Ville Wallenius Frances M Platt Michael Lebens Susann Teneberg Lars Fändriks Jennifer J Kohler Ulf Yrlid |
| author_facet | Jakob Cervin Amberlyn M Wands Anna Casselbrant Han Wu Soumya Krishnamurthy Aleksander Cvjetkovic Johanna Estelius Benjamin Dedic Anirudh Sethi Kerri-Lee Wallom Rebecca Riise Malin Bäckström Ville Wallenius Frances M Platt Michael Lebens Susann Teneberg Lars Fändriks Jennifer J Kohler Ulf Yrlid |
| author_sort | Jakob Cervin |
| collection | DOAJ |
| description | Cholera toxin (CT) enters and intoxicates host cells after binding cell surface receptors via its B subunit (CTB). We have recently shown that in addition to the previously described binding partner ganglioside GM1, CTB binds to fucosylated proteins. Using flow cytometric analysis of primary human jejunal epithelial cells and granulocytes, we now show that CTB binding correlates with expression of the fucosylated Lewis X (LeX) glycan. This binding is competitively blocked by fucosylated oligosaccharides and fucose-binding lectins. CTB binds the LeX glycan in vitro when this moiety is linked to proteins but not to ceramides, and this binding can be blocked by mAb to LeX. Inhibition of glycosphingolipid synthesis or sialylation in GM1-deficient C6 rat glioma cells results in sensitization to CT-mediated intoxication. Finally, CT gavage produces an intact diarrheal response in knockout mice lacking GM1 even after additional reduction of glycosphingolipids. Hence our results show that CT can induce toxicity in the absence of GM1 and support a role for host glycoproteins in CT intoxication. These findings open up new avenues for therapies to block CT action and for design of detoxified enterotoxin-based adjuvants. |
| first_indexed | 2024-12-19T21:20:16Z |
| format | Article |
| id | doaj.art-f798db5d3c714c6f9abd3318d6d329e7 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-19T21:20:16Z |
| publishDate | 2018-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-f798db5d3c714c6f9abd3318d6d329e72022-12-21T20:05:15ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742018-02-01142e100686210.1371/journal.ppat.1006862GM1 ganglioside-independent intoxication by Cholera toxin.Jakob CervinAmberlyn M WandsAnna CasselbrantHan WuSoumya KrishnamurthyAleksander CvjetkovicJohanna EsteliusBenjamin DedicAnirudh SethiKerri-Lee WallomRebecca RiiseMalin BäckströmVille WalleniusFrances M PlattMichael LebensSusann TenebergLars FändriksJennifer J KohlerUlf YrlidCholera toxin (CT) enters and intoxicates host cells after binding cell surface receptors via its B subunit (CTB). We have recently shown that in addition to the previously described binding partner ganglioside GM1, CTB binds to fucosylated proteins. Using flow cytometric analysis of primary human jejunal epithelial cells and granulocytes, we now show that CTB binding correlates with expression of the fucosylated Lewis X (LeX) glycan. This binding is competitively blocked by fucosylated oligosaccharides and fucose-binding lectins. CTB binds the LeX glycan in vitro when this moiety is linked to proteins but not to ceramides, and this binding can be blocked by mAb to LeX. Inhibition of glycosphingolipid synthesis or sialylation in GM1-deficient C6 rat glioma cells results in sensitization to CT-mediated intoxication. Finally, CT gavage produces an intact diarrheal response in knockout mice lacking GM1 even after additional reduction of glycosphingolipids. Hence our results show that CT can induce toxicity in the absence of GM1 and support a role for host glycoproteins in CT intoxication. These findings open up new avenues for therapies to block CT action and for design of detoxified enterotoxin-based adjuvants.https://doi.org/10.1371/journal.ppat.1006862 |
| spellingShingle | Jakob Cervin Amberlyn M Wands Anna Casselbrant Han Wu Soumya Krishnamurthy Aleksander Cvjetkovic Johanna Estelius Benjamin Dedic Anirudh Sethi Kerri-Lee Wallom Rebecca Riise Malin Bäckström Ville Wallenius Frances M Platt Michael Lebens Susann Teneberg Lars Fändriks Jennifer J Kohler Ulf Yrlid GM1 ganglioside-independent intoxication by Cholera toxin. PLoS Pathogens |
| title | GM1 ganglioside-independent intoxication by Cholera toxin. |
| title_full | GM1 ganglioside-independent intoxication by Cholera toxin. |
| title_fullStr | GM1 ganglioside-independent intoxication by Cholera toxin. |
| title_full_unstemmed | GM1 ganglioside-independent intoxication by Cholera toxin. |
| title_short | GM1 ganglioside-independent intoxication by Cholera toxin. |
| title_sort | gm1 ganglioside independent intoxication by cholera toxin |
| url | https://doi.org/10.1371/journal.ppat.1006862 |
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