<i>Bordetella</i> Adenylate Cyclase Toxin Elicits Airway Mucin Secretion through Activation of the cAMP Response Element Binding Protein
The mucus layer protects airway epithelia from damage by noxious agents. Intriguingly, <i>Bordetella pertussis</i> bacteria provoke massive mucus production by nasopharyngeal epithelia during the initial coryza-like catarrhal stage of human pertussis and the pathogen transmits in mucus-c...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/16/9064 |
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| author | Anna Malandra Waheed Ur Rahman Nela Klimova Gaia Streparola Jana Holubova Adriana Osickova Simone Bariselli Peter Sebo Radim Osicka |
| author_facet | Anna Malandra Waheed Ur Rahman Nela Klimova Gaia Streparola Jana Holubova Adriana Osickova Simone Bariselli Peter Sebo Radim Osicka |
| author_sort | Anna Malandra |
| collection | DOAJ |
| description | The mucus layer protects airway epithelia from damage by noxious agents. Intriguingly, <i>Bordetella pertussis</i> bacteria provoke massive mucus production by nasopharyngeal epithelia during the initial coryza-like catarrhal stage of human pertussis and the pathogen transmits in mucus-containing aerosol droplets expelled by sneezing and post-nasal drip-triggered cough. We investigated the role of the cAMP-elevating adenylate cyclase (CyaA) and pertussis (PT) toxins in the upregulation of mucin production in <i>B. pertussis-</i>infected airway epithelia. Using human pseudostratified airway epithelial cell layers cultured at air–liquid interface (ALI), we show that purified CyaA and PT toxins (100 ng/mL) can trigger production of the major airway mucins Muc5AC and Muc5B. Upregulation of mucin secretion involved activation of the cAMP response element binding protein (CREB) and was blocked by the 666-15-Calbiochem inhibitor of CREB-mediated gene transcription. Intriguingly, a <i>B. pertussis</i> mutant strain secreting only active PT and producing the enzymatically inactive CyaA-AC<sup>–</sup> toxoid failed to trigger any important mucus production in infected epithelial cell layers in vitro or in vivo in the tracheal epithelia of intranasally infected mice. In contrast, the PT<sup>–</sup> toxoid-producing <i>B. pertussis</i> mutant secreting the active CyaA toxin elicited a comparable mucin production as infection of epithelial cell layers or tracheal epithelia of infected mice by the wild-type <i>B. pertussis</i> secreting both PT and CyaA toxins. Hence, the cAMP-elevating activity of <i>B. pertussis</i>-secreted CyaA was alone sufficient for activation of mucin production through a CREB-dependent mechanism in <i>B. pertussis</i>-infected airway epithelia in vivo. |
| first_indexed | 2024-03-10T08:44:18Z |
| format | Article |
| id | doaj.art-c8c7de1cdf384ae88be2fb1d02340f98 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T08:44:18Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c8c7de1cdf384ae88be2fb1d02340f982023-11-22T08:04:55ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-012216906410.3390/ijms22169064<i>Bordetella</i> Adenylate Cyclase Toxin Elicits Airway Mucin Secretion through Activation of the cAMP Response Element Binding ProteinAnna Malandra0Waheed Ur Rahman1Nela Klimova2Gaia Streparola3Jana Holubova4Adriana Osickova5Simone Bariselli6Peter Sebo7Radim Osicka8Institute of Microbiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech RepublicInstitute of Microbiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech RepublicInstitute of Microbiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech RepublicInstitute of Microbiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech RepublicInstitute of Microbiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech RepublicInstitute of Microbiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech RepublicCzech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prumyslova 595, 252 50 Vestec, Czech RepublicInstitute of Microbiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech RepublicInstitute of Microbiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech RepublicThe mucus layer protects airway epithelia from damage by noxious agents. Intriguingly, <i>Bordetella pertussis</i> bacteria provoke massive mucus production by nasopharyngeal epithelia during the initial coryza-like catarrhal stage of human pertussis and the pathogen transmits in mucus-containing aerosol droplets expelled by sneezing and post-nasal drip-triggered cough. We investigated the role of the cAMP-elevating adenylate cyclase (CyaA) and pertussis (PT) toxins in the upregulation of mucin production in <i>B. pertussis-</i>infected airway epithelia. Using human pseudostratified airway epithelial cell layers cultured at air–liquid interface (ALI), we show that purified CyaA and PT toxins (100 ng/mL) can trigger production of the major airway mucins Muc5AC and Muc5B. Upregulation of mucin secretion involved activation of the cAMP response element binding protein (CREB) and was blocked by the 666-15-Calbiochem inhibitor of CREB-mediated gene transcription. Intriguingly, a <i>B. pertussis</i> mutant strain secreting only active PT and producing the enzymatically inactive CyaA-AC<sup>–</sup> toxoid failed to trigger any important mucus production in infected epithelial cell layers in vitro or in vivo in the tracheal epithelia of intranasally infected mice. In contrast, the PT<sup>–</sup> toxoid-producing <i>B. pertussis</i> mutant secreting the active CyaA toxin elicited a comparable mucin production as infection of epithelial cell layers or tracheal epithelia of infected mice by the wild-type <i>B. pertussis</i> secreting both PT and CyaA toxins. Hence, the cAMP-elevating activity of <i>B. pertussis</i>-secreted CyaA was alone sufficient for activation of mucin production through a CREB-dependent mechanism in <i>B. pertussis</i>-infected airway epithelia in vivo.https://www.mdpi.com/1422-0067/22/16/9064adenylate cyclase toxin<i>Bordetella</i>cAMPCREBepitheliummucin |
| spellingShingle | Anna Malandra Waheed Ur Rahman Nela Klimova Gaia Streparola Jana Holubova Adriana Osickova Simone Bariselli Peter Sebo Radim Osicka <i>Bordetella</i> Adenylate Cyclase Toxin Elicits Airway Mucin Secretion through Activation of the cAMP Response Element Binding Protein International Journal of Molecular Sciences adenylate cyclase toxin <i>Bordetella</i> cAMP CREB epithelium mucin |
| title | <i>Bordetella</i> Adenylate Cyclase Toxin Elicits Airway Mucin Secretion through Activation of the cAMP Response Element Binding Protein |
| title_full | <i>Bordetella</i> Adenylate Cyclase Toxin Elicits Airway Mucin Secretion through Activation of the cAMP Response Element Binding Protein |
| title_fullStr | <i>Bordetella</i> Adenylate Cyclase Toxin Elicits Airway Mucin Secretion through Activation of the cAMP Response Element Binding Protein |
| title_full_unstemmed | <i>Bordetella</i> Adenylate Cyclase Toxin Elicits Airway Mucin Secretion through Activation of the cAMP Response Element Binding Protein |
| title_short | <i>Bordetella</i> Adenylate Cyclase Toxin Elicits Airway Mucin Secretion through Activation of the cAMP Response Element Binding Protein |
| title_sort | i bordetella i adenylate cyclase toxin elicits airway mucin secretion through activation of the camp response element binding protein |
| topic | adenylate cyclase toxin <i>Bordetella</i> cAMP CREB epithelium mucin |
| url | https://www.mdpi.com/1422-0067/22/16/9064 |
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