{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:17:25Z","timestamp":1760235445021,"version":"build-2065373602"},"reference-count":76,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T00:00:00Z","timestamp":1629676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001824","name":"Grantov\u00e1 Agentura \u010cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["19-12695S","19-27630X"],"award-info":[{"award-number":["19-12695S","19-27630X"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001823","name":"Ministerstvo \u0160kolstv\u00ed, Ml\u00e1de\u017ee a T\u011blov\u00fdchovy","doi-asserted-by":"publisher","award":["LM2018133","LM2018126"],"award-info":[{"award-number":["LM2018133","LM2018126"]}],"id":[{"id":"10.13039\/501100001823","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministerstvo \u0160kolstv\u00ed, Ml\u00e1de\u017ee a T\u011blov\u00fdchovy, ESIF","award":["OP RDE CZ.02.1.01\/0.0\/0.0\/18_046\/0015861 CCP Infrastructure Upgrade II"],"award-info":[{"award-number":["OP RDE CZ.02.1.01\/0.0\/0.0\/18_046\/0015861 CCP Infrastructure Upgrade II"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The mucus layer protects airway epithelia from damage by noxious agents. Intriguingly, Bordetella pertussis 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 B. pertussis-infected airway epithelia. Using human pseudostratified airway epithelial cell layers cultured at air\u2013liquid 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 B. pertussis mutant strain secreting only active PT and producing the enzymatically inactive CyaA-AC\u2013 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\u2013 toxoid-producing B. pertussis 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 B. pertussis secreting both PT and CyaA toxins. Hence, the cAMP-elevating activity of B. pertussis-secreted CyaA was alone sufficient for activation of mucin production through a CREB-dependent mechanism in B. pertussis-infected airway epithelia in vivo.<\/jats:p>","DOI":"10.3390\/ijms22169064","type":"journal-article","created":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T10:24:17Z","timestamp":1629714257000},"page":"9064","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Bordetella Adenylate Cyclase Toxin Elicits Airway Mucin Secretion through Activation of the cAMP Response Element Binding Protein"],"prefix":"10.3390","volume":"22","author":[{"given":"Anna","family":"Malandra","sequence":"first","affiliation":[{"name":"Institute of Microbiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8902-0096","authenticated-orcid":false,"given":"Waheed Ur","family":"Rahman","sequence":"additional","affiliation":[{"name":"Institute of Microbiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9425-6386","authenticated-orcid":false,"given":"Nela","family":"Klimova","sequence":"additional","affiliation":[{"name":"Institute of Microbiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2473-0978","authenticated-orcid":false,"given":"Gaia","family":"Streparola","sequence":"additional","affiliation":[{"name":"Institute of Microbiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic"},{"name":"Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prumyslova 595, 252 50 Vestec, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0829-0976","authenticated-orcid":false,"given":"Jana","family":"Holubova","sequence":"additional","affiliation":[{"name":"Institute of Microbiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriana","family":"Osickova","sequence":"additional","affiliation":[{"name":"Institute of Microbiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simone","family":"Bariselli","sequence":"additional","affiliation":[{"name":"Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prumyslova 595, 252 50 Vestec, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9755-7715","authenticated-orcid":false,"given":"Peter","family":"Sebo","sequence":"additional","affiliation":[{"name":"Institute of Microbiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2626-5456","authenticated-orcid":false,"given":"Radim","family":"Osicka","sequence":"additional","affiliation":[{"name":"Institute of Microbiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1128\/CMR.18.2.326-382.2005","article-title":"Molecular pathogenesis, epidemiology, and clinical manifestations of respiratory infections due to Bordetella pertussis and other Bordetella subspecies","volume":"18","author":"Mattoo","year":"2005","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Althouse, B.M., and Scarpino, S.V. (2015). Asymptomatic transmission and the resurgence of Bordetella pertussis. BMC Med., 13.","DOI":"10.1186\/s12916-015-0382-8"},{"key":"ref_3","first-page":"20152309","article-title":"The pertussis enigma: Reconciling epidemiology, immunology and evolution","volume":"283","author":"Magpantay","year":"2016","journal-title":"Proc. Biol. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e65663","DOI":"10.7554\/eLife.65663","article-title":"Asymptomatic Bordetella pertussis infections in a longitudinal cohort of young African infants and their mothers","volume":"10","author":"Gill","year":"2021","journal-title":"eLife"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1016\/S1473-3099(17)30390-0","article-title":"An update of the global burden of pertussis in children younger than 5 years: A modelling study","volume":"17","author":"Yeung","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/5584_2019_403","article-title":"Role of Major Toxin Virulence Factors in Pertussis Infection and Disease Pathogenesis","volume":"1183","author":"Scanlon","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1111\/j.1574-6976.2010.00231.x","article-title":"RTX proteins: A highly diverse family secreted by a common mechanism","volume":"34","author":"Linhartova","year":"2010","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3445","DOI":"10.1128\/iai.58.10.3445-3447.1990","article-title":"Adenylate cyclase toxin is critical for colonization and pertussis toxin is critical for lethal infection by Bordetella pertussis in infant mice","volume":"58","author":"Goodwin","year":"1990","journal-title":"Infect. Immun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/0882-4010(89)90040-5","article-title":"Bordetella adenylate cyclase is a virulence associated factor and an immunoprotective antigen","volume":"7","author":"Guiso","year":"1989","journal-title":"Microb. Pathog."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e00937-16","DOI":"10.1128\/IAI.00937-16","article-title":"Cyclic AMP-Elevating Capacity of Adenylate Cyclase Toxin-Hemolysin Is Sufficient for Lung Infection but Not for Full Virulence of Bordetella pertussis","volume":"85","author":"Skopova","year":"2017","journal-title":"Infect. Immun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"ftv075","DOI":"10.1093\/femspd\/ftv075","article-title":"Bordetella adenylate cyclase toxin: A unique combination of a pore-forming moiety with a cell-invading adenylate cyclase enzyme","volume":"73","author":"Masin","year":"2015","journal-title":"Pathog. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Novak, J., Cerny, O., Osickova, A., Linhartova, I., Masin, J., Bumba, L., Sebo, P., and Osicka, R. (2017). Structure-Function Relationships Underlying the Capacity of Bordetella Adenylate Cyclase Toxin to Disarm Host Phagocytes. Toxins, 9.","DOI":"10.3390\/toxins9100300"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1084\/jem.193.9.1035","article-title":"The adenylate cyclase toxin of Bordetella pertussis binds to target cells via the alpha(M)beta(2) integrin (CD11b\/CD18)","volume":"193","author":"Guermonprez","year":"2001","journal-title":"J. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5355","DOI":"10.1073\/pnas.0711400105","article-title":"RTX cytotoxins recognize beta2 integrin receptors through N-linked oligosaccharides","volume":"105","author":"Morova","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e10766","DOI":"10.7554\/eLife.10766","article-title":"Bordetella adenylate cyclase toxin is a unique ligand of the integrin complement receptor 3","volume":"4","author":"Osicka","year":"2015","journal-title":"eLife"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.febslet.2014.12.023","article-title":"Interaction of Bordetella adenylate cyclase toxin with complement receptor 3 involves multivalent glycan binding","volume":"589","author":"Hasan","year":"2015","journal-title":"FEBS Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"ftw008","DOI":"10.1093\/femspd\/ftw008","article-title":"Transmembrane segments of complement receptor 3 do not participate in cytotoxic activities but determine receptor structure required for action of Bordetella adenylate cyclase toxin","volume":"74","author":"Wald","year":"2016","journal-title":"Pathog. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9349","DOI":"10.1074\/jbc.RA120.013630","article-title":"Retargeting from the CR3 to the LFA-1 receptor uncovers the adenylyl cyclase enzyme-translocating segment of Bordetella adenylate cyclase toxin","volume":"295","author":"Masin","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1111\/j.1365-2958.2010.07077.x","article-title":"Adenylate cyclase toxin translocates across target cell membrane without forming a pore","volume":"75","author":"Osickova","year":"2010","journal-title":"Mol. Microbiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3841","DOI":"10.1073\/pnas.77.7.3841","article-title":"Calmodulin activates prokaryotic adenylate cyclase","volume":"77","author":"Wolff","year":"1980","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1126\/science.6287574","article-title":"Phagocyte impotence caused by an invasive bacterial adenylate cyclase","volume":"217","author":"Confer","year":"1982","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5256","DOI":"10.1128\/IAI.02487-14","article-title":"Cyclic AMP-mediated suppression of neutrophil extracellular trap formation and apoptosis by the Bordetella pertussis adenylate cyclase toxin","volume":"82","author":"Eby","year":"2014","journal-title":"Infect. Immun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.4049\/jimmunol.1601309","article-title":"cAMP Signaling of Adenylate Cyclase Toxin Blocks the Oxidative Burst of Neutrophils through Epac-Mediated Inhibition of Phospholipase C Activity","volume":"198","author":"Cerny","year":"2017","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5587","DOI":"10.4049\/jimmunol.181.8.5587","article-title":"Adenylate cyclase toxin subverts phagocyte function by RhoA inhibition and unproductive ruffling","volume":"181","author":"Kamanova","year":"2008","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Hasan, S., Rahman, W.U., Sebo, P., and Osicka, R. (2019). Distinct Spatiotemporal Distribution of Bacterial Toxin-Produced Cellular cAMP Differentially Inhibits Opsonophagocytic Signaling. Toxins, 11.","DOI":"10.3390\/toxins11060362"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1128\/IAI.66.4.1718-1725.1998","article-title":"Role of adenylate cyclase-hemolysin in alveolar macrophage apoptosis during Bordetella pertussis infection in vivo","volume":"66","author":"Gueirard","year":"1998","journal-title":"Infect. Immun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1111\/cmi.12519","article-title":"cAMP signalling of Bordetella adenylate cyclase toxin through the SHP-1 phosphatase activates the BimEL-Bax pro-apoptotic cascade in phagocytes","volume":"18","author":"Ahmad","year":"2016","journal-title":"Cell. Microbiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e01743-19","DOI":"10.1128\/mBio.01743-19","article-title":"Bordetella Adenylate Cyclase Toxin Inhibits Monocyte-to-Macrophage Transition and Dedifferentiates Human Alveolar Macrophages into Monocyte-like Cells","volume":"10","author":"Ahmad","year":"2019","journal-title":"mBio"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.3389\/fimmu.2020.02181","article-title":"Adenylate Cyclase Toxin Tinkering With Monocyte-Macrophage Differentiation","volume":"11","author":"Ahmad","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"14792","DOI":"10.1016\/S0021-9258(18)63769-X","article-title":"Adenylate cyclase toxins from Bacillus anthracis and Bordetella pertussis. Different processes for interaction with and entry into target cells","volume":"264","author":"Gordon","year":"1989","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1165\/ajrcmb.19.3.f144","article-title":"Airway epithelial integrins: Why so many?","volume":"19","author":"Sheppard","year":"1998","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1152\/physrev.00033.2002","article-title":"Functions of pulmonary epithelial integrins: From development to disease","volume":"83","author":"Sheppard","year":"2003","journal-title":"Physiol. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1128\/IAI.00110-13","article-title":"Quantification of the adenylate cyclase toxin of Bordetella pertussis in vitro and during respiratory infection","volume":"81","author":"Eby","year":"2013","journal-title":"Infect. Immun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4668","DOI":"10.1111\/j.1742-4658.2011.08237.x","article-title":"The ins and outs of pertussis toxin","volume":"278","author":"Locht","year":"2011","journal-title":"FEBS J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"8677","DOI":"10.1016\/S0021-9258(18)68358-9","article-title":"Use of glycosyltransferases to restore pertussis toxin receptor activity to asialoagalactofetuin","volume":"263","author":"Armstrong","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_36","first-page":"40","article-title":"Endocytosis and retrograde transport of pertussis toxin to the Golgi complex as a prerequisite for cellular intoxication","volume":"73","author":"Linnemann","year":"1997","journal-title":"Eur. J. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1111\/j.1462-5822.2006.00813.x","article-title":"Pertussis toxin transiently affects barrier integrity, organelle organization and transmigration of monocytes in a human brain microvascular endothelial cell barrier model","volume":"9","author":"Kugler","year":"2007","journal-title":"Cell. Microbiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1111\/j.1462-5822.2007.01115.x","article-title":"Retrograde transport of pertussis toxin in the mammalian cell","volume":"10","author":"Plaut","year":"2008","journal-title":"Cell. Microbiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3388","DOI":"10.1128\/IAI.00732-16","article-title":"Thermal Unfolding of the Pertussis Toxin S1 Subunit Facilitates Toxin Translocation to the Cytosol by the Mechanism of Endoplasmic Reticulum-Associated Degradation","volume":"84","author":"Banerjee","year":"2016","journal-title":"Infect. Immun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11051","DOI":"10.1021\/bi971383p","article-title":"Accumulating evidence suggests that several AB-toxins subvert the endoplasmic reticulum-associated protein degradation pathway to enter target cells","volume":"36","author":"Hazes","year":"1997","journal-title":"Biochemistry"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Ernst, K., Eberhardt, N., Mittler, A.K., Sonnabend, M., Anastasia, A., Freisinger, S., Schiene-Fischer, C., Malesevic, M., and Barth, H. (2018). Pharmacological Cyclophilin Inhibitors Prevent Intoxication of Mammalian Cells with Bordetella pertussis Toxin. Toxins, 10.","DOI":"10.3390\/toxins10050181"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5429","DOI":"10.1038\/s41598-021-84817-2","article-title":"Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo","volume":"11","author":"Ernst","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3129","DOI":"10.1073\/pnas.79.10.3129","article-title":"Direct modification of the membrane adenylate cyclase system by islet-activating protein due to ADP-ribosylation of a membrane protein","volume":"79","author":"Katada","year":"1982","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1097\/00006454-198409000-00019","article-title":"The concept of pertussis as a toxin-mediated disease","volume":"3","author":"Pittman","year":"1984","journal-title":"Pediatric Infect. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"884","DOI":"10.3390\/toxins3070884","article-title":"G(i\/o) protein-dependent and -independent actions of Pertussis Toxin (PTX)","volume":"3","author":"Mangmool","year":"2011","journal-title":"Toxins"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"ftw087","DOI":"10.1093\/femspd\/ftw087","article-title":"Pertussis leukocytosis: Mechanisms, clinical relevance and treatment","volume":"74","author":"Carbonetti","year":"2016","journal-title":"Pathog. Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1086\/589753","article-title":"Pathology and pathogenesis of fatal Bordetella pertussis infection in infants","volume":"47","author":"Paddock","year":"2008","journal-title":"Clin. Infect. Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1093\/cid\/civ472","article-title":"Risk Factors Associated With Infant Deaths From Pertussis: A Case-Control Study","volume":"61","author":"Winter","year":"2015","journal-title":"Clin. Infect. Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/ni.3045","article-title":"Respiratory epithelial cells orchestrate pulmonary innate immunity","volume":"16","author":"Whitsett","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"254","DOI":"10.4161\/gmic.1.4.12778","article-title":"Mucin-bacterial interactions in the human oral cavity and digestive tract","volume":"1","author":"Derrien","year":"2010","journal-title":"Gut Microbes"},{"key":"ref_51","first-page":"89","article-title":"The role of airway mucus in pulmonary toxicology","volume":"102","author":"Samet","year":"1994","journal-title":"Env. Health Perspect."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1159\/000453594","article-title":"Transmembrane Mucins: Signaling Receptors at the Intersection of Inflammation and Cancer","volume":"9","author":"Strijbis","year":"2017","journal-title":"J. Innate Immun."},{"key":"ref_53","first-page":"189","article-title":"Regulation of mucin expression: Mechanistic aspects and implications for cancer and inflammatory diseases","volume":"1765","author":"Andrianifahanana","year":"2006","journal-title":"Biochim. Et Biophys. Acta"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1056\/NEJMra0910061","article-title":"Airway mucus function and dysfunction","volume":"363","author":"Fahy","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e24997","DOI":"10.4161\/tisb.24997","article-title":"Barrier function of airway tract epithelium","volume":"1","author":"Ganesan","year":"2013","journal-title":"Tissue Barriers"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"13847","DOI":"10.1073\/pnas.230262797","article-title":"The transcriptional responses of respiratory epithelial cells to Bordetella pertussis reveal host defensive and pathogen counter-defensive strategies","volume":"97","author":"Belcher","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e00445-17","DOI":"10.1128\/IAI.00445-17","article-title":"Bordetella pertussis Adenylate Cyclase Toxin Disrupts Functional Integrity of Bronchial Epithelial Layers","volume":"86","author":"Hasan","year":"2018","journal-title":"Infect. Immun."},{"key":"ref_58","first-page":"256","article-title":"Distinct mechanisms of forskolin-stimulated cyclic AMP accumulation and forskolin-potentiated hormone responses in C6-2B cells","volume":"25","author":"Barovsky","year":"1984","journal-title":"Mol. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"6933","DOI":"10.1128\/MCB.02385-06","article-title":"Regulation of mucin gene expression by CREB via a nonclassical retinoic acid signaling pathway","volume":"27","author":"Kim","year":"2007","journal-title":"Mol. Cell Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1210\/endo.140.3.6567","article-title":"Increased osteoblastic c-fos expression by parathyroid hormone requires protein kinase A phosphorylation of the cyclic adenosine 3\u2032,5\u2032-monophosphate response element-binding protein at serine 133","volume":"140","author":"Tyson","year":"1999","journal-title":"Endocrinology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4901","DOI":"10.4049\/jimmunol.1402941","article-title":"Bordetella pertussis Adenylate Cyclase Toxin Blocks Induction of Bactericidal Nitric Oxide in Macrophages through cAMP-Dependent Activation of the SHP-1 Phosphatase","volume":"194","author":"Cerny","year":"2015","journal-title":"J. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1189\/jlb.72.5.962","article-title":"Pertussis toxin and the adenylate cyclase toxin from Bordetella pertussis activate human monocyte-derived dendritic cells and dominantly inhibit cytokine production through a cAMP-dependent pathway","volume":"72","author":"Bagley","year":"2002","journal-title":"J. Leukoc. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"5075","DOI":"10.1021\/acs.jmedchem.5b00468","article-title":"Identification of a Potent Inhibitor of CREB-Mediated Gene Transcription with Efficacious in Vivo Anticancer Activity","volume":"58","author":"Xie","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"34513","DOI":"10.1038\/srep34513","article-title":"Systemic Inhibition of CREB is Well-tolerated in vivo","volume":"6","author":"Li","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"22599","DOI":"10.1016\/S0021-9258(18)41715-2","article-title":"Distinct steps in the penetration of adenylate cyclase toxin of Bordetella pertussis into sheep erythrocytes. Translocation of the toxin across the membrane","volume":"267","author":"Rogel","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"5405","DOI":"10.1038\/sj.emboj.7601408","article-title":"Cell entry and cAMP imaging of anthrax edema toxin","volume":"25","author":"Tonello","year":"2006","journal-title":"EMBO J."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Teter, K. (2019). Intracellular Trafficking and Translocation of Pertussis Toxin. Toxins, 11.","DOI":"10.3390\/toxins11080437"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"10662","DOI":"10.1074\/jbc.M109.089219","article-title":"Selective translocation of the Bordetella pertussis adenylate cyclase toxin across the basolateral membranes of polarized epithelial cells","volume":"285","author":"Eby","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3109\/23744235.2015.1100323","article-title":"Highly differentiated human airway epithelial cells: A model to study host cell-parasite interactions in pertussis","volume":"48","author":"Guevara","year":"2016","journal-title":"Infect. Dis."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Zhu, Y., Abdullah, L.H., Doyle, S.P., Nguyen, K., Ribeiro, C.M., Vasquez, P.A., Forest, M.G., Lethem, M.I., Dickey, B.F., and Davis, C.W. (2015). Baseline Goblet Cell Mucin Secretion in the Airways Exceeds Stimulated Secretion over Extended Time Periods, and Is Sensitive to Shear Stress and Intracellular Mucin Stores. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0127267"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Stanek, O., Masin, J., Osicka, R., Jurnecka, D., Osickova, A., and Sebo, P. (2019). Rapid Purification of Endotoxin-Free RTX Toxins. Toxins, 11.","DOI":"10.3390\/toxins11060336"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1128\/IAI.68.1.247-256.2000","article-title":"Delivery of CD8(+) T-cell epitopes into major histocompatibility complex class I antigen presentation pathway by Bordetella pertussis adenylate cyclase: Delineation of cell invasive structures and permissive insertion sites","volume":"68","author":"Osicka","year":"2000","journal-title":"Infect. Immun."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1126\/science.2683073","article-title":"Mutants of pertussis toxin suitable for vaccine development","volume":"246","author":"Pizza","year":"1989","journal-title":"Science"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.molcel.2016.03.018","article-title":"Calcium-Driven Folding of RTX Domain beta-Rolls Ratchets Translocation of RTX Proteins through Type I Secretion Ducts","volume":"62","author":"Bumba","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1128\/IAI.67.5.2090-2095.1999","article-title":"Epitope mapping of monoclonal antibodies against Bordetella pertussis adenylate cyclase toxin","volume":"67","author":"Lee","year":"1999","journal-title":"Infect. Immun."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: Open source software for digital pathology image analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/9064\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:49:34Z","timestamp":1760165374000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/9064"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,23]]},"references-count":76,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22169064"],"URL":"https:\/\/doi.org\/10.3390\/ijms22169064","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2021,8,23]]}}}