Selective Enhancement of the Cell-Permeabilizing Activity of Adenylate Cyclase Toxin Does Not Increase Virulence of <i>Bordetella pertussis</i>

The whooping cough agent, <i>Bordetella pertussis</i>, secretes an adenylate cyclase toxin–hemolysin (CyaA, ACT, or AC-Hly) that catalyzes the conversion of intracellular ATP to cAMP and through its signaling annihilates the bactericidal activities of host sentinel phagocytes. In paralle...

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Autores principales:	Jana Holubova, Attila Juhasz, Jiri Masin, Ondrej Stanek, David Jurnecka, Adriana Osickova, Peter Sebo, Radim Osicka
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	adenylate cyclase toxin <i>Bordetella pertussis</i> cAMP intoxication lung colonization lung inflammation pore-forming activity Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/0803fecdd7814728ba5514a977f1ed41
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spelling	oai:doaj.org-article:0803fecdd7814728ba5514a977f1ed412021-11-11T17:08:10ZSelective Enhancement of the Cell-Permeabilizing Activity of Adenylate Cyclase Toxin Does Not Increase Virulence of <i>Bordetella pertussis</i>10.3390/ijms2221116551422-00671661-6596https://doaj.org/article/0803fecdd7814728ba5514a977f1ed412021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11655https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067The whooping cough agent, <i>Bordetella pertussis</i>, secretes an adenylate cyclase toxin–hemolysin (CyaA, ACT, or AC-Hly) that catalyzes the conversion of intracellular ATP to cAMP and through its signaling annihilates the bactericidal activities of host sentinel phagocytes. In parallel, CyaA permeabilizes host cells by the formation of cation-selective membrane pores that account for the hemolytic activity of CyaA. The pore-forming activity contributes to the overall cytotoxic effect of CyaA in vitro, and it has previously been proposed to synergize with the cAMP-elevating activity in conferring full virulence on <i>B. pertussis</i> in the mouse model of pneumonic infection. CyaA primarily targets myeloid phagocytes through binding of their complement receptor 3 (CR3, integrin α<sub>M</sub>β<sub>2</sub>, or CD11b/CD18). However, with a reduced efficacy, the toxin can promiscuously penetrate and permeabilize the cell membrane of a variety of non-myeloid cells that lack CR3 on the cell surface, including airway epithelial cells or erythrocytes, and detectably intoxicates them by cAMP. Here, we used CyaA variants with strongly and selectively enhanced or reduced pore-forming activity that, at the same time, exhibited a full capacity to elevate cAMP concentrations in both CR3-expressing and CR3-non-expressing target cells. Using <i>B. pertussis</i> mutants secreting such CyaA variants, we show that a selective enhancement of the cell-permeabilizing activity of CyaA does not increase the overall virulence and lethality of pneumonic <i>B. pertussis</i> infection of mice any further. In turn, a reduction of the cell-permeabilizing activity of CyaA did not reduce <i>B. pertussis</i> virulence any importantly. These results suggest that the phagocyte-paralyzing cAMP-elevating capacity of CyaA prevails over the cell-permeabilizing activity of CyaA that appears to play an auxiliary role in the biological activity of the CyaA toxin in the course of <i>B. pertussis</i> infections in vivo.Jana HolubovaAttila JuhaszJiri MasinOndrej StanekDavid JurneckaAdriana OsickovaPeter SeboRadim OsickaMDPI AGarticleadenylate cyclase toxin<i>Bordetella pertussis</i>cAMP intoxicationlung colonizationlung inflammationpore-forming activityBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11655, p 11655 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	adenylate cyclase toxin <i>Bordetella pertussis</i> cAMP intoxication lung colonization lung inflammation pore-forming activity Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	adenylate cyclase toxin <i>Bordetella pertussis</i> cAMP intoxication lung colonization lung inflammation pore-forming activity Biology (General) QH301-705.5 Chemistry QD1-999 Jana Holubova Attila Juhasz Jiri Masin Ondrej Stanek David Jurnecka Adriana Osickova Peter Sebo Radim Osicka Selective Enhancement of the Cell-Permeabilizing Activity of Adenylate Cyclase Toxin Does Not Increase Virulence of <i>Bordetella pertussis</i>
description	The whooping cough agent, <i>Bordetella pertussis</i>, secretes an adenylate cyclase toxin–hemolysin (CyaA, ACT, or AC-Hly) that catalyzes the conversion of intracellular ATP to cAMP and through its signaling annihilates the bactericidal activities of host sentinel phagocytes. In parallel, CyaA permeabilizes host cells by the formation of cation-selective membrane pores that account for the hemolytic activity of CyaA. The pore-forming activity contributes to the overall cytotoxic effect of CyaA in vitro, and it has previously been proposed to synergize with the cAMP-elevating activity in conferring full virulence on <i>B. pertussis</i> in the mouse model of pneumonic infection. CyaA primarily targets myeloid phagocytes through binding of their complement receptor 3 (CR3, integrin α<sub>M</sub>β<sub>2</sub>, or CD11b/CD18). However, with a reduced efficacy, the toxin can promiscuously penetrate and permeabilize the cell membrane of a variety of non-myeloid cells that lack CR3 on the cell surface, including airway epithelial cells or erythrocytes, and detectably intoxicates them by cAMP. Here, we used CyaA variants with strongly and selectively enhanced or reduced pore-forming activity that, at the same time, exhibited a full capacity to elevate cAMP concentrations in both CR3-expressing and CR3-non-expressing target cells. Using <i>B. pertussis</i> mutants secreting such CyaA variants, we show that a selective enhancement of the cell-permeabilizing activity of CyaA does not increase the overall virulence and lethality of pneumonic <i>B. pertussis</i> infection of mice any further. In turn, a reduction of the cell-permeabilizing activity of CyaA did not reduce <i>B. pertussis</i> virulence any importantly. These results suggest that the phagocyte-paralyzing cAMP-elevating capacity of CyaA prevails over the cell-permeabilizing activity of CyaA that appears to play an auxiliary role in the biological activity of the CyaA toxin in the course of <i>B. pertussis</i> infections in vivo.
format	article
author	Jana Holubova Attila Juhasz Jiri Masin Ondrej Stanek David Jurnecka Adriana Osickova Peter Sebo Radim Osicka
author_facet	Jana Holubova Attila Juhasz Jiri Masin Ondrej Stanek David Jurnecka Adriana Osickova Peter Sebo Radim Osicka
author_sort	Jana Holubova
title	Selective Enhancement of the Cell-Permeabilizing Activity of Adenylate Cyclase Toxin Does Not Increase Virulence of <i>Bordetella pertussis</i>
title_short	Selective Enhancement of the Cell-Permeabilizing Activity of Adenylate Cyclase Toxin Does Not Increase Virulence of <i>Bordetella pertussis</i>
title_full	Selective Enhancement of the Cell-Permeabilizing Activity of Adenylate Cyclase Toxin Does Not Increase Virulence of <i>Bordetella pertussis</i>
title_fullStr	Selective Enhancement of the Cell-Permeabilizing Activity of Adenylate Cyclase Toxin Does Not Increase Virulence of <i>Bordetella pertussis</i>
title_full_unstemmed	Selective Enhancement of the Cell-Permeabilizing Activity of Adenylate Cyclase Toxin Does Not Increase Virulence of <i>Bordetella pertussis</i>
title_sort	selective enhancement of the cell-permeabilizing activity of adenylate cyclase toxin does not increase virulence of <i>bordetella pertussis</i>
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/0803fecdd7814728ba5514a977f1ed41
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Selective Enhancement of the Cell-Permeabilizing Activity of Adenylate Cyclase Toxin Does Not Increase Virulence of <i>Bordetella pertussis</i>

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