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Selective enhancement of the cell-permeabilizing activity of adenylate cyclase toxin does not increase virulence of bordetella pertussis
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SYSNO ASEP 0549727 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Selective enhancement of the cell-permeabilizing activity of adenylate cyclase toxin does not increase virulence of bordetella pertussis Author(s) Holubová, Jana (MBU-M) RID, ORCID
Juhasz, Attila (MBU-M)
Mašín, Jiří (MBU-M) RID, ORCID
Staněk, Ondřej (MBU-M) RID, ORCID
Jurnečka, David (MBU-M) ORCID
Osičková, Adriana (MBU-M) RID, ORCID
Šebo, Peter (MBU-M) RID, ORCID
Osička, Radim (MBU-M) RID, ORCIDArticle number 11655 Source Title International Journal of Molecular Sciences. - : MDPI
Roč. 22, č. 21 (2021)Number of pages 18 s. Language eng - English Country CH - Switzerland Keywords Adenylate cyclase toxin ; Bordetella pertussis ; CAMP intoxication ; Lung colonization ; Lung inflammation ; Pore-forming activity ; RTX toxin ; Virulence Subject RIV EE - Microbiology, Virology OECD category Microbiology R&D Projects LM2018133 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) GA19-12695S GA ČR - Czech Science Foundation (CSF) Research Infrastructure CIISB II - 90127 - Masarykova univerzita
CCP II - 90126 - Ústav molekulární genetiky AV ČR, v. v. i.Method of publishing Open access Institutional support MBU-M - RVO:61388971 UT WOS 000726625300001 EID SCOPUS 85117920332 DOI 10.3390/ijms222111655 Annotation The whooping cough agent, Bordetella pertussis, 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 B. pertussis in the mouse model of pneumonic infection. CyaA primarily targets myeloid phagocytes through binding of their complement receptor 3 (CR3, integrin αMβ2, 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 B. pertussis 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 B. pertussis infection of mice any further. In turn, a reduction of the cell-permeabilizing activity of CyaA did not reduce B. pertussis 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 B. pertussis infections in vivo. Workplace Institute of Microbiology Contact Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Year of Publishing 2022 Electronic address https://www.mdpi.com/1422-0067/22/21/11655
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