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The Bordetella effector protein BteA induces host cell death by disruption of calcium homeostasis
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SYSNO ASEP 0601747 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title The Bordetella effector protein BteA induces host cell death by disruption of calcium homeostasis Author(s) Zmuda, Martin (MBU-M)
Sedláčková, Eliška (MBU-M)
Pravdová, Barbora (MBU-M)
Čížková, Mária (MBU-M) ORCID
Dalecka, M. (CZ)
Černý, Ondřej (MBU-M) ORCID
Allsop Romero, Tania (MBU-M)
Groušl, Tomáš (MBU-M) RID, ORCID
Malcová, Ivana (MBU-M) RID, ORCID
Kamanová, Jana (MBU-M) ORCID, RIDArticle number e0192524 Source Title mBio. - : American Society for Microbiology - ISSN 2150-7511
Roč. 2024, NOV 21 (2024)Number of pages 21 s. Language eng - English Country US - United States Keywords Bordetella ; type III secretion system (T3SS) ; effector protein BteA ; calcium homeostasis ; host cell death mechanism OECD category Microbiology R&D Projects GA21-05466S GA ČR - Czech Science Foundation (CSF) EH22_008/0004597 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF18_053/0017705 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support MBU-M - RVO:61388971 ; UMG-J - RVO:68378050 UT WOS 001361327400003 EID SCOPUS 85212312967 DOI https://doi.org/10.1128/mbio.01925-24 Annotation Bordetella pertussis is the causative agent of whooping cough in humans, a disease that has recently experienced a resurgence. In contrast, Bordetella bronchiseptica infects the respiratory tract of various mammalian species, causing a range of symptoms from asymptomatic chronic carriage to acute illness. Both pathogens utilize type III secretion system (T3SS) to deliver the effector protein BteA into host cells. Once injected, BteA triggers a cascade of events leading to caspase 1-independent necrosis through a mechanism that remains incompletely understood. We demonstrate that BteA-induced cell death is characterized by the fragmentation of the cellular endoplasmic reticulum and mitochondria, the formation of necrotic balloon-like protrusions, and plasma membrane permeabilization. Importantly, genome-wide CRISPR-Cas9 screen targeting 19,050 genes failed to identify any host factors required for BteA cytotoxicity, suggesting that BteA does not require a single nonessential host factor for its cytotoxicity. We further reveal that BteA triggers a rapid and sustained influx of calcium ions, which is associated with organelle fragmentation and plasma membrane permeabilization. The sustained elevation of cytosolic Ca2+ levels results in mitochondrial calcium overload, mitochondrial swelling, cristolysis, and loss of mitochondrial membrane potential. Inhibition of calcium channels with 2-APB delays both the Ca2+ influx and BteA-induced cell death. Our findings indicate that BteA exploits essential host processes and/or redundant pathways to disrupt calcium homeostasis and mitochondrial function, ultimately leading to host cell death.IMPORTANCEThe respiratory pathogens Bordetella pertussis and Bordetella bronchiseptica exhibit cytotoxicity toward a variety of mammalian cells, which depends on the type III secretion effector BteA. Moreover, the increased virulence of B. bronchiseptica is associated with enhanced expression of T3SS and BteA. However, the molecular mechanism underlying BteA cytotoxicity is elusive. In this study, we performed a CRISPR-Cas9 screen, revealing that BteA-induced cell death depends on essential or redundant host processes. Additionally, we demonstrate that BteA disrupts calcium homeostasis, which leads to mitochondrial dysfunction and cell death. These findings contribute to closing the gap in our understanding of the signaling cascades targeted by BteA. Workplace Institute of Microbiology Contact Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Year of Publishing 2025 Electronic address https://journals.asm.org/doi/10.1128/mbio.01925-24
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