Počet záznamů: 1  

Cyclic AMP-Elevating Capacity of Adenylate Cyclase Toxin-Hemolysin Is Sufficient for Lung Infection but Not for Full Virulence of Bordetella pertussis

  1. 1.
    0476224 - MBU-M 2018 RIV US eng J - Článek v odborném periodiku
    Škopová, Karolína - Tomalová, Barbora - Kanchev, Ivan - Rossmann, Pavel - Švédová, Martina - Adkins, Irena - Bíbová, Ilona - Tomala, Jakub - Mašín, Jiří - Guiso, N. - Osička, Radim - Sedláček, Radislav - Kovář, Marek - Šebo, Peter
    Cyclic AMP-Elevating Capacity of Adenylate Cyclase Toxin-Hemolysin Is Sufficient for Lung Infection but Not for Full Virulence of Bordetella pertussis.
    Infection and Immunity. Roč. 85, č. 6 (2017), s. 1-22, č. článku e00937-16. ISSN 0019-9567
    Grant CEP: GA MZd(CZ) NV16-28126A; GA ČR(CZ) GA13-14547S; GA ČR GA13-12885S; GA ČR GA15-09157S; GA ČR(CZ) GAP302/12/0460; GA MŠk(CZ) LM2015064; GA MŠk(CZ) LM2015040
    Institucionální podpora: RVO:61388971 ; RVO:68378050
    Klíčová slova: Bordetella pertussis * adenylate cyclase toxin-hemolysin * cAMP intoxication
    Kód oboru RIV: EE - Mikrobiologie, virologie; EE - Mikrobiologie, virologie (UMG-J)
    Obor OECD: Microbiology; Microbiology (UMG-J)
    Impakt faktor: 3.256, rok: 2017

    The adenylate cyclase toxin-hemolysin (CyaA, ACT, or AC-Hly) of Bordetella pertussis targets phagocytic cells expressing the complement receptor 3 (CR3, Mac-1, αMbeta2 integrin, or CD11b/CD18). CyaA delivers into cells an N-terminal adenylyl cyclase (AC) enzyme domain that is activated by cytosolic calmodulin and catalyzes unregulated conversion of cellular ATP into cyclic AMP (cAMP), a key second messenger subverting bactericidal activities of phagocytes. In parallel, the hemolysin (Hly) moiety of CyaA forms cation-selective hemolytic pores that permeabilize target cell membranes. We constructed the first B. pertussis mutant secreting a CyaA toxin having an intact capacity to deliver the AC enzyme into CD11b-expressing (CD11b+) host phagocytes but impaired in formation of cell-permeabilizing pores and defective in cAMP elevation in CD11b- cells. The nonhemolytic AC+ Hly- bacteria inhibited the antigen-presenting capacities of coincubated mouse dendritic cells in vitro and skewed their Toll-like receptor (TLR)-triggered maturation toward a tolerogenic phenotype. The AC+ Hly- mutant also infected mouse lungs as efficiently as the parental AC+ Hly+ strain. Hence, elevation of cAMP in CD11b- cells and/or the pore-forming capacity of CyaA were not required for infection of mouse airways. The latter activities were, however, involved in bacterial penetration across the epithelial layer, enhanced neutrophil influx into lung parenchyma during sublethal infections, and the exacerbated lung pathology and lethality of B. pertussis infections at higher inoculation doses (more than 107 CFU/mouse). The pore-forming activity of CyaA further synergized with the cAMP-elevating activity in downregulation of major histocompatibility complex class II (MHC-II) molecules on infiltrating myeloid cells, likely contributing to immune subversion of host defenses by the whooping cough agent.
    Trvalý link: http://hdl.handle.net/11104/0272781