Cyclic AMP-Elevating Capacity of Adenylate Cyclase Toxin-Hemolysin Is Sufficient for Lung Infection but Not for Full Virulence of Bordetella pertussis
The adenylate cyclase toxin-hemolysin (CyaA, ACT, or AC-Hly) of targets phagocytic cells expressing the complement receptor 3 (CR3, Mac-1, α β integrin, or CD11b/CD18). CyaA delivers into cells an N-terminal adenylyl cyclase (AC) enzyme domain that is activated by cytosolic calmodulin and catalyzes...
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Veröffentlicht in: | Infection and immunity 2017-06, Vol.85 (6) |
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Zusammenfassung: | The adenylate cyclase toxin-hemolysin (CyaA, ACT, or AC-Hly) of
targets phagocytic cells expressing the complement receptor 3 (CR3, Mac-1, α
β
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
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
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
infections at higher inoculation doses (>10
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. |
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ISSN: | 0019-9567 1098-5522 |
DOI: | 10.1128/IAI.00937-16 |