Abstract
Adenylate cyclase toxin (CyaA) is released in the course of B. pertussis infection in the host’s respiratory tract in order to suppress its early innate and subsequent adaptive immune defense. CD11b-expressing dendritic cells (DC), macrophages and neutrophils are professional phagocytes and key players of the innate immune system that provide a first line of defense against invading pathogens. Recent findings revealed the capacity of B. pertussis CyaA to intoxicate DC with high concentrations of 3′,5′-cyclic adenosine monophosphate (cAMP), which ultimately skews the host immune response towards the expansion of Th17 cells and regulatory T cells. CyaA-induced cAMP signaling swiftly incapacitates opsonophagocytosis, oxidative burst and NO-mediated killing of bacteria by neutrophils and macrophages. The subversion of host immune responses by CyaA after delivery into DC, macrophages and neutrophils is the subject of this review.
Highlights
The whooping cough agent Bordetella pertussis is endowed with an arsenal of virulence factors.This includes several protein toxins and numerous adhesins and autotransporter surface proteins, involved in infection and colonization of the host [1].The adenylate cyclase toxin-hemolysin (ACT, adenylyl cyclase (AC)-Hly or CyaA) is a key virulence factor of B. pertussis, regulated by the Bordetella virulence gene system
In monocytes and macrophages, the CyaA-produced cyclic adenosine monophosphate (cAMP) signaling through the cAMP/protein kinase A (PKA) pathway blocks the production of reactive oxygen species (ROS) and the complement-mediated uptake of opsonized particles already at very low (
CyaA-produced cAMP signaling in macrophages was shown to activate through the proteinkinase kinase (PKA) pathway the Src homology domain 2 containing protein tyrosine phosphatase (SHP) 1, which plays a major role in regulation of receptor signaling in leukocytes
Summary
The whooping cough agent Bordetella pertussis is endowed with an arsenal of virulence factors. Colonization of the mucosal surface of the host respiratory tract by B. pertussis triggers an immune response, in which multiple bacterial molecules engage the pathogen recognition receptors expressed by both epithelial cells and resident antigen-presenting cells. CyaA insertion into the membrane of phagocytes induces an influx of calcium ions that leads to a calpain-mediated cleavage of talin [52,53,54] This mobilizes the CyaA–CR3 complex for relocation into lipid rafts. The RTX hemolysin part of CyaA is functionally independent of the invasive AC domain and forms oligomeric cation-selective pores that permeabilize cellular membranes for efflux of cytosolic potassium ions from cells [54] (Figure 1)
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