Adenylate Cyclase Toxin Tinkering With Monocyte-Macrophage Differentiation

Abstract

Circulating inflammatory monocytes are attracted to infected mucosa and differentiate into macrophage or dendritic cells endowed with enhanced bactericidal and antigen presenting capacities. In this brief Perspective we discuss the newly emerging insight into how the cAMP signaling capacity of Bordetella pertussis adenylate cyclase toxin manipulates the differentiation of monocytes and trigger dedifferentiation of the alveolar macrophages to facilitate bacterial colonization of human airways.

Keywords: Bordetella pertussis; adenylate cyclase toxin; dedifferentiation; macrophages; monocytes.

Figure 1

CyaA manipulates phagocyte differentiation. Monocytes get recruited to the infected tissue by the secreted chemoattractants and mature into macrophages. B. pertussis secreted CyaA and in part pertussis toxin action blocks the differentiation of monocytes into macrophage cells and provokes de-differentiation of patrolling alveolar human macrophages to less bactericidal monocyte-like cells.

Figure 2

Model for B. pertussis CyaA regulated complex signaling pathways to block the monocyte differentiation and to trigger macrophage dedifferentiation. CyaA toxin recognizes CD11b molecule on phagocytes to translocate its adenylate cyclase (AC) domain across the cell membrane. Upon interaction with the host cell protein calmodulin, AC enzyme gets activated and catalyzes the conversion of cellular ATP to cAMP. cAMP signal transduction via PKA then inactivates RhoA and/OR activates LATS1/2 to inhibit Yap regulated gene expression and prevents monocytes from acquiring bigger cell size, a typical macrophage feature; this signaling pathway could also block the macrophages from retaining large cell size and triggers their dedifferentiation. The decrease in Yap activity is paralleled by the inactivation of AKT/PKB to suppress the cell growth signaling in order to reduce cell size. Elevated cAMP level subverts IL-2 receptor signaling which upregulates the M-CSF receptor expression and that makes the monocyte less sensitive to pro-differentiating M-CSF growth factor. These complex CyaA-mediated signaling events culminate in subverting macrophage-based host protective functions to compromise the anti-Bordetella host immune responses.