Interaction of <i>Bordetella</i> adenylate cyclase toxin with complement receptor 3 involves multivalent glycan binding

Hasan, Shakir; Osičková, Adriana; Bumba, Ladislav; Novák, Petr; Šebo, Peter; Osička, Radim

doi:10.1016/j.febslet.2014.12.023

Cited by 29 publications

(33 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The apparently higher efficacy of CyaA translocation through the basal membrane might then potentially be due to its lipid composition and higher cholesterol or glycolipid content. The expression of the CyaA receptor CD11b/CD18 has not been observed on airway epithelial cells (50,51), and in the absence of CD11b/ CD18 expression, the toxin might bind to surface-expressed glycosylated structures, such as gangliosides clustered in the membrane microdomains (52)(53)(54)(55). This hypothesis would go well with the observed apicobasal polarity in the distribution of receptors on airway epithelia (56,57).…”

Section: Discussionmentioning

confidence: 75%

See 1 more Smart Citation

Bordetella pertussis Adenylate Cyclase Toxin Disrupts Functional Integrity of Bronchial Epithelial Layers

et al. 2018

Self Cite

View full text Add to dashboard Cite

The airway epithelium restricts the penetration of inhaled pathogens into the underlying tissue and plays a crucial role in the innate immune defense against respiratory infections. The whooping cough agent, , adheres to ciliated cells of the human airway epithelium and subverts its defense functions through the action of secreted toxins and other virulence factors. We examined the impact of infection and of adenylate cyclase toxin-hemolysin (CyaA) action on the functional integrity of human bronchial epithelial cells cultured at the air-liquid interface (ALI). adhesion to the apical surface of polarized pseudostratified VA10 cell layers provoked a disruption of tight junctions and caused a drop in transepithelial electrical resistance (TEER). The reduction of TEER depended on the capacity of the secreted CyaA toxin to elicit cAMP signaling in epithelial cells through its adenylyl cyclase enzyme activity. Both purified CyaA and cAMP-signaling drugs triggered a decrease in the TEER of VA10 cell layers. Toxin-produced cAMP signaling caused actin cytoskeleton rearrangement and induced mucin 5AC production and interleukin-6 (IL-6) secretion, while it inhibited the IL-17A-induced secretion of the IL-8 chemokine and of the antimicrobial peptide beta-defensin 2. These results indicate that CyaA toxin activity compromises the barrier and innate immune functions ofinfected airway epithelia.

show abstract

Section: Discussionmentioning

confidence: 75%

“…The reaction was stopped by lysing the cells with 0.2% Tween in 50 mM HCl. cAMP levels in the lysate were determined by a competitive ELISA as mentioned elsewhere (52,89). cAMP concentrations were normalized to the total protein content, which was determined using a micro-BCA protein assay kit (Bio-Rad, Rockford, IL, USA).…”

Section: Methodsmentioning

confidence: 99%

Bordetella pertussis Adenylate Cyclase Toxin Disrupts Functional Integrity of Bronchial Epithelial Layers

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…Upon initial interaction with N-linked oligosaccharides (31,32), CyaA specifically binds a loop outside the I domain of the CD11b subunit of the ␣ M ␤ 2 integrin (CR3) (5), and the toxin delivers the AC enzyme into phagocyte cytosol in two steps (33). Compelling indirect evidence suggests that the AC-translocating and pore-forming activities of CyaA are mutually independent and are accomplished by two distinct subpopulations of CyaA conformers that employ the same transmembrane CyaA segments in an alternative manner (34).…”

mentioning

confidence: 99%

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

et al. 2017

Self Cite

View full text Add to dashboard Cite

The adenylate cyclase toxin-hemolysin (CyaA, ACT, or AC-Hly) of Bordetella pertussis targets phagocytic cells expressing the complement receptor 3 (CR3, Mac-1, ␣ M ␤ 2 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 ϩ ) host phagocytes but impaired in formation of cell-permeabilizing pores and defective in cAMP elevation in CD11b Ϫ cells. The nonhemolytic AC ϩ Hly Ϫ 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 ϩ Hly Ϫ mutant also infected mouse lungs as efficiently as the parental AC ϩ Hly ϩ strain. Hence, elevation of cAMP in CD11b Ϫ cells and/or the poreforming 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 (Ͼ10 7 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.KEYWORDS Bordetella pertussis, adenylate cyclase toxin-hemolysin, cAMP intoxication, lung colonization, pore-forming activity, virulence T he adenylate cyclase toxin-hemolysin is produced by all three Bordetella species pathogenic to mammals, and it plays a prominent role in the early phases of respiratory tract infection by the whooping cough agent, Bordetella pertussis (1-3). The toxin specifically binds the CD11b subunit of the complement receptor 3 (CR3) (4, 5) and exerts an array of immunosubversive and cytotoxic activities on myeloid phagocytes. CyaA delivers a cell-invasive adenylyl cyclase (AC) enzyme domain into cytosol of CD11b ϩ cells, where the AC is activated by calmodulin and converts cytosolic ATP to the signaling molecule cyclic AMP (cAMP). The generated supraphysiological levels of cAMP then nearly instantly ablate the bactericidal oxidative burst and opsonophago-

show abstract

“…Galectin-4 or -8, may bind to and cross-link multivalent glycoproteins and glycolipids on the cell surface in appropriately formed lipid rafts, leading to formation of microdomains and lattices that initiate signal specific pathways [64,134]. High affinity ligands to selectins, antibodies, and other types of GBPs [105,135,136], are favored by the presence uncommon conformations of glycans in HBGA enhanced clustered saccharide patches. Such GBPs (siglecs and galectins) play critical roles in diverse cellular functions such as cell adhesion, signal transduction and immune response [137].…”

Section: Glycan Reactionsmentioning

confidence: 99%

Blood Type Diets (BTD) and Aging: An Overview

Menapace¹

2019

J Aging Sci

View full text Add to dashboard Cite

It has recently been proposed that glycans, being the third alphabet of life, interact intricately with endogenous biomolecules to modulate tolerance, immune and inflammatory responses. Specifically, food glycans could impact health and be a source of inflammation and age-related diseases. These special carbohydrates are present as glycoconjugates (glycoproteins or glycolipids) in and on the surface of all the cells (glycocalyx) of all organisms or are found in free form in biological fluids. Recent advances in glycobiology and glycochemistry have shown how glycans bind with naturally present human proteins (lectins), through protein-carbohydrate interactions (or PCI), but also how oligosaccharides can interact with other glycans, present throughout the human body (through carbohydrate-carbohydrate interactions, or CCI). Oligosaccharides present in food sources, which go beyond the definition of normal fibers, once ingested are then either absorbed in the bloodstream, where they are recognized by the immune system, or interact with the surface of GI epithelial cells, thus generating appropriate biochemical cascades that induce a tolerance or immune/inflammatory response. Because the ABO epitopes have been encountered on all human cells, not just erythrocytes and based on the different biotypology (A, AB, B, and O) impose morphic changes in the distribution of the glycans on the glycocalyx (lipid rafts and clustered saccharide patches), their CCI with food and microbe glycans will be different, thus, eliciting contrasting responses. This can explain the epidemiological data for blood type diets (BTD). Through continuous consumption of the wrong types of glycans, processes of chronic inflammation could be initiated and progress to accelerated aging. Four basic modes of action have been identified showing how glycans can trigger inflamm-aging. Since glycobiology is a young science, further studies with newer technologies are warranted for advancement in this field.

show abstract

Interaction of Bordetella adenylate cyclase toxin with complement receptor 3 involves multivalent glycan binding

Cited by 29 publications

References 25 publications

Bordetella pertussis Adenylate Cyclase Toxin Disrupts Functional Integrity of Bronchial Epithelial Layers

Bordetella pertussis Adenylate Cyclase Toxin Disrupts Functional Integrity of Bronchial Epithelial Layers

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

Blood Type Diets (BTD) and Aging: An Overview

Contact Info

Product

Resources

About