scholarly journals Almost half of the RTX domain is dispensable for complement receptor 3 binding and cell-invasive activity of the adenylate cyclase toxin

2021 ◽  
pp. 100833
Author(s):  
Carlos Angel Espinosa-Vinals ◽  
Jiri Masin ◽  
Jana Holubova ◽  
Ondrej Stanek ◽  
David Jurnecka ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Complement Receptor ◽  
Adenylate Cyclase Toxin ◽  
Complement Receptor 3

scholarly journals Bordetella adenylate cyclase toxin is a unique ligand of the integrin complement receptor 3

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Radim Osicka ◽  
Adriana Osickova ◽  
Shakir Hasan ◽  
Ladislav Bumba ◽  
Jiri Cerny ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Whooping Cough ◽  
Complement Receptor ◽  
Ligand Interaction ◽  
Downstream Signaling ◽  
Cell Functions ◽  
Natural Ligand ◽  
Adenylate Cyclase Toxin ◽  
Complement Receptor 3 ◽  
Signaling Receptors

Integrins are heterodimeric cell surface adhesion and signaling receptors that are essential for metazoan existence. Some integrins contain an I-domain that is a major ligand binding site. The ligands preferentially engage the active forms of the integrins and trigger signaling cascades that alter numerous cell functions. Here we found that the adenylate cyclase toxin (CyaA), a key virulence factor of the whooping cough agent Bordetella pertussis, preferentially binds an inactive form of the integrin complement receptor 3 (CR3), using a site outside of its I-domain. CyaA binding did not trigger downstream signaling of CR3 in human monocytes and CyaA-catalyzed elevation of cAMP effectively blocked CR3 signaling initiated by a natural ligand. This unprecedented type of integrin-ligand interaction distinguishes CyaA from all other known ligands of the I-domain-containing integrins and provides a mechanistic insight into the previously observed central role of CyaA in the pathogenesis of B. pertussis.

scholarly journals Author response: Bordetella adenylate cyclase toxin is a unique ligand of the integrin complement receptor 3

2015 ◽  
Author(s):  
Radim Osicka ◽  
Adriana Osickova ◽  
Shakir Hasan ◽  
Ladislav Bumba ◽  
Jiri Cerny ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Author Response ◽  
Complement Receptor ◽  
Adenylate Cyclase Toxin ◽  
Complement Receptor 3

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

FEBS Letters ◽  
2014 ◽  
Vol 589 (3) ◽  
pp. 374-379 ◽  
Author(s):  
Shakir Hasan ◽  
Adriana Osickova ◽  
Ladislav Bumba ◽  
Petr Novák ◽  
Peter Sebo ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Complement Receptor ◽  
Adenylate Cyclase Toxin ◽  
Complement Receptor 3

scholarly journals Retargeting from the CR3 to the LFA-1 receptor uncovers the adenylyl cyclase enzyme–translocating segment of Bordetella adenylate cyclase toxin

2020 ◽  
Vol 295 (28) ◽  
pp. 9349-9365
Author(s):  
Jiri Masin ◽  
Adriana Osickova ◽  
David Jurnecka ◽  
Nela Klimova ◽  
Humaira Khaliq ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Adenylate Cyclase ◽  
Adenylyl Cyclase ◽  
Specific Capacity ◽  
Target Cells ◽  
Jurkat T Cells ◽  
Membrane Interaction ◽  
The Family ◽  
Adenylate Cyclase Toxin ◽  
Complement Receptor 3

The Bordetella adenylate cyclase toxin-hemolysin (CyaA) and the α-hemolysin (HlyA) of Escherichia coli belong to the family of cytolytic pore-forming Repeats in ToXin (RTX) cytotoxins. HlyA preferentially binds the αLβ2 integrin LFA-1 (CD11a/CD18) of leukocytes and can promiscuously bind and also permeabilize many other cells. CyaA bears an N-terminal adenylyl cyclase (AC) domain linked to a pore-forming RTX cytolysin (Hly) moiety, binds the complement receptor 3 (CR3, αMβ2, CD11b/CD18, or Mac-1) of myeloid phagocytes, penetrates their plasma membrane, and delivers the AC enzyme into the cytosol. We constructed a set of CyaA/HlyA chimeras and show that the CyaC-acylated segment and the CR3-binding RTX domain of CyaA can be functionally replaced by the HlyC-acylated segment and the much shorter RTX domain of HlyA. Instead of binding CR3, a CyaA1-710/HlyA411-1024 chimera bound the LFA-1 receptor and effectively delivered AC into Jurkat T cells. At high chimera concentrations (25 nm), the interaction with LFA-1 was not required for CyaA1-710/HlyA411-1024 binding to CHO cells. However, interaction with the LFA-1 receptor strongly enhanced the specific capacity of the bound CyaA1-710/HlyA411-1024 chimera to penetrate cells and deliver the AC enzyme into their cytosol. Hence, interaction of the acylated segment and/or the RTX domain of HlyA with LFA-1 promoted a productive membrane interaction of the chimera. These results help delimit residues 400–710 of CyaA as an “AC translocon” sufficient for translocation of the AC polypeptide across the plasma membrane of target cells.

scholarly journals Use of a Toxin Neutralization Assay To Characterize the Serologic Response to Adenylate Cyclase Toxin after Infection with Bordetella pertussis

2016 ◽  
Vol 24 (1) ◽  
Author(s):  
Joshua C. Eby ◽  
Mary C. Gray ◽  
Jason M. Warfel ◽  
Tod J. Merkel ◽  
Erik L. Hewlett
Keyword(s):  
Adenylate Cyclase ◽  
Bordetella Pertussis ◽  
Neutralization Assay ◽  
Enzyme Linked Immunosorbent Assay ◽  
Immunologic Response ◽  
Serum Samples ◽  
Content Type ◽  
Adenylate Cyclase Toxin ◽  
Strong Candidate ◽  
Candidate Antigen

ABSTRACT Adenylate cyclase toxin (ACT) is an essential virulence factor of Bordetella pertussis, and antibodies to ACT protect against B. pertussis infection in mice. The toxin is therefore a strong candidate antigen for addition to future acellular pertussis vaccines. In order to characterize the functionality of the immunologic response to ACT after infection, we developed an assay for testing the ability of serum samples from subjects infected with B. pertussis to neutralize ACT-induced cytotoxicity in J774 macrophage cells. Baboons develop neutralizing anti-ACT antibodies following infection with B. pertussis, and all sera from baboons with positive anti-ACT IgG enzyme-linked immunosorbent assay (ELISA) results neutralized ACT cytotoxicity. The toxin neutralization assay (TNA) was positive in some baboon sera in which ELISA remained negative. Of serum samples obtained from humans diagnosed with pertussis by PCR, anti-ACT IgG ELISA was positive in 72%, and TNA was positive in 83%. All samples positive for anti-ACT IgG ELISA were positive by TNA, and none of the samples from humans without pertussis neutralized toxin activity. These findings indicate that antibodies to ACT generated following infection with B. pertussis consistently neutralize toxin-induced cytotoxicity and that TNA can be used to improve understanding of the immunologic response to ACT after infection or vaccination.

scholarly journals β-Glucan enhances complement-mediated hematopoietic recovery after bone marrow injury

Blood ◽  
2006 ◽  
Vol 107 (2) ◽  
pp. 835-840 ◽  
Author(s):  
Daniel E. Cramer ◽  
Daniel J. Allendorf ◽  
Jarek T. Baran ◽  
Richard Hansen ◽  
Jose Marroquin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mouse Serum ◽  
Complement Receptor ◽  
Dependent Manner ◽  
Complement Receptor 3 ◽  
Total Body ◽  
Stimulating Factor ◽  
Sublethal Irradiation ◽  
Classic Pathway

AbstractMyelotoxic injury in the bone marrow (BM) as a consequence of total body irradiation (TBI) or granulocyte colony-stimulating factor (G-CSF) mobilization results in the deposition of iC3b on BM stroma (stroma-iC3b). In the present study, we have examined how stroma-iC3b interacts with hematopoietic progenitor cells (HPCs) and the role of complement (C) and complement receptor 3 (CR3) in BM injury/repair. We demonstrate here that stroma-iC3b tethers HPCs via the inserted (I) domain of HPC complement receptor 3 (CR3, CD11b/CD18, Mac-1). Following irradiation, stroma-iC3b was observed in the presence of purified IgM and normal mouse serum (NMS), but not serum from Rag-2-/- mice, implicating a role for antibody (Ab) and the classic pathway of C activation. Furthermore, a novel role for soluble yeast β-glucan, a ligand for the CR3 lectin-like domain (LLD), in the priming of CR3+ HPC is suggested. Soluble yeast β-glucan could enhance the proliferation of tethered HPCs, promote leukocyte recovery following sublethal irradiation, and increase the survival of lethally irradiated animals following allogeneic HPC transplantation in a CR3-dependent manner. Taken together, these observations suggest a novel role for C, CR3, and β-glucan in the restoration of hematopoiesis following injury. (Blood. 2006;107:835-840)

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