CAMP Signaling of Adenylate Cyclase Toxin Blocks M-CSF Triggered Upregulation of Iron Acquisition Receptors on Differentiating CD14 Monocytes

Overview

Journal mSphere

Publisher American Society for Microbiology

Specialties Microbiology
Parasitology

Date 2024 Jul 30

PMID 39078132

Authors

Jawid Nazir Ahmad

Peter Sebo

Affiliations

Soon will be listed here.

Abstract

infects the upper airways of humans and disarms host defense by the potent immuno-subversive activities of its pertussis (PT) and adenylate cyclase (CyaA) toxins. CyaA action near-instantly ablates the bactericidal activities of sentinel CR3-expressing myeloid phagocytes by hijacking cellular signaling pathways through the unregulated production of cAMP. Moreover, CyaA-elicited cAMP signaling also inhibits the macrophage colony-stimulating factor (M-CSF)-induced differentiation of incoming inflammatory monocytes into bactericidal macrophages. We show that CyaA/cAMP signaling via protein kinase A (PKA) downregulates the M-CSF-elicited expression of monocyte receptors for transferrin (CD71) and hemoglobin-haptoglobin (CD163), as well as the expression of heme oxygenase-1 (HO-1) involved in iron liberation from internalized heme. The impact of CyaA action on CD71 and CD163 levels in differentiating monocytes is largely alleviated by the histone deacetylase inhibitor trichostatin A (TSA), indicating that CyaA/cAMP signaling triggers epigenetic silencing of genes for micronutrient acquisition receptors. These results suggest a new mechanism by which evades host sentinel phagocytes to achieve proliferation on airway mucosa.IMPORTANCETo establish a productive infection of the nasopharyngeal mucosa and proliferate to sufficiently high numbers that trigger rhinitis and aerosol-mediated transmission, the pertussis agent deploys several immunosuppressive protein toxins that compromise the sentinel functions of mucosa patrolling phagocytes. We show that cAMP signaling elicited by very low concentrations (22 pM) of adenylate cyclase toxin downregulates the iron acquisition systems of CD14 monocytes. The resulting iron deprivation of iron, a key micronutrient, then represents an additional aspect of CyaA toxin action involved in the inhibition of differentiation of monocytes into the enlarged bactericidal macrophage cells. This corroborates the newly discovered paradigm of host defense evasion mechanisms employed by bacterial pathogens, where manipulation of cellular cAMP levels blocks monocyte to macrophage transition and replenishment of exhausted phagocytes, thereby contributing to the formation of a safe niche for pathogen proliferation and dissemination.

References

Ahmad J, Sebo P . Adenylate Cyclase Toxin Tinkering With Monocyte-Macrophage Differentiation. Front Immunol. 2020; 11:2181. PMC: 7516048. DOI: 10.3389/fimmu.2020.02181. View

Guo Q, Shen Y, Lee Y, Gibbs C, Mrksich M, Tang W . Structural basis for the interaction of Bordetella pertussis adenylyl cyclase toxin with calmodulin. EMBO J. 2005; 24(18):3190-201. PMC: 1224690. DOI: 10.1038/sj.emboj.7600800. View

Osicka R, Osickova A, Basar T, Guermonprez P, Rojas M, Leclerc C . Delivery of CD8(+) T-cell epitopes into major histocompatibility complex class I antigen presentation pathway by Bordetella pertussis adenylate cyclase: delineation of cell invasive structures and permissive insertion sites. Infect Immun. 1999; 68(1):247-56. PMC: 97128. DOI: 10.1128/IAI.68.1.247-256.2000. View

Adkins I, Kamanova J, Kocourkova A, Svedova M, Tomala J, Janova H . Bordetella adenylate cyclase toxin differentially modulates toll-like receptor-stimulated activation, migration and T cell stimulatory capacity of dendritic cells. PLoS One. 2014; 9(8):e104064. PMC: 4118975. DOI: 10.1371/journal.pone.0104064. View

Walkinshaw D, Weist R, Xiao L, Yan K, Kim G, Yang X . Dephosphorylation at a conserved SP motif governs cAMP sensitivity and nuclear localization of class IIa histone deacetylases. J Biol Chem. 2013; 288(8):5591-605. PMC: 3581380. DOI: 10.1074/jbc.M112.445668. View

Coutte L, Locht C . Investigating pertussis toxin and its impact on vaccination. Future Microbiol. 2015; 10(2):241-54. DOI: 10.2217/fmb.14.123. View

Scanlon K, Skerry C, Carbonetti N . Association of Pertussis Toxin with Severe Pertussis Disease. Toxins (Basel). 2019; 11(7). PMC: 6669598. DOI: 10.3390/toxins11070373. View

Schaer D, Schaer C, Buehler P, Boykins R, Schoedon G, Alayash A . CD163 is the macrophage scavenger receptor for native and chemically modified hemoglobins in the absence of haptoglobin. Blood. 2005; 107(1):373-80. DOI: 10.1182/blood-2005-03-1014. View

Gazitt Y, Reddy S, Alcantara O, Yang J, Boldt D . A new molecular role for iron in regulation of cell cycling and differentiation of HL-60 human leukemia cells: iron is required for transcription of p21(WAF1/CIP1) in cells induced by phorbol myristate acetate. J Cell Physiol. 2001; 187(1):124-35. DOI: 10.1002/1097-4652(2001)9999:9999<::AID-JCP1061>3.0.CO;2-E. View

10.

Persson C, Andersson M, Greiff L, Svensson C, Erjefalt J, Sundler F . Airway permeability. Clin Exp Allergy. 1995; 25(9):807-14. PMC: 7162050. DOI: 10.1111/j.1365-2222.1995.tb00022.x. View

11.

Komohara Y, Ohnishi K, Kuratsu J, Takeya M . Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol. 2008; 216(1):15-24. DOI: 10.1002/path.2370. View

12.

Cerny O, Kamanova J, Masin J, Bibova I, Skopova K, Sebo P . Bordetella pertussis Adenylate Cyclase Toxin Blocks Induction of Bactericidal Nitric Oxide in Macrophages through cAMP-Dependent Activation of the SHP-1 Phosphatase. J Immunol. 2015; 194(10):4901-13. DOI: 10.4049/jimmunol.1402941. View

13.

Christensen A, Selheim F, de Rooij J, Dremier S, Schwede F, Dao K . cAMP analog mapping of Epac1 and cAMP kinase. Discriminating analogs demonstrate that Epac and cAMP kinase act synergistically to promote PC-12 cell neurite extension. J Biol Chem. 2003; 278(37):35394-402. DOI: 10.1074/jbc.M302179200. View

14.

Gautam N, Herwald H, Hedqvist P, Lindbom L . Signaling via beta(2) integrins triggers neutrophil-dependent alteration in endothelial barrier function. J Exp Med. 2000; 191(11):1829-39. PMC: 2213534. DOI: 10.1084/jem.191.11.1829. View

15.

van de Laar L, Saelens W, De Prijck S, Martens L, Scott C, Van Isterdael G . Yolk Sac Macrophages, Fetal Liver, and Adult Monocytes Can Colonize an Empty Niche and Develop into Functional Tissue-Resident Macrophages. Immunity. 2016; 44(4):755-68. DOI: 10.1016/j.immuni.2016.02.017. View

16.

de Figueiredo P, Doody A, Polizotto R, Drecktrah D, Wood S, Banta M . Inhibition of transferrin recycling and endosome tubulation by phospholipase A2 antagonists. J Biol Chem. 2001; 276(50):47361-70. DOI: 10.1074/jbc.M108508200. View

17.

Aisen P . Transferrin receptor 1. Int J Biochem Cell Biol. 2004; 36(11):2137-43. DOI: 10.1016/j.biocel.2004.02.007. View

18.

Ahmad J, Cerny O, Linhartova I, Masin J, Osicka R, Sebo P . cAMP signalling of Bordetella adenylate cyclase toxin through the SHP-1 phosphatase activates the BimEL-Bax pro-apoptotic cascade in phagocytes. Cell Microbiol. 2015; 18(3):384-98. DOI: 10.1111/cmi.12519. View

19.

Fedele G, Schiavoni I, Adkins I, Klimova N, Sebo P . Invasion of Dendritic Cells, Macrophages and Neutrophils by the Bordetella Adenylate Cyclase Toxin: A Subversive Move to Fool Host Immunity. Toxins (Basel). 2017; 9(10). PMC: 5666340. DOI: 10.3390/toxins9100293. View

20.

Li J, Wang L, Liu X, Zhang Z, Guo H, Liu W . In vitro cancer cell imaging and therapy using transferrin-conjugated gold nanoparticles. Cancer Lett. 2008; 274(2):319-26. DOI: 10.1016/j.canlet.2008.09.024. View