Bordetellae, pathogenic to mammals, produce an immunomodulatory adenylate cyclase toxin-hemolysin (CyaA, ACT or AC-Hly) that enables them to overcome the innate immune defense of the host. CyaA subverts host phagocytic cells by an orchestrated action of its functional domains, where an extremely catalytically active adenylyl cyclase enzyme is delivered into phagocyte cytosol by a pore-forming repeat-in-toxin (RTX) cytolysin moiety. By targeting sentinel cells expressing the complement receptor 3, known as the CD11b/CD18 (αMβ₂) integrin, CyaA compromises the bactericidal functions of host phagocytes and supports infection of host airways by Bordetellae. Here, we review the state of knowledge on structural and functional aspects of CyaA toxin action, placing particular emphasis on signaling mechanisms by which the toxin-produced 3',5'-cyclic adenosine monophosphate (cAMP) subverts the physiology of phagocytic cells.

Faculty of Science Charles University Prague 128 43 Prague Czech Republic

Institute of Microbiology of the CAS v v i 142 20 Prague Czech Republic

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Melvin J.A., Scheller E.V., Miller J.F., Cotter P.A. Bordetella pertussis pathogenesis: Current and future challenges. Nat. Rev. Microbiol. 2014;12:274–288. doi: 10.1038/nrmicro3235. PubMed DOI PMC

Yeung K.H.T., Duclos P., Nelson E.A.S., Hutubessy R.C.W. An update of the global burden of pertussis in children younger than 5 years: A modelling study. Lancet Infect. Dis. 2017;17:974–980. doi: 10.1016/S1473-3099(17)30390-0. PubMed DOI

Cherry J.D. Pertussis in young infants throughout the world. Clin. Infect. Dis. 2016;63:S119–S122. doi: 10.1093/cid/ciw550. PubMed DOI PMC

Vojtova J., Kamanova J., Sebo P. Bordetella adenylate cyclase toxin: A swift saboteur of host defense. Curr. Opin. Microbiol. 2006;9:69–75. doi: 10.1016/j.mib.2005.12.011. PubMed DOI

Sebo P., Osicka R., Masin J. Adenylate cyclase toxin-hemolysin relevance for pertussis vaccines. Expert Rev. Vaccines. 2014;13:1215–1227. doi: 10.1586/14760584.2014.944900. PubMed DOI

Linhartova I., Bumba L., Masin J., Basler M., Osicka R., Kamanova J., Prochazkova K., Adkins I., Hejnova-Holubova J., Sadilkova L., et al. RTX proteins: A highly diverse family secreted by a common mechanism. FEMS Microbiol. Rev. 2010;34:1076–1112. doi: 10.1111/j.1574-6976.2010.00231.x. PubMed DOI PMC

Rose T., Sebo P., Bellalou J., Ladant D. Interaction of calcium with Bordetella pertussis adenylate cyclase toxin. Characterization of multiple calcium-binding sites and calcium-induced conformational changes. J. Biol. Chem. 1995;270:26370–26376. doi: 10.1074/jbc.270.44.26370. PubMed DOI

Masin J., Osicka R., Bumba L., Sebo P. Bordetella adenylate cyclase toxin: A unique combination of a pore-forming moiety with a cell-invading adenylate cyclase enzyme. Pathog. Dis. 2015;73:ftv075. doi: 10.1093/femspd/ftv075. PubMed DOI PMC

Glaser P., Sakamoto H., Bellalou J., Ullmann A., Danchin A. Secretion of cyclolysin, the calmodulin-sensitive adenylate cyclase-haemolysin bifunctional protein of Bordetella pertussis. EMBO J. 1988;7:3997–4004. PubMed PMC

Iwaki M., Ullmann A., Sebo P. Identification by in vitro complementation of regions required for cell-invasive activity of Bordetella pertussis adenylate cyclase toxin. Mol. Microbiol. 1995;17:1015–1024. doi: 10.1111/j.1365-2958.1995.mmi_17061015.x. PubMed DOI

Benz R., Maier E., Ladant D., Ullmann A., Sebo P. Adenylate cyclase toxin (CyaA) of Bordetella pertussis. Evidence for the formation of small ion-permeable channels and comparison with HlyA of Escherichia coli. J. Biol. Chem. 1994;269:27231–27239. PubMed

Hackett M., Guo L., Shabanowitz J., Hunt D.F., Hewlett E.L. Internal lysine palmitoylation in adenylate cyclase toxin from Bordetella pertussis. Science. 1994;266:433–435. doi: 10.1126/science.7939682. PubMed DOI

Hackett M., Walker C.B., Guo L., Gray M.C., Van Cuyk S., Ullmann A., Shabanowitz J., Hunt D.F., Hewlett E.L., Sebo P. Hemolytic, but not cell-invasive activity, of adenylate cyclase toxin is selectively affected by differential fatty-acylation in Escherichia coli. J. Biol. Chem. 1995;270:20250–20253. doi: 10.1074/jbc.270.35.20250. PubMed DOI

Osicka R., Osickova A., Basar T., Guermonprez P., Rojas M., Leclerc C., Sebo P. 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. 2000;68:247–256. PubMed PMC

Bumba L., Masin J., Macek P., Wald T., Motlova L., Bibova I., Klimova N., Bednarova L., Veverka V., Kachala M., et al. Calcium-driven folding of RTX domain beta-rolls ratchets translocation of RTX proteins through type I secretion ducts. Mol. Cell. 2016;62:47–62. doi: 10.1016/j.molcel.2016.03.018. PubMed DOI

Sebo P., Ladant D. Repeat sequences in the Bordetella pertussis adenylate cyclase toxin can be recognized as alternative carboxy-proximal secretion signals by the Escherichia coli alpha-haemolysin translocator. Mol. Microbiol. 1993;9:999–1009. doi: 10.1111/j.1365-2958.1993.tb01229.x. PubMed DOI

Guermonprez P., Khelef N., Blouin E., Rieu P., Ricciardi-Castagnoli P., Guiso N., Ladant D., Leclerc C. The adenylate cyclase toxin of Bordetella pertussis binds to target cells via the alpha(M)beta(2) integrin (CD11b/CD18) J. Exp. Med. 2001;193:1035–1044. doi: 10.1084/jem.193.9.1035. PubMed DOI PMC

Osicka R., Osickova A., Hasan S., Bumba L., Cerny J., Sebo P. Bordetella adenylate cyclase toxin is a unique ligand of the integrin complement receptor 3. eLife. 2015;4:e10766. doi: 10.7554/eLife.10766. PubMed DOI PMC

Bellalou J., Sakamoto H., Ladant D., Geoffroy C., Ullmann A. Deletions affecting hemolytic and toxin activities of Bordetella pertussis adenylate cyclase. Infect. Immun. 1990;58:3242–3247. PubMed PMC

Gordon V.M., Young W.W., Jr., Lechler S.M., Gray M.C., Leppla S.H., Hewlett E.L. Adenylate cyclase toxins from Bacillus anthracis and Bordetella pertussis. Different processes for interaction with and entry into target cells. J. Biol. Chem. 1989;264:14792–14796. PubMed

Holubova J., Kamanova J., Jelinek J., Tomala J., Masin J., Kosova M., Stanek O., Bumba L., Michalek J., Kovar M., et al. Delivery of large heterologous polypeptides across the cytoplasmic membrane of antigen-presenting cells by the Bordetella RTX hemolysin moiety lacking the adenylyl cyclase domain. Infect. Immun. 2012;80:1181–1192. doi: 10.1128/IAI.05711-11. PubMed DOI PMC

Wolff J., Cook G.H., Goldhammer A.R., Berkowitz S.A. Calmodulin activates prokaryotic adenylate cyclase. Proc. Natl. Acad. Sci. USA. 1980;77:3841–3844. doi: 10.1073/pnas.77.7.3841. PubMed DOI PMC

Confer D.L., Eaton J.W. Phagocyte impotence caused by an invasive bacterial adenylate cyclase. Science. 1982;217:948–950. doi: 10.1126/science.6287574. PubMed DOI

Ladant D., Ullmann A. Bordetella pertussis adenylate cyclase: A toxin with multiple talents. Trends Microbiol. 1999;7:172–176. doi: 10.1016/S0966-842X(99)01468-7. PubMed DOI

Szabo G., Gray M.C., Hewlett E.L. Adenylate cyclase toxin from Bordetella pertussis produces ion conductance across artificial lipid bilayers in a calcium- and polarity-dependent manner. J. Biol. Chem. 1994;269:22496–22499. PubMed

Ehrmann I.E., Gray M.C., Gordon V.M., Gray L.S., Hewlett E.L. Hemolytic activity of adenylate cyclase toxin from Bordetella pertussis. FEBS Lett. 1991;278:79–83. PubMed

Basler M., Masin J., Osicka R., Sebo P. Pore-forming and enzymatic activities of Bordetella pertussis adenylate cyclase toxin synergize in promoting lysis of monocytes. Infect. Immun. 2006;74:2207–2214. doi: 10.1128/IAI.74.4.2207-2214.2006. PubMed DOI PMC

Fiser R., Masin J., Basler M., Krusek J., Spulakova V., Konopasek I., Sebo P. Third activity of Bordetella adenylate cyclase (AC) toxin-hemolysin. Membrane translocation of AC domain polypeptide promotes calcium influx into CD11b+ monocytes independently of the catalytic and hemolytic activities. J. Biol. Chem. 2007;282:2808–2820. doi: 10.1074/jbc.M609979200. PubMed DOI

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;194:4901–4913. doi: 10.4049/jimmunol.1402941. PubMed DOI

Cerny O., Anderson K.E., Stephens L.R., Hawkins P.T., Sebo P. cAMP signaling of adenylate cyclase toxin blocks the oxidative burst of neutrophils through Epac-mediated inhibition of phospholipase C activity. J. Immunol. 2017;198:1285–1296. doi: 10.4049/jimmunol.1601309. PubMed DOI

Kamanova J., Kofronova O., Masin J., Genth H., Vojtova J., Linhartova I., Benada O., Just I., Sebo P. Adenylate cyclase toxin subverts phagocyte function by RhoA inhibition and unproductive ruffling. J. Immunol. 2008;181:5587–5597. doi: 10.4049/jimmunol.181.8.5587. PubMed DOI

Dunne A., Ross P.J., Pospisilova E., Masin J., Meaney A., Sutton C.E., Iwakura Y., Tschopp J., Sebo P., Mills K.H. Inflammasome activation by adenylate cyclase toxin directs Th17 responses and protection against Bordetella pertussis. J. Immunol. 2010;185:1711–1719. doi: 10.4049/jimmunol.1000105. PubMed DOI

Fiser R., Masin J., Bumba L., Pospisilova E., Fayolle C., Basler M., Sadilkova L., Adkins I., Kamanova J., Cerny J., et al. Calcium influx rescues adenylate cyclase-hemolysin from rapid cell membrane removal and enables phagocyte permeabilization by toxin pores. PLoS Pathog. 2012;8:e1002580. doi: 10.1371/journal.ppat.1002580. PubMed DOI PMC

Gray M., Szabo G., Otero A.S., Gray L., Hewlett E. Distinct mechanisms for K+ efflux, intoxication, and hemolysis by Bordetella pertussis AC toxin. J. Biol. Chem. 1998;273:18260–18267. doi: 10.1074/jbc.273.29.18260. PubMed DOI

Svedova M., Masin J., Fiser R., Cerny O., Tomala J., Freudenberg M., Tuckova L., Kovar M., Dadaglio G., Adkins I., et al. Pore-formation by adenylate cyclase toxoid activates dendritic cells to prime CD8+ and CD4+ T cells. Immunol. Cell Biol. 2016;94:322–333. doi: 10.1038/icb.2015.87. PubMed DOI

Wald T., Petry-Podgorska I., Fiser R., Matousek T., Dedina J., Osicka R., Sebo P., Masin J. Quantification of potassium levels in cells treated with Bordetella adenylate cyclase toxin. Anal. Biochem. 2014;450:57–62. doi: 10.1016/j.ab.2013.10.039. PubMed DOI

Bachelet M., Richard M.J., Francois D., Polla B.S. Mitochondrial alterations precede Bordetella pertussis-induced apoptosis. FEMS Immunol. Med. Microbiol. 2002;32:125–131. doi: 10.1111/j.1574-695X.2002.tb00544.x. PubMed DOI

Hewlett E.L., Donato G.M., Gray M.C. Macrophage cytotoxicity produced by adenylate cyclase toxin from Bordetella pertussis: More than just making cyclic amp! Mol. Microbiol. 2006;59:447–459. doi: 10.1111/j.1365-2958.2005.04958.x. PubMed DOI

Khelef N., Guiso N. Induction of macrophage apoptosis by Bordetella pertussis adenylate cyclase-hemolysin. FEMS Microbiol. Lett. 1995;134:27–32. doi: 10.1111/j.1574-6968.1995.tb07909.x. PubMed DOI

Barzu O., Danchin A. Adenylyl cyclases: A heterogeneous class of ATP-utilizing enzymes. Prog. Nucleic Acid Res. Mol. Biol. 1994;49:241–283. PubMed

Shen Y., Zhukovskaya N.L., Guo Q., Florian J., Tang W.J. Calcium-independent calmodulin binding and two-metal-ion catalytic mechanism of anthrax edema factor. EMBO J. 2005;24:929–941. doi: 10.1038/sj.emboj.7600574. PubMed DOI PMC

Tang W.J., Guo Q. The adenylyl cyclase activity of anthrax edema factor. Mol. Asp. Med. 2009;30:423–430. doi: 10.1016/j.mam.2009.06.001. PubMed DOI PMC

Morrow K.A., Frank D.W., Balczon R., Stevens T. The Pseudomonas aeruginosa exoenzyme Y: A promiscuous nucleotidyl cyclase edema factor and virulence determinant. Handb. Exp. Pharmacol. 2017;238:67–85. PubMed PMC

Yahr T.L., Vallis A.J., Hancock M.K., Barbieri J.T., Frank D.W. ExoY, an adenylate cyclase secreted by the Pseudomonas aeruginosa type III system. Proc. Natl. Acad. Sci. USA. 1998;95:13899–13904. doi: 10.1073/pnas.95.23.13899. PubMed DOI PMC

Belyy A., Raoux-Barbot D., Saveanu C., Namane A., Ogryzko V., Worpenberg L., David V., Henriot V., Fellous S., Merrifield C., et al. Actin activates Pseudomonas aeruginosa ExoY nucleotidyl cyclase toxin and ExoY-like effector domains from MARTX toxins. Nat. Commun. 2016;7:13582. doi: 10.1038/ncomms13582. PubMed DOI PMC

Ladant D. Interaction of Bordetella pertussis adenylate cyclase with calmodulin. Identification of two separated calmodulin-binding domains. J. Biol. Chem. 1988;263:2612–2618. PubMed

Rogel A., Schultz J.E., Brownlie R.M., Coote J.G., Parton R., Hanski E. Bordetella pertussis adenylate cyclase: Purification and characterization of the toxic form of the enzyme. EMBO J. 1989;8:2755–2760. PubMed PMC

Gottle M., Dove S., Kees F., Schlossmann J., Geduhn J., Konig B., Shen Y., Tang W.J., Kaever V., Seifert R. Cytidylyl and uridylyl cyclase activity of Bacillus anthracis edema factor and Bordetella pertussis CyaA. Biochemistry. 2010;49:5494–5503. doi: 10.1021/bi100684g. PubMed DOI PMC

Glaser P., Elmaoglou-Lazaridou A., Krin E., Ladant D., Barzu O., Danchin A. Identification of residues essential for catalysis and binding of calmodulin in Bordetella pertussis adenylate cyclase by site-directed mutagenesis. EMBO J. 1989;8:967–972. PubMed PMC

Ladant D., Michelson S., Sarfati R., Gilles A.M., Predeleanu R., Barzu O. Characterization of the calmodulin-binding and of the catalytic domains of Bordetella pertussis adenylate cyclase. J. Biol. Chem. 1989;264:4015–4020. PubMed

Munier H., Bouhss A., Krin E., Danchin A., Gilles A.M., Glaser P., Barzu O. The role of histidine 63 in the catalytic mechanism of Bordetella pertussis adenylate cyclase. J. Biol. Chem. 1992;267:9816–9820. PubMed

Glaser P., Munier H., Gilles A.M., Krin E., Porumb T., Barzu O., Sarfati R., Pellecuer C., Danchin A. Functional consequences of single amino acid substitutions in calmodulin-activated adenylate cyclase of Bordetella pertussis. EMBO J. 1991;10:1683–1688. PubMed PMC

Guo Q., Shen Y., Lee Y.S., Gibbs C.S., Mrksich M., Tang W.J. Structural basis for the interaction of Bordetella pertussis adenylyl cyclase toxin with calmodulin. EMBO J. 2005;24:3190–3201. doi: 10.1038/sj.emboj.7600800. PubMed DOI PMC

Bouhss A., Krin E., Munier H., Gilles A.M., Danchin A., Glaser P., Barzu O. Cooperative phenomena in binding and activation of Bordetella pertussis adenylate cyclase by calmodulin. J. Biol. Chem. 1993;268:1690–1694. PubMed

Guo Q., Jureller J.E., Warren J.T., Solomaha E., Florian J., Tang W.J. Protein-protein docking and analysis reveal that two homologous bacterial adenylyl cyclase toxins interact with calmodulin differently. J. Biol. Chem. 2008;283:23836–23845. doi: 10.1074/jbc.M802168200. PubMed DOI PMC

Springer T.I., Goebel E., Hariraju D., Finley N.L. Mutation in the beta-hairpin of the Bordetella pertussis adenylate cyclase toxin modulates N-lobe conformation in calmodulin. Biochem. Biophys. Res. Commun. 2014;453:43–48. doi: 10.1016/j.bbrc.2014.09.048. PubMed DOI

Springer T.I., Emerson C.C., Johns C.W., Finley N.L. Interaction with adenylate cyclase toxin from Bordetella pertussis affects the metal binding properties of calmodulin. FEBS Open Bio. 2017;7:25–34. doi: 10.1002/2211-5463.12138. PubMed DOI PMC

Bumba L., Masin J., Fiser R., Sebo P. Bordetella adenylate cyclase toxin mobilizes its beta2 integrin receptor into lipid rafts to accomplish translocation across target cell membrane in two steps. PLoS Pathog. 2010;6:e1000901. doi: 10.1371/journal.ppat.1000901. PubMed DOI PMC

Otero A.S., Yi X.B., Gray M.C., Szabo G., Hewlett E.L. Membrane depolarization prevents cell invasion by Bordetella pertussis adenylate cyclase toxin. J. Biol. Chem. 1995;270:9695–9697. doi: 10.1074/jbc.270.17.9695. PubMed DOI

Shen Y., Lee Y.S., Soelaiman S., Bergson P., Lu D., Chen A., Beckingham K., Grabarek Z., Mrksich M., Tang W.J. Physiological calcium concentrations regulate calmodulin binding and catalysis of adenylyl cyclase exotoxins. EMBO J. 2002;21:6721–6732. doi: 10.1093/emboj/cdf681. PubMed DOI PMC

Subrini O., Sotomayor Perez A.C., Hessel A., Spiaczka-Karst J., Selwa E., Sapay N., Veneziano R., Pansieri J., Chopineau J., Ladant D., et al. Characterization of a membrane-active peptide from the Bordetella pertussis CyaA toxin. J. Biol. Chem. 2013;288:32585–32598. doi: 10.1074/jbc.M113.508838. PubMed DOI PMC

Masin J., Osickova A., Sukova A., Fiser R., Halada P., Bumba L., Linhartova I., Osicka R., Sebo P. Negatively charged residues of the segment linking the enzyme and cytolysin moieties restrict the membrane-permeabilizing capacity of adenylate cyclase toxin. Sci. Rep. 2016;6:29137. doi: 10.1038/srep29137. PubMed DOI PMC

Karst J.C., Barker R., Devi U., Swann M.J., Davi M., Roser S.J., Ladant D., Chenal A. Identification of a region that assists membrane insertion and translocation of the catalytic domain of Bordetella pertussis CyaA toxin. J. Biol. Chem. 2012;287:9200–9212. doi: 10.1074/jbc.M111.316166. PubMed DOI PMC

Gray M.C., Lee S.J., Gray L.S., Zaretzky F.R., Otero A.S., Szabo G., Hewlett E.L. Translocation-specific conformation of adenylate cyclase toxin from Bordetella pertussis inhibits toxin-mediated hemolysis. J. Bacteriol. 2001;183:5904–5910. doi: 10.1128/JB.183.20.5904-5910.2001. PubMed DOI PMC

Masin J., Fiser R., Linhartova I., Osicka R., Bumba L., Hewlett E.L., Benz R., Sebo P. Differences in purinergic amplification of osmotic cell lysis by the pore-forming RTX toxins Bordetella pertussis CyaA and Actinobacillus pleuropneumoniae ApxIA: The role of pore size. Infect. Immun. 2013;81:4571–4582. doi: 10.1128/IAI.00711-13. PubMed DOI PMC

Basler M., Knapp O., Masin J., Fiser R., Maier E., Benz R., Sebo P., Osicka R. Segments crucial for membrane translocation and pore-forming activity of Bordetella adenylate cyclase toxin. J. Biol. Chem. 2007;282:12419–12429. doi: 10.1074/jbc.M611226200. PubMed DOI

Masin J., Roderova J., Osickova A., Novak P., Bumba L., Fiser R., Sebo P., Osicka R. The conserved tyrosine residue 940 plays a key structural role in membrane interaction of Bordetella adenylate cyclase toxin. Sci. Rep. 2017;7:9330. doi: 10.1038/s41598-017-09575-6. PubMed DOI PMC

Osickova A., Osicka R., Maier E., Benz R., Sebo P. An amphipathic alpha-helix including glutamates 509 and 516 is crucial for membrane translocation of adenylate cyclase toxin and modulates formation and cation selectivity of its membrane channels. J. Biol. Chem. 1999;274:37644–37650. PubMed

Osickova A., Masin J., Fayolle C., Krusek J., Basler M., Pospisilova E., Leclerc C., Osicka R., Sebo P. Adenylate cyclase toxin translocates across target cell membrane without forming a pore. Mol. Microbiol. 2010;75:1550–1562. doi: 10.1111/j.1365-2958.2010.07077.x. PubMed DOI

Weiss A.A., Hewlett E.L., Myers G.A., Falkow S. Pertussis toxin and extracytoplasmic adenylate cyclase as virulence factors of Bordetella pertussis. J. Infect. Dis. 1984;150:219–222. doi: 10.1093/infdis/150.2.219. PubMed DOI

Rogel A., Hanski E. Distinct steps in the penetration of adenylate cyclase toxin of Bordetella pertussis into sheep erythrocytes. Translocation of the toxin across the membrane. J. Biol. Chem. 1992;267:22599–22605. PubMed

Rogel A., Meller R., Hanski E. Adenylate cyclase toxin from Bordetella pertussis. The relationship between induction of cAMP and hemolysis. J. Biol. Chem. 1991;266:3154–3161. PubMed

Masin J., Konopasek I., Svobodova J., Sebo P. Different structural requirements for adenylate cyclase toxin interactions with erythrocyte and liposome membranes. Biochim. Biophys. Acta. 2004;1660:144–154. doi: 10.1016/j.bbamem.2003.11.008. PubMed DOI

Bauche C., Chenal A., Knapp O., Bodenreider C., Benz R., Chaffotte A., Ladant D. Structural and functional characterization of an essential RTX subdomain of Bordetella pertussis adenylate cyclase toxin. J. Biol. Chem. 2006;281:16914–16926. doi: 10.1074/jbc.M601594200. PubMed DOI

Chenal A., Guijarro J.I., Raynal B., Delepierre M., Ladant D. RTX calcium binding motifs are intrinsically disordered in the absence of calcium: Implication for protein secretion. J. Biol. Chem. 2009;284:1781–1789. doi: 10.1074/jbc.M807312200. PubMed DOI

Knapp O., Maier E., Polleichtner G., Masin J., Sebo P., Benz R. Channel formation in model membranes by the adenylate cyclase toxin of Bordetella pertussis: Effect of calcium. Biochemistry. 2003;42:8077–8084. doi: 10.1021/bi034295f. PubMed DOI

Fiser R., Konopasek I. Different modes of membrane permeabilization by two RTX toxins: HlyA from Escherichia coli and CyaA from Bordetella pertussis. Biochim. Biophys. Acta. 2009;1788:1249–1254. doi: 10.1016/j.bbamem.2009.03.019. PubMed DOI

Martin C., Requero M.A., Masin J., Konopasek I., Goni F.M., Sebo P., Ostolaza H. Membrane restructuring by Bordetella pertussis adenylate cyclase toxin, a member of the RTX toxin family. J. Bacteriol. 2004;186:3760–3765. doi: 10.1128/JB.186.12.3760-3765.2004. PubMed DOI PMC

Knapp O., Maier E., Masin J., Sebo P., Benz R. Pore formation by the Bordetella adenylate cyclase toxin in lipid bilayer membranes: Role of voltage and pH. Biochim. Biophys. Acta. 2008;1778:260–269. doi: 10.1016/j.bbamem.2007.09.026. PubMed DOI

Barry E.M., Weiss A.A., Ehrmann I.E., Gray M.C., Hewlett E.L., Goodwin M.S. Bordetella pertussis adenylate cyclase toxin and hemolytic activities require a second gene, cyaC, for activation. J. Bacteriol. 1991;173:720–726. doi: 10.1128/jb.173.2.720-726.1991. PubMed DOI PMC

Sebo P., Glaser P., Sakamoto H., Ullmann A. High-level synthesis of active adenylate cyclase toxin of Bordetella pertussis in a reconstructed Escherichia coli system. Gene. 1991;104:19–24. doi: 10.1016/0378-1119(91)90459-O. PubMed DOI

Havlicek V., Higgins L., Chen W., Halada P., Sebo P., Sakamoto H., Hackett M. Mass spectrometric analysis of recombinant adenylate cyclase toxin from Bordetella pertussis strain 18323/pHSP9. J. Mass Spectrom. JMS. 2001;36:384–391. doi: 10.1002/jms.139. PubMed DOI

Basar T., Havlicek V., Bezouskova S., Halada P., Hackett M., Sebo P. The conserved lysine 860 in the additional fatty-acylation site of Bordetella pertussis adenylate cyclase is crucial for toxin function independently of its acylation status. J. Biol. Chem. 1999;274:10777–10783. doi: 10.1074/jbc.274.16.10777. PubMed DOI

Masin J., Basler M., Knapp O., El-Azami-El-Idrissi M., Maier E., Konopasek I., Benz R., Leclerc C., Sebo P. Acylation of lysine 860 allows tight binding and cytotoxicity of Bordetella adenylate cyclase on CD11b-expressing cells. Biochemistry. 2005;44:12759–12766. doi: 10.1021/bi050459b. PubMed DOI

Basar T., Havlicek V., Bezouskova S., Hackett M., Sebo P. Acylation of lysine 983 is sufficient for toxin activity of Bordetella pertussis adenylate cyclase. Substitutions of alanine 140 modulate acylation site selectivity of the toxin acyltransferase CyaC. J. Biol. Chem. 2001;276:348–354. doi: 10.1074/jbc.M006463200. PubMed DOI

Baumann U. Crystal structure of the 50 kda metallo protease from Serratia marcescens. J. Mol. Biol. 1994;242:244–251. doi: 10.1006/jmbi.1994.1576. PubMed DOI

Baumann U., Wu S., Flaherty K.M., McKay D.B. Three-dimensional structure of the alkaline protease of Pseudomonas aeruginosa: A two-domain protein with a calcium binding parallel beta roll motif. EMBO J. 1993;12:3357–3364. PubMed PMC

Meier R., Drepper T., Svensson V., Jaeger K.E., Baumann U. A calcium-gated lid and a large beta-roll sandwich are revealed by the crystal structure of extracellular lipase from Serratia marcescens. J. Biol. Chem. 2007;282:31477–31483. doi: 10.1074/jbc.M704942200. PubMed DOI

Cannella S.E., Ntsogo Enguene V.Y., Davi M., Malosse C., Sotomayor Perez A.C., Chamot-Rooke J., Vachette P., Durand D., Ladant D., Chenal A. Stability, structural and functional properties of a monomeric, calcium-loaded adenylate cyclase toxin, CyaA, from Bordetella pertussis. Sci. Rep. 2017;7:42065. doi: 10.1038/srep42065. PubMed DOI PMC

El-Azami-El-Idrissi M., Bauche C., Loucka J., Osicka R., Sebo P., Ladant D., Leclerc C. Interaction of Bordetella pertussis adenylate cyclase with CD11b/CD18: Role of toxin acylation and identification of the main integrin interaction domain. J. Biol. Chem. 2003;278:38514–38521. doi: 10.1074/jbc.M304387200. PubMed DOI

Wang X., Stapleton J.A., Klesmith J.R., Hewlett E.L., Whitehead T.A., Maynard J.A. Fine epitope mapping of two antibodies neutralizing the Bordetella adenylate cyclase toxin. Biochemistry. 2017;56:1324–1336. doi: 10.1021/acs.biochem.6b01163. PubMed DOI PMC

Masure H.R., Au D.C., Gross M.K., Donovan M.G., Storm D.R. Secretion of the Bordetella pertussis adenylate cyclase from Escherichia coli containing the hemolysin operon. Biochemistry. 1990;29:140–145. doi: 10.1021/bi00453a017. PubMed DOI

Holland I.B., Peherstorfer S., Kanonenberg K., Lenders M., Reimann S., Schmitt L. Type I protein secretion-deceptively simple yet with a wide range of mechanistic variability across the family. EcoSal Plus. 2016;7 doi: 10.1128/ecosalplus.ESP-0019-2015. PubMed DOI

Thomas S., Holland I.B., Schmitt L. The type 1 secretion pathway—The hemolysin system and beyond. Biochim. Biophys. Acta. 2014;1843:1629–1641. doi: 10.1016/j.bbamcr.2013.09.017. PubMed DOI

O’Brien D.P., Hernandez B., Durand D., Hourdel V., Sotomayor-Perez A.C., Vachette P., Ghomi M., Chamot-Rooke J., Ladant D., Brier S., et al. Structural models of intrinsically disordered and calcium-bound folded states of a protein adapted for secretion. Sci. Rep. 2015;5:14223. doi: 10.1038/srep14223. PubMed DOI PMC

Sotomayor-Perez A.C., Ladant D., Chenal A. Disorder-to-order transition in the CyaA toxin RTX domain: Implications for toxin secretion. Toxins. 2014;7:1–20. doi: 10.3390/toxins7010001. PubMed DOI PMC

Szilvay G.R., Blenner M.A., Shur O., Cropek D.M., Banta S. A fret-based method for probing the conformational behavior of an intrinsically disordered repeat domain from Bordetella pertussis adenylate cyclase. Biochemistry. 2009;48:11273–11282. doi: 10.1021/bi901447j. PubMed DOI

Lenders M.H., Weidtkamp-Peters S., Kleinschrodt D., Jaeger K.E., Smits S.H., Schmitt L. Directionality of substrate translocation of the hemolysin A type I secretion system. Sci. Rep. 2015;5:12470. doi: 10.1038/srep12470. PubMed DOI PMC

Gray M.C., Ross W., Kim K., Hewlett E.L. Characterization of binding of adenylate cyclase toxin to target cells by flow cytometry. Infect. Immun. 1999;67:4393–4399. PubMed PMC

Hanski E. Invasive adenylate cyclase toxin of Bordetella pertussis. Trends Biochem. Sci. 1989;14:459–463. doi: 10.1016/0968-0004(89)90106-0. PubMed DOI

Vojtova J., Kofronova O., Sebo P., Benada O. Bordetella adenylate cyclase toxin induces a cascade of morphological changes of sheep erythrocytes and localizes into clusters in erythrocyte membranes. Microsc. Res. Tech. 2006;69:119–129. doi: 10.1002/jemt.20277. PubMed DOI

Pearson R.D., Symes P., Conboy M., Weiss A.A., Hewlett E.L. Inhibition of monocyte oxidative responses by Bordetella pertussis adenylate cyclase toxin. J. Immunol. 1987;139:2749–2754. PubMed

Gueirard P., Druilhe A., Pretolani M., Guiso N. Role of adenylate cyclase-hemolysin in alveolar macrophage apoptosis during Bordetella pertussis infection in vivo. Infect. Immun. 1998;66:1718–1725. PubMed PMC

Harvill E.T., Cotter P.A., Yuk M.H., Miller J.F. Probing the function of Bordetella bronchiseptica adenylate cyclase toxin by manipulating host immunity. Infect. Immun. 1999;67:1493–1500. PubMed PMC

Ambagala T.C., Ambagala A.P., Srikumaran S. The leukotoxin of Pasteurella haemolytica binds to beta(2) integrins on bovine leukocytes. FEMS Microbiol. Lett. 1999;179:161–167. PubMed

Jeyaseelan S., Hsuan S.L., Kannan M.S., Walcheck B., Wang J.F., Kehrli M.E., Lally E.T., Sieck G.C., Maheswaran S.K. Lymphocyte function-associated antigen 1 is a receptor for Pasteurella haemolytica leukotoxin in bovine leukocytes. Infect. Immun. 2000;68:72–79. doi: 10.1128/IAI.68.1.72-79.2000. PubMed DOI PMC

Lally E.T., Kieba I.R., Sato A., Green C.L., Rosenbloom J., Korostoff J., Wang J.F., Shenker B.J., Ortlepp S., Robinson M.K., et al. RTX toxins recognize a beta2 integrin on the surface of human target cells. J. Biol. Chem. 1997;272:30463–30469. doi: 10.1074/jbc.272.48.30463. PubMed DOI

Li J., Clinkenbeard K.D., Ritchey J.W. Bovine CD18 identified as a species specific receptor for Pasteurella haemolytica leukotoxin. Vet. Microbiol. 1999;67:91–97. doi: 10.1016/S0378-1135(99)00040-1. PubMed DOI

Arnaout M.A. Structure and function of the leukocyte adhesion molecules CD11/CD18. Blood. 1990;75:1037–1050. PubMed

Mazzone A., Ricevuti G. Leukocyte CD11/CD18 integrins: Biological and clinical relevance. Haematologica. 1995;80:161–175. PubMed

Eby J.C., Gray M.C., Warfel J.M., Paddock C.D., Jones T.F., Day S.R., Bowden J., Poulter M.D., Donato G.M., Merkel T.J., et al. Quantification of the adenylate cyclase toxin of Bordetella pertussis in vitro and during respiratory infection. Infect. Immun. 2013;81:1390–1398. doi: 10.1128/IAI.00110-13. PubMed DOI PMC

Ahmad J.N., 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. 2016;18:384–398. doi: 10.1111/cmi.12519. PubMed DOI

Corbi A.L., Kishimoto T.K., Miller L.J., Springer T.A. The human leukocyte adhesion glycoprotein Mac-1 (complement receptor type 3, CD11b) alpha subunit. Cloning, primary structure, and relation to the integrins, von Willebrand factor and factor B. J. Biol. Chem. 1988;263:12403–12411. PubMed

Hickstein D.D., Hickey M.J., Ozols J., Baker D.M., Back A.L., Roth G.J. cDNA sequence for the alpha M subunit of the human neutrophil adherence receptor indicates homology to integrin alpha subunits. Proc. Natl. Acad. Sci. USA. 1989;86:257–261. doi: 10.1073/pnas.86.1.257. PubMed DOI PMC

Diamond M.S., Garcia-Aguilar J., Bickford J.K., Corbi A.L., Springer T.A. The I domain is a major recognition site on the leukocyte integrin Mac-1 (CD11b/CD18) for four distinct adhesion ligands. J. Cell Biol. 1993;120:1031–1043. doi: 10.1083/jcb.120.4.1031. PubMed DOI PMC

Oxvig C., Springer T.A. Experimental support for a beta-propeller domain in integrin alpha-subunits and a calcium binding site on its lower surface. Proc. Natl. Acad. Sci. USA. 1998;95:4870–4875. doi: 10.1073/pnas.95.9.4870. PubMed DOI PMC

Lee J.O., Rieu P., Arnaout M.A., Liddington R. Crystal structure of the A domain from the alpha subunit of integrin CR3 (CD11b/CD18) Cell. 1995;80:631–638. doi: 10.1016/0092-8674(95)90517-0. PubMed DOI

Michishita M., Videm V., Arnaout M.A. A novel divalent cation-binding site in the a domain of the beta 2 integrin cr3 (cd11b/cd18) is essential for ligand binding. Cell. 1993;72:857–867. doi: 10.1016/0092-8674(93)90575-B. PubMed DOI

Gahmberg C.G., Tolvanen M., Kotovuori P. Leukocyte adhesion-structure and function of human leukocyte beta2-integrins and their cellular ligands. Eur. J. Biochem. 1997;245:215–232. doi: 10.1111/j.1432-1033.1997.00215.x. PubMed DOI

Hasan S., Osickova A., Bumba L., Novak P., Sebo P., Osicka R. Interaction of Bordetella adenylate cyclase toxin with complement receptor 3 involves multivalent glycan binding. FEBS Lett. 2015;589:374–379. doi: 10.1016/j.febslet.2014.12.023. PubMed DOI

Asada M., Furukawa K., Kantor C., Gahmberg C.G., Kobata A. Structural study of the sugar chains of human leukocyte cell adhesion molecules CD11/CD18. Biochemistry. 1991;30:1561–1571. doi: 10.1021/bi00220a017. PubMed DOI

Morova J., Osicka R., Masin J., Sebo P. RTX cytotoxins recognize beta2 integrin receptors through N-linked oligosaccharides. Proc. Natl. Acad. Sci. USA. 2008;105:5355–5360. doi: 10.1073/pnas.0711400105. PubMed DOI PMC

Hirai M., Iwase H., Hayakawa T., Koizumi M., Takahashi H. Determination of asymmetric structure of ganglioside-DPPC mixed vesicle using SANS, SAXS, and DLS. Biophys. J. 2003;85:1600–1610. doi: 10.1016/S0006-3495(03)74591-3. PubMed DOI PMC

Wald T., Osickova A., Masin J., Liskova P.M., Petry-Podgorska I., Matousek T., Sebo P., Osicka R. Transmembrane segments of complement receptor 3 do not participate in cytotoxic activities but determine receptor structure required for action of Bordetella adenylate cyclase toxin. Pathog. Dis. 2016;74 doi: 10.1093/femspd/ftw008. PubMed DOI

Veneziano R., Rossi C., Chenal A., Devoisselle J.M., Ladant D., Chopineau J. Bordetella pertussis adenylate cyclase toxin translocation across a tethered lipid bilayer. Proc. Natl. Acad. Sci. USA. 2013;110:20473–20478. doi: 10.1073/pnas.1312975110. PubMed DOI PMC

Powthongchin B., Angsuthanasombat C. Effects on haemolytic activity of single proline substitutions in the Bordetella pertussis CyaA pore-forming fragment. Arch. Microbiol. 2009;191:1–9. doi: 10.1007/s00203-008-0421-3. PubMed DOI

Betsou F., Sebo P., Guiso N. CyaC-mediated activation is important not only for toxic but also for protective activities of Bordetella pertussis adenylate cyclase-hemolysin. Infect. Immun. 1993;61:3583–3589. PubMed PMC

Vojtova-Vodolanova J., Basler M., Osicka R., Knapp O., Maier E., Cerny J., Benada O., Benz R., Sebo P. Oligomerization is involved in pore formation by Bordetella adenylate cyclase toxin. FASEB J. 2009;23:2831–2843. doi: 10.1096/fj.09-131250. PubMed DOI

Bejerano M., Nisan I., Ludwig A., Goebel W., Hanski E. Characterization of the C-terminal domain essential for toxic activity of adenylate cyclase toxin. Mol. Microbiol. 1999;31:381–392. doi: 10.1046/j.1365-2958.1999.01183.x. PubMed DOI

Kurehong C., Powthongchin B., Thamwiriyasati N., Angsuthanasombat C. Functional significance of the highly conserved Glu(570) in the putative pore-forming helix 3 of the Bordetella pertussis haemolysin toxin. Toxicon. 2011;57:897–903. doi: 10.1016/j.toxicon.2011.03.010. PubMed DOI

Anthis N.J., Campbell I.D. The tail of integrin activation. Trends Biochem. Sci. 2011;36:191–198. doi: 10.1016/j.tibs.2010.11.002. PubMed DOI PMC

Tan S.M. The leucocyte beta2 (CD18) integrins: The structure, functional regulation and signalling properties. Biosci. Rep. 2012;32:241–269. doi: 10.1042/BSR20110101. PubMed DOI

Kinashi T. Adhere upright: A switchblade-like extension of beta2 integrins. Immunity. 2006;25:521–522. doi: 10.1016/j.immuni.2006.09.002. PubMed DOI

Luo B.H., Springer T.A. Integrin structures and conformational signaling. Curr. Opin. Cell Biol. 2006;18:579–586. doi: 10.1016/j.ceb.2006.08.005. PubMed DOI PMC

Yalamanchili P., Lu C., Oxvig C., Springer T.A. Folding and function of I domain-deleted Mac-1 and lymphocyte function-associated antigen-1. J. Biol. Chem. 2000;275:21877–21882. doi: 10.1074/jbc.M908868199. PubMed DOI

Jakus Z., Fodor S., Abram C.L., Lowell C.A., Mocsai A. Immunoreceptor-like signaling by beta 2 and beta 3 integrins. Trends Cell Biol. 2007;17:493–501. doi: 10.1016/j.tcb.2007.09.001. PubMed DOI

Mocsai A., Zhou M., Meng F., Tybulewicz V.L., Lowell C.A. Syk is required for integrin signaling in neutrophils. Immunity. 2002;16:547–558. doi: 10.1016/S1074-7613(02)00303-5. PubMed DOI

Mocsai A., Abram C.L., Jakus Z., Hu Y., Lanier L.L., Lowell C.A. Integrin signaling in neutrophils and macrophages uses adaptors containing immunoreceptor tyrosine-based activation motifs. Nat. Immunol. 2006;7:1326–1333. doi: 10.1038/ni1407. PubMed DOI PMC

Mocsai A., Ruland J., Tybulewicz V.L. The Syk tyrosine kinase: A crucial player in diverse biological functions. Nat. Rev. Immunol. 2010;10:387–402. doi: 10.1038/nri2765. PubMed DOI PMC

Schymeinsky J., Mocsai A., Walzog B. Neutrophil activation via beta2 integrins (CD11/CD18): Molecular mechanisms and clinical implications. Thromb. Haemost. 2007;98:262–273. PubMed

Crowley M.T., Costello P.S., Fitzer-Attas C.J., Turner M., Meng F., Lowell C., Tybulewicz V.L., DeFranco A.L. A critical role for Syk in signal transduction and phagocytosis mediated by Fcgamma receptors on macrophages. J. Exp. Med. 1997;186:1027–1039. doi: 10.1084/jem.186.7.1027. PubMed DOI PMC

Kiefer F., Brumell J., Al-Alawi N., Latour S., Cheng A., Veillette A., Grinstein S., Pawson T. The Syk protein tyrosine kinase is essential for Fcgamma receptor signaling in macrophages and neutrophils. Mol. Cell Biol. 1998;18:4209–4220. doi: 10.1128/MCB.18.7.4209. PubMed DOI PMC

Shi Y., Tohyama Y., Kadono T., He J., Miah S.M., Hazama R., Tanaka C., Tohyama K., Yamamura H. Protein-tyrosine kinase Syk is required for pathogen engulfment in complement-mediated phagocytosis. Blood. 2006;107:4554–4562. doi: 10.1182/blood-2005-09-3616. PubMed DOI

Caron E., Hall A. Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases. Science. 1998;282:1717–1721. doi: 10.1126/science.282.5394.1717. PubMed DOI

Lenz D.H., Weingart C.L., Weiss A.A. Phagocytosed Bordetella pertussis fails to survive in human neutrophils. Infect. Immun. 2000;68:956–959. doi: 10.1128/IAI.68.2.956-959.2000. PubMed DOI PMC

Willeke T., Schymeinsky J., Prange P., Zahler S., Walzog B. A role for Syk-kinase in the control of the binding cycle of the beta2 integrins (CD11/CD18) in human polymorphonuclear neutrophils. J. Leukoc. Biol. 2003;74:260–269. doi: 10.1189/jlb.0102016. PubMed DOI

Gevrey J.C., Isaac B.M., Cox D. Syk is required for monocyte/macrophage chemotaxis to CX3CL1 (fractalkine) J. Immunol. 2005;175:3737–3745. doi: 10.4049/jimmunol.175.6.3737. PubMed DOI

Forsberg M., Lofgren R., Zheng L., Stendahl O. Tumour necrosis factor-alpha potentiates CR3-induced respiratory burst by activating p38 MAP kinase in human neutrophils. Immunology. 2001;103:465–472. doi: 10.1046/j.1365-2567.2001.01270.x. PubMed DOI PMC

Van Ziffle J.A., Lowell C.A. Neutrophil-specific deletion of Syk kinase results in reduced host defense to bacterial infection. Blood. 2009;114:4871–4882. doi: 10.1182/blood-2009-05-220806. PubMed DOI PMC

Friedman R.L., Fiederlein R.L., Glasser L., Galgiani J.N. Bordetella pertussis adenylate cyclase: Effects of affinity-purified adenylate cyclase on human polymorphonuclear leukocyte functions. Infect. Immun. 1987;55:135–140. PubMed PMC

Eby J.C., Gray M.C., Hewlett E.L. Cyclic AMP-mediated suppression of neutrophil extracellular trap formation and apoptosis by the Bordetella pertussis adenylate cyclase toxin. Infect. Immun. 2014;82:5256–5269. doi: 10.1128/IAI.02487-14. PubMed DOI PMC

Guth A.M., Janssen W.J., Bosio C.M., Crouch E.C., Henson P.M., Dow S.W. Lung environment determines unique phenotype of alveolar macrophages. Am. J. Physiol. Lung Cell. Mol. Physiol. 2009;296:L936–L946. doi: 10.1152/ajplung.90625.2008. PubMed DOI PMC

Gordon S. Alternative activation of macrophages. Nat. Rev. Immunol. 2003;3:23–35. doi: 10.1038/nri978. PubMed DOI

Pinilla-Vera M., Xiong Z., Zhao Y., Zhao J., Donahoe M.P., Barge S., Horne W.T., Kolls J.K., McVerry B.J., Birukova A., et al. Full spectrum of LPS activation in alveolar macrophages of healthy volunteers by whole transcriptomic profiling. PLoS ONE. 2016;11:e0159329. doi: 10.1371/journal.pone.0159329. PubMed DOI PMC

Craig A., Mai J., Cai S., Jeyaseelan S. Neutrophil recruitment to the lungs during bacterial pneumonia. Infect. Immun. 2009;77:568–575. doi: 10.1128/IAI.00832-08. PubMed DOI PMC

Skopova K., Tomalova B., Kanchev I., Rossmann P., Svedova M., Adkins I., Bibova I., Tomala J., Masin J., Guiso N., et al. Cyclic AMP-elevating capacity of adenylate cyclase toxin-hemolysin is sufficient for lung infection but not for full virulence of Bordetella pertussis. Infect. Immun. 2017;85 doi: 10.1128/IAI.00937-16. PubMed DOI PMC

Friedman R.L., Nordensson K., Wilson L., Akporiaye E.T., Yocum D.E. Uptake and intracellular survival of Bordetella pertussis in human macrophages. Infect. Immun. 1992;60:4578–4585. PubMed PMC

Valdez H.A., Oviedo J.M., Gorgojo J.P., Lamberti Y., Rodriguez M.E. Bordetella pertussis modulates human macrophage defense gene expression. Pathog. Dis. 2016;74 doi: 10.1093/femspd/ftw073. PubMed DOI

Cheung G.Y., Dickinson P., Sing G., Craigon M., Ghazal P., Parton R., Coote J.G. Transcriptional responses of murine macrophages to the adenylate cyclase toxin of Bordetella pertussis. Microb. Pathog. 2008;44:61–70. doi: 10.1016/j.micpath.2007.08.007. PubMed DOI

Gray M.C., Hewlett E.L. Cell cycle arrest induced by the bacterial adenylate cyclase toxins from Bacillus anthracis and Bordetella pertussis. Cell. Microbiol. 2011;13:123–134. doi: 10.1111/j.1462-5822.2010.01525.x. PubMed DOI PMC

Lee S.W., Park H.J., Jeon S.H., Lee C., Seong R.H., Park S.H., Hong S. Ubiquitous over-expression of chromatin remodeling factor SRG3 ameliorates the T cell-mediated exacerbation of EAE by modulating the phenotypes of both dendritic cells and macrophages. PLoS ONE. 2015;10:e0132329. doi: 10.1371/journal.pone.0132329. PubMed DOI PMC

Sica A., Mantovani A. Macrophage plasticity and polarization: In vivo veritas. J. Clin. Investig. 2012;122:787–795. doi: 10.1172/JCI59643. PubMed DOI PMC

Novak J., Fabrik I., Linhartova I., Link M., Cerny O., Stulik J., Sebo P. Phosphoproteomics of cAMP signaling of Bordetella adenylate cyclase toxin in mouse dendritic cells. Sci. Rep. under revision. PubMed PMC

Yong Kim S., Jeong S., Chah K.H., Jung E., Baek K.H., Kim S.T., Shim J.H., Chun E., Lee K.Y. Salt-inducible kinases 1 and 3 negatively regulate Toll-like receptor 4-mediated signal. Mol. Endocrinol. 2013;27:1958–1968. doi: 10.1210/me.2013-1240. PubMed DOI PMC

Clark K., MacKenzie K.F., Petkevicius K., Kristariyanto Y., Zhang J., Choi H.G., Peggie M., Plater L., Pedrioli P.G., McIver E., et al. Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages. Proc. Natl. Acad. Sci. USA. 2012;109:16986–16991. doi: 10.1073/pnas.1215450109. PubMed DOI PMC

MacKenzie K.F., Clark K., Naqvi S., McGuire V.A., Nöehren G., Kristariyanto Y., van den Bosch M., Mudaliar M., McCarthy P.C., Pattison M.J., et al. PGE(2) induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway. J. Immunol. 2013;190:565–577. doi: 10.4049/jimmunol.1202462. PubMed DOI PMC

Khelef N., Zychlinsky A., Guiso N. Bordetella pertussis induces apoptosis in macrophages: Role of adenylate cyclase-hemolysin. Infect. Immun. 1993;61:4064–4071. PubMed PMC

Moujalled D., Weston R., Anderton H., Ninnis R., Goel P., Coley A., Huang D.C., Wu L., Strasser A., Puthalakath H. Cyclic-AMP-dependent protein kinase A regulates apoptosis by stabilizing the BH3-only protein Bim. EMBO Rep. 2011;12:77–83. doi: 10.1038/embor.2010.190. PubMed DOI PMC

Palen D.I., Belmadani S., Lucchesi P.A., Matrougui K. Role of SHP-1, Kv.1.2, and cGMP in nitric oxide-induced ERK1/2 map kinase dephosphorylation in rat vascular smooth muscle cells. Cardiovasc. Res. 2005;68:268–277. doi: 10.1016/j.cardiores.2005.05.031. PubMed DOI

Ley R., Ewings K.E., Hadfield K., Howes E., Balmanno K., Cook S.J. Extracellular signal-regulated kinases 1/2 are serum-stimulated “Bim(EL) kinases” that bind to the BH3-only protein Bim(EL) causing its phosphorylation and turnover. J. Biol. Chem. 2004;279:8837–8847. doi: 10.1074/jbc.M311578200. PubMed DOI

Van Haarst J.M., de Wit H.J., Drexhage H.A., Hoogsteden H.C. Distribution and immunophenotype of mononuclear phagocytes and dendritic cells in the human lung. Am. J. Respir. Cell Mol. Biol. 1994;10:487–492. doi: 10.1165/ajrcmb.10.5.8179911. PubMed DOI

Baharom F., Rankin G., Blomberg A., Smed-Sorensen A. Human lung mononuclear phagocytes in health and disease. Front. Immunol. 2017;8:499. doi: 10.3389/fimmu.2017.00499. PubMed DOI PMC

Guilliams M., Lambrecht B.N., Hammad H. Division of labor between lung dendritic cells and macrophages in the defense against pulmonary infections. Mucosal Immunol. 2013;6:464–473. doi: 10.1038/mi.2013.14. PubMed DOI

Tee A.R., Fingar D.C., Manning B.D., Kwiatkowski D.J., Cantley L.C., Blenis J. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc. Natl. Acad. Sci. USA. 2002;99:13571–13576. doi: 10.1073/pnas.202476899. PubMed DOI PMC

Sancak Y., Thoreen C.C., Peterson T.R., Lindquist R.A., Kang S.A., Spooner E., Carr S.A., Sabatini D.M. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell. 2007;25:903–915. doi: 10.1016/j.molcel.2007.03.003. PubMed DOI

Gingras A.C., Gygi S.P., Raught B., Polakiewicz R.D., Abraham R.T., Hoekstra M.F., Aebersold R., Sonenberg N. Regulation of 4E-BP1 phosphorylation: A novel two-step mechanism. Genes Dev. 1999;13:1422–1437. doi: 10.1101/gad.13.11.1422. PubMed DOI PMC

Schmitz F., Heit A., Dreher S., Eisenächer K., Mages J., Haas T., Krug A., Janssen K.P., Kirschning C.J., Wagner H. Mammalian target of rapamycin (mTOR) orchestrates the defense program of innate immune cells. Eur. J. Immunol. 2008;38:2981–2992. doi: 10.1002/eji.200838761. PubMed DOI

Weichhart T., Costantino G., Poglitsch M., Rosner M., Zeyda M., Stuhlmeier K.M., Kolbe T., Stulnig T.M., Hörl W.H., Hengstschläger M., et al. The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity. 2008;29:565–577. doi: 10.1016/j.immuni.2008.08.012. PubMed DOI

Thomson A.W., Turnquist H.R., Raimondi G. Immunoregulatory functions of mTOR inhibition. Nat. Rev. Immunol. 2009;9:324–337. doi: 10.1038/nri2546. PubMed DOI PMC

Perkins D.J., Gray M.C., Hewlett E.L., Vogel S.N. Bordetella pertussis adenylate cyclase toxin (ACT) induces cyclooxygenase-2 (COX-2) in murine macrophages and is facilitated by act interaction with CD11b/CD18 (Mac-1) Mol. Microbiol. 2007;66:1003–1015. doi: 10.1111/j.1365-2958.2007.05972.x. PubMed DOI

Kreisel D., Nava R.G., Li W., Zinselmeyer B.H., Wang B., Lai J., Pless R., Gelman A.E., Krupnick A.S., Miller M.J. In Vivo two-photon imaging reveals monocyte-dependent neutrophil extravasation during pulmonary inflammation. Proc. Natl. Acad. Sci. USA. 2010;107:18073–18078. doi: 10.1073/pnas.1008737107. PubMed DOI PMC

Pechous R.D. With friends like these: The complex role of neutrophils in the progression of severe pneumonia. Front. Cell. Infect. Microbiol. 2017;7:160. doi: 10.3389/fcimb.2017.00160. PubMed DOI PMC

Eby J.C., Hoffman C.L., Gonyar L.A., Hewlett E.L. Review of the neutrophil response to Bordetella pertussis infection. Pathog. Dis. 2015;73:ftv081. doi: 10.1093/femspd/ftv081. PubMed DOI PMC

Weingart C.L., Mobberley-Schuman P.S., Hewlett E.L., Gray M.C., Weiss A.A. Neutralizing antibodies to adenylate cyclase toxin promote phagocytosis of Bordetella pertussis by human neutrophils. Infect. Immun. 2000;68:7152–7155. doi: 10.1128/IAI.68.12.7152-7155.2000. PubMed DOI PMC

Weingart C.L., Weiss A.A. Bordetella pertussis virulence factors affect phagocytosis by human neutrophils. Infect. Immun. 2000;68:1735–1739. doi: 10.1128/IAI.68.3.1735-1739.2000. PubMed DOI PMC

Mobberley-Schuman P.S., Connelly B., Weiss A.A. Phagocytosis of Bordetella pertussis incubated with convalescent serum. J. Infect. Dis. 2003;187:1646–1653. doi: 10.1086/374741. PubMed DOI

Goodwin M.S., Weiss A.A. Adenylate cyclase toxin is critical for colonization and pertussis toxin is critical for lethal infection by Bordetella pertussis in infant mice. Infect. Immun. 1990;58:3445–3447. PubMed PMC

Gross M.K., Au D.C., Smith A.L., Storm D.R. Targeted mutations that ablate either the adenylate cyclase or hemolysin function of the bifunctional cyaa toxin of Bordetella pertussis abolish virulence. Proc. Natl. Acad. Sci. USA. 1992;89:4898–4902. doi: 10.1073/pnas.89.11.4898. PubMed DOI PMC

Guiso N., Rocancourt M., Szatanik M., Alonso J.M. Bordetella adenylate cyclase is a virulence associated factor and an immunoprotective antigen. Microb. Pathog. 1989;7:373–380. doi: 10.1016/0882-4010(89)90040-5. PubMed DOI

Guiso N., Szatanik M., Rocancourt M. Protective activity of Bordetella adenylate cyclase-hemolysin against bacterial colonization. Microb. Pathog. 1991;11:423–431. doi: 10.1016/0882-4010(91)90038-C. PubMed DOI

Weiss A.A., Hewlett E.L., Myers G.A., Falkow S. Tn5-induced mutations affecting virulence factors of Bordetella pertussis. Infect. Immun. 1983;42:33–41. PubMed PMC

Chenal-Francisque V., Caro V., Boursaux-Eude C., Guiso N. Genomic analysis of the adenylate cyclase-hemolysin C-terminal region of Bordetella pertussis, Bordetella parapertussis and Bordetella bronchiseptica. Res. Microbiol. 2009;160:330–336. doi: 10.1016/j.resmic.2009.03.006. PubMed DOI

Bart M.J., Harris S.R., Advani A., Arakawa Y., Bottero D., Bouchez V., Cassiday P.K., Chiang C.S., Dalby T., Fry N.K., et al. Global population structure and evolution of Bordetella pertussis and their relationship with vaccination. mBio. 2014;5:e01074. doi: 10.1128/mBio.01074-14. PubMed DOI PMC

Khelef N., Bachelet C.M., Vargaftig B.B., Guiso N. Characterization of murine lung inflammation after infection with parental Bordetella pertussis and mutants deficient in adhesins or toxins. Infect. Immun. 1994;62:2893–2900. PubMed PMC

Khelef N., Sakamoto H., Guiso N. Both adenylate cyclase and hemolytic activities are required by Bordetella pertussis to initiate infection. Microb. Pathog. 1992;12:227–235. doi: 10.1016/0882-4010(92)90057-U. PubMed DOI

Andreasen C., Carbonetti N.H. Role of neutrophils in response to Bordetella pertussis infection in mice. Infect. Immun. 2009;77:1182–1188. doi: 10.1128/IAI.01150-08. PubMed DOI PMC

Gorgojo J., Scharrig E., Gomez R.M., Harvill E.T., Rodriguez M.E. Bordetella parapertussis circumvents neutrophil extracellular bactericidal mechanisms. PLoS ONE. 2017;12:e0169936. doi: 10.1371/journal.pone.0169936. PubMed DOI PMC

Avirulent phenotype promotes Bordetella pertussis adaptation to the intramacrophage environment

The adenylate cyclase toxin RTX domain follows a series templated folding mechanism with implications for toxin activity

A conserved tryptophan in the acylated segment of RTX toxins controls their β2 integrin-independent cell penetration

Filamentous Hemagglutinin of Bordetella pertussis Does Not Interact with the β2 Integrin CD11b/CD18

Pertussis toxin suppresses dendritic cell-mediated delivery of B. pertussis into lung-draining lymph nodes

The Fim and FhaB adhesins play a crucial role in nasal cavity infection and Bordetella pertussis transmission in a novel mouse catarrhal infection model

Kingella kingae RtxA Cytotoxin in the Context of Other RTX Toxins

Selective Enhancement of the Cell-Permeabilizing Activity of Adenylate Cyclase Toxin Does Not Increase Virulence of Bordetella pertussis

Different roles of conserved tyrosine residues of the acylated domains in folding and activity of RTX toxins

Bordetella Adenylate Cyclase Toxin Elicits Airway Mucin Secretion through Activation of the cAMP Response Element Binding Protein

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

Adenylate Cyclase Toxin Tinkering With Monocyte-Macrophage Differentiation

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

Distinct Spatiotemporal Distribution of Bacterial Toxin-Produced Cellular cAMP Differentially Inhibits Opsonophagocytic Signaling

Rapid Purification of Endotoxin-Free RTX Toxins

Residues 529 to 549 participate in membrane penetration and pore-forming activity of the Bordetella adenylate cyclase toxin

Cytotoxic activity of Kingella kingae RtxA toxin depends on post-translational acylation of lysine residues and cholesterol binding

Bordetella Pertussis Adenylate Cyclase Toxin Does Not Possess a Phospholipase A Activity; Serine 606 and Aspartate 1079 Residues Are Not Involved in Target Cell Delivery of the Adenylyl Cyclase Enzyme Domain