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.

Laboratory of Molecular Biology of Bacterial Pathogens Institute of Microbiology of the CAS Prague Czechia

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Finlay BB, Mcfadden G. Anti-immunology: evasion of the host immune system by bacterial and viral pathogens. Cell. (2006) 124:767–82. 10.1016/j.cell.2006.01.034 PubMed DOI

Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol. (2011) 11:762–74. 10.1038/nri3070 PubMed DOI PMC

Randolph GJ, Beaulieu S, Lebecque S, Steinman RM, Muller WA. Differentiation of monocytes into dendritic cells in a model of transendothelial trafficking. Science. (1998) 282:480–3. 10.1126/science.282.5388.480 PubMed DOI

Randolph GJ, Inaba K, Robbiani DF, Steinman RM, Muller WA. Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo. Immunity. (1999) 11:753–61. 10.1016/S1074-7613(00)80149-1 PubMed DOI

Varol C, Landsman L, Fogg DK, Greenshtein L, Gildor B, Margalit R, et al. . Monocytes give rise to mucosal, but not splenic, conventional dendritic cells. J Exp Med. (2007) 204:171–80. 10.1084/jem.20061011 PubMed DOI PMC

Jakubzick CV, Randolph GJ, Henson PM. Monocyte differentiation and antigen-presenting functions. Nat Rev Immunol. (2017) 17:349–62. 10.1038/nri.2017.28 PubMed DOI

Tagliani E, Shi C, Nancy P, Tay CS, Pamer EG, Erlebacher A. Coordinate regulation of tissue macrophage and dendritic cell population dynamics by CSF-1. J Exp Med. (2011) 208:1901–16. 10.1084/jem.20110866 PubMed DOI PMC

Bain CC, Hawley CA, Garner H, Scott CL, Schridde A, Steers NJ, et al. . Long-lived self-renewing bone marrow-derived macrophages displace embryo-derived cells to inhabit adult serous cavities. Nat Commun. (2016) 7:ncomms11852. 10.1038/ncomms11852 PubMed DOI PMC

Scott CL, Zheng F, De Baetselier P, Martens L, Saeys Y, De Prijck S, et al. . Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat Commun. (2016) 7:10321. 10.1038/ncomms10321 PubMed DOI PMC

Ginhoux F, Tacke F, Angeli V, Bogunovic M, Loubeau M, Dai XM, et al. . Langerhans cells arise from monocytes in vivo. Nat Immunol. (2006) 7:265–73. 10.1038/ni1307 PubMed DOI PMC

Elahi S, Ertelt JM, Kinder JM, Jiang TT, Zhang X, Xin L, et al. . Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection. Nature. (2013) 504:158–62. 10.1038/nature12675 PubMed DOI PMC

Mattoo S, Cherry JD. Molecular pathogenesis, epidemiology, and clinical manifestations of respiratory infections due to Bordetella pertussis and other Bordetella subspecies. Clin Microbiol Rev. (2005) 18:326–82. 10.1128/CMR.18.2.326-382.2005 PubMed DOI PMC

Yeung KHT, Duclos P, Nelson EAS, Hutubessy RCW. An update of the global burden of pertussis in children younger than 5 years: a modelling study. Lancet Infect Dis. (2017) 17:974–80. 10.1016/S1473-3099(17)30390-0 PubMed DOI

Cherry JD, Paddock CD. Pathogenesis and histopathology of pertussis: implications for immunization. Expert Rev Vaccines. (2014) 13:1115–23. 10.1586/14760584.2014.935766 PubMed DOI

Conover MS, Sloan GP, Love CF, Sukumar N, Deora R. The Bps polysaccharide of Bordetella pertussis promotes colonization and biofilm formation in the nose by functioning as an adhesin. Mol Microbiol. (2010) 77:1439–55. 10.1111/j.1365-2958.2010.07297.x PubMed DOI PMC

Melvin JA, Scheller EV, Miller JF, Cotter PA. Bordetella pertussis pathogenesis: current and future challenges. Nat Rev Microbiol. (2014) 12:274–88. 10.1038/nrmicro3235 PubMed DOI PMC

Fennelly NK, Sisti F, Higgins SC, Ross PJ, Van Der Heide H, Mooi FR, et al. . Bordetella pertussis expresses a functional type III secretion system that subverts protective innate and adaptive immune responses. Infect Immun. (2008) 76:1257–66. 10.1128/IAI.00836-07 PubMed DOI PMC

Bayram J, Malcova I, Sinkovec L, Holubova J, Streparola G, Jurnecka D, et al. . Cytotoxicity of the effector protein BteA was attenuated in Bordetella pertussis by insertion of an alanine residue. PLoS Pathog. (2020) 16:e1008512. 10.1371/journal.ppat.1008512 PubMed DOI PMC

Locht C, Coutte L, Mielcarek N. The ins and outs of pertussis toxin. FEBS J. (2011) 278:4668–82. 10.1111/j.1742-4658.2011.08237.x PubMed DOI

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

Carbonetti NH. Pertussis leukocytosis: mechanisms, clinical relevance and treatment. Pathog Dis. (2016) 74:ftw087. 10.1093/femspd/ftw087 PubMed DOI PMC

Paddock CD, Sanden GN, Cherry JD, Gal AA, Langston C, Tatti KM, et al. . Pathology and pathogenesis of fatal Bordetella pertussis infection in infants. Clin Infect Dis. (2008) 47:328–38. 10.1086/589753 PubMed DOI

Eby JC, Gray MC, Warfel JM, Paddock CD, Jones TF, Day SR, et al. . Quantification of the adenylate cyclase toxin of Bordetella pertussis in vitro and during respiratory infection. Infect Immun. (2013) 81:1390–8. 10.1128/IAI.00110-13 PubMed DOI PMC

Gonyar LA, Gray MC, Christianson GJ, Mehrad B, Hewlett EL. Albumin, in the presence of calcium, elicits a massive increase in extracellular bordetella adenylate cyclase toxin. Infect Immun. (2017) 85:e00198-17. 10.1128/IAI.00198-17 PubMed DOI PMC

Hasan S, Kulkarni NN, Asbjarnarson A, Linhartova I, Osicka R, Sebo P, et al. . Bordetella pertussis adenylate cyclase toxin disrupts functional integrity of bronchial epithelial layers. Infect Immun. (2018) 86:e00445-17. 10.1128/IAI.00445-17 PubMed DOI PMC

Guermonprez P, Khelef N, Blouin E, Rieu P, Ricciardi-Castagnoli P, Guiso N, et al. . The adenylate cyclase toxin of Bordetella pertussis binds to target cells via the alpha(M)beta(2) integrin. (CD11b/CD18). J Exp Med. (2001) 193:1035–44. 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. 10.7554/eLife.10766.034 PubMed DOI PMC

Novak J, Cerny O, Osickova A, Linhartova I, Masin J, Bumba L, et al. . Structure-function relationships underlying the capacity of bordetella adenylate cyclase toxin to disarm host phagocytes. Toxins. (2017) 9:300. 10.3390/toxins9100300 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. 10.1371/journal.ppat.1000901 PubMed DOI PMC

Confer DL, Eaton JW. Phagocyte impotence caused by an invasive bacterial adenylate cyclase. Science. (1982) 217:948–50. 10.1126/science.6287574 PubMed DOI

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

Kamanova J, Kofronova O, Masin J, Genth H, Vojtova J, Linhartova I, et al. . Adenylate cyclase toxin subverts phagocyte function by RhoA inhibition and unproductive ruffling. J Immunol. (2008) 181:5587–97. 10.4049/jimmunol.181.8.5587 PubMed DOI

Gray MC, Hewlett EL. Cell cycle arrest induced by the bacterial adenylate cyclase toxins from Bacillus anthracis and Bordetella pertussis. Cell Microbiol. (2011) 13:123–34. 10.1111/j.1462-5822.2010.01525.x PubMed DOI PMC

Cerny O, Anderson KE, Stephens LR, Hawkins PT, 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) 198:1285–96. 10.4049/jimmunol.1601309 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) 194:4901–13. 10.4049/jimmunol.1402941 PubMed DOI

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

Fedele G, Spensieri F, Palazzo R, Nasso M, Cheung GY, Coote JG, et al. . Bordetella pertussis commits human dendritic cells to promote a Th1/Th17 response through the activity of adenylate cyclase toxin and MAPK-pathways. PLoS ONE. (2010) 5:e8734. 10.1371/journal.pone.0008734 PubMed DOI PMC

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. (2017) 9:293. 10.3390/toxins9100293 PubMed DOI PMC

Skopova K, Tomalova B, Kanchev I, Rossmann P, Svedova M, Adkins I, 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:e00937-16. 10.1128/IAI.00937-16 PubMed DOI PMC

Bachelet M, Richard MJ, Francois D, Polla BS. Mitochondrial alterations precede Bordetella pertussis-induced apoptosis. FEMS Immunol Med Microbiol. (2002) 32:125–31. 10.1111/j.1574-695X.2002.tb00544.x PubMed DOI

Ahmad JN, 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) 18:384–98. 10.1111/cmi.12519 PubMed DOI

Ahmad JN, Holubova J, Benada O, Kofronova O, Stehlik L, Vasakova M, et al. . Bordetella adenylate cyclase toxin inhibits monocyte-to-macrophage transition and dedifferentiates human alveolar macrophages into monocyte-like cells. mBio. (2019) 10:e01743-19. 10.1128/mBio.01743-19 PubMed DOI PMC

Steigbigel RT, Lambert LHJr, Remington JS. Phagocytic and bacterial properties of normal human monocytes. J Clin Invest. (1974) 53:131–42. 10.1172/JCI107531 PubMed DOI PMC

Sokol RJ, Hudson G, James NT, Frost IJ, Wales J. Human macrophage development: a morphometric study. J Anat. (1987) 151:27–35. PubMed PMC

Gagnon E, Duclos S, Rondeau C, Chevet E, Cameron PH, Steele-Mortimer O, et al. . Endoplasmic reticulum-mediated phagocytosis is a mechanism of entry into macrophages. Cell. (2002) 110:119–31. 10.1016/S0092-8674(02)00797-3 PubMed DOI

Manderson AP, Kay JG, Hammond LA, Brown DL, Stow JL. Subcompartments of the macrophage recycling endosome direct the differential secretion of IL-6 and TNFalpha. J Cell Biol. (2007) 178:57–69. 10.1083/jcb.200612131 PubMed DOI PMC

Stow JL, Murray RZ. Intracellular trafficking and secretion of inflammatory cytokines. Cytokine Growth Factor Rev. (2013) 24:227–39. 10.1016/j.cytogfr.2013.04.001 PubMed DOI

Espinoza-Delgado I, Longo DL, Gusella GL, Varesio L. IL-2 enhances c-fms expression in human monocytes. J Immunol. (1990) 145:1137–43. PubMed

Ivashkiv LB, Schmitt EM, Castro A. Inhibition of transcription factor Stat1 activity in mononuclear cell cultures and T cells by the cyclic AMP signaling pathway. J Immunol. (1996) 157:1415–21. PubMed

Cole FS, Matthews WJJr, Marino JT, Gash DJ, Colten HR. Control of complement synthesis and secretion in bronchoalveolar and peritoneal macrophages. J Immunol. (1980) 125:1120–4. PubMed

Goodrum KJ. Complement component C3 secretion by mouse macrophage-like cell lines. J Leukoc Biol. (1987) 41:295–301. 10.1002/jlb.41.4.295 PubMed DOI

Kim M, Kim M, Lee S, Kuninaka S, Saya H, Lee H, et al. . cAMP/PKA signalling reinforces the LATS-YAP pathway to fully suppress YAP in response to actin cytoskeletal changes. EMBO J. (2013) 32:1543–55. 10.1038/emboj.2013.102 PubMed DOI PMC

Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell. (2015) 163:811–28. 10.1016/j.cell.2015.10.044 PubMed DOI PMC

Zhao B, Li L, Tumaneng K, Wang CY, Guan KL. A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev. (2010) 24:72–85. 10.1101/gad.1843810 PubMed DOI PMC

Hasan S, Rahman WU, Sebo P, Osicka R. Distinct spatiotemporal distribution of bacterial toxin-produced cellular cAMP differentially inhibits opsonophagocytic signaling. Toxins. (2019) 11:362. 10.3390/toxins11060362 PubMed DOI PMC

Yu FX, Zhang Y, Park HW, Jewell JL, Chen Q, Deng Y, et al. . Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation. Genes Dev. (2013) 27:1223–32. 10.1101/gad.219402.113 PubMed DOI PMC

Ben-Sasson SZ, Hu-Li J, Quiel J, Cauchetaux S, Ratner M, Shapira I, et al. . IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation. Proc Natl Acad Sci USA. (2009) 106:7119–24. 10.1073/pnas.0902745106 PubMed DOI PMC

Gueirard P, Ave P, Balazuc AM, Thiberge S, Huerre M, Milon G, et al. . Bordetella bronchiseptica persists in the nasal cavities of mice and triggers early delivery of dendritic cells in the lymph nodes draining the lower and upper respiratory tract. Infect Immun. (2003) 71:4137–43. 10.1128/IAI.71.7.4137-4143.2003 PubMed DOI PMC

Carrasco YR, Batista FD. B cells acquire particulate antigen in a macrophage-rich area at the boundary between the follicle and the subcapsular sinus of the lymph node. Immunity. (2007) 27:160–71. 10.1016/j.immuni.2007.06.007 PubMed DOI

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