Mast cells are potent immune sensors of the tissue microenvironment. Within seconds of activation, they release various preformed biologically active products and initiate the process of de novo synthesis of cytokines, chemokines, and other inflammatory mediators. This process is regulated at multiple levels. Besides the extensively studied IgE and IgG receptors, toll-like receptors, MRGPR, and other protein receptor signaling pathways, there is a critical activation pathway based on cholesterol-dependent, pore-forming cytolytic exotoxins produced by Gram-positive bacterial pathogens. This pathway is initiated by binding the exotoxins to the cholesterol-rich membrane, followed by their dimerization, multimerization, pre-pore formation, and pore formation. At low sublytic concentrations, the exotoxins induce mast cell activation, including degranulation, intracellular calcium concentration changes, and transcriptional activation, resulting in production of cytokines and other inflammatory mediators. Higher toxin concentrations lead to cell death. Similar activation events are observed when mast cells are exposed to sublytic concentrations of saponins or some other compounds interfering with the membrane integrity. We review the molecular mechanisms of mast cell activation by pore-forming bacterial exotoxins, and other compounds inducing cholesterol-dependent plasma membrane perturbations. We discuss the importance of these signaling pathways in innate and acquired immunity.

Department of Signal Transduction Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czechia

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Galli SJ, Nakae S, Tsai M. Mast Cells in the Development of Adaptive Immune Responses. Nat Immunol (2005) 6:135–42. 10.1038/ni1158 PubMed DOI

Rivera J, Gilfillan AM. Molecular Regulation of Mast Cell Activation. J Allergy Clin Immunol (2006) 117:1214–25.  10.1016/j.jaci.2006.04.015 PubMed DOI

Abraham SN, St John AL. Mast Cell-Orchestrated Immunity to Pathogens. Nat Rev Immunol (2010) 10:440–52. 10.1038/nri2782 PubMed DOI PMC

Harvima IT, Levi-Schaffer F, Draber P, Friedman S, Polakovicova I, Gibbs BF, et al. . Molecular Targets on Mast Cells and Basophils for Novel Therapies. J Allergy Clin Immunol (2014) 134:530–44.  10.1016/j.jaci.2014.03.007 PubMed DOI

Mukai K, Tsai M, Saito H, Galli SJ. Mast Cells as Sources of Cytokines, Chemokines, and Growth Factors. Immunol Rev (2018) 282:121–50.  10.1111/imr.12634 PubMed DOI PMC

Trinchieri G, Sher A. Cooperation of Toll-like Receptor Signals in Innate Immune Defence. Nat Rev Immunol (2007) 7:179–90.  10.1038/nri2038 PubMed DOI

Agier J, Pastwinska J, Brzezinska-Blaszczyk E. An Overview of Mast Cell Pattern Recognition Receptors. Inflammation Res (2018) 67:737–46.  10.1007/s00011-018-1164-5 PubMed DOI PMC

Subramanian H, Gupta K, Guo Q, Price R, Ali H. Mas-Related Gene X2 (MrgX2) is a Novel G Protein-Coupled Receptor for the Antimicrobial Peptide LL-37 in Human Mast Cells: Resistance to Receptor Phosphorylation, Desensitization, and Internalization. J Biol Chem (2011) 286:44739–49.  10.1074/jbc.M111.277152 PubMed DOI PMC

Arifuzzaman M, Mobley YR, Choi HW, Bist P, Salinas CA, Brown ZD, et al. . MRGPR-Mediated Activation of Local Mast Cells Clears Cutaneous Bacterial Infection and Protects Against Reinfection. Sci Adv (2019) 5:eaav0216.  10.1126/sciadv.aav0216 PubMed DOI PMC

Chompunud Na AC, Roy S, Thapaliya M, Ali H. Roles of a Mast Cell-Specific Receptor MRGPRX2 in Host Defense and Inflammation. J Dent Res (2020) 99:882–90.  10.1177/0022034520919107 PubMed DOI PMC

Bulfone-Paus S, Nilsson G, Draber P, Blank U, Levi-Schaffer F. Positive and Negative Signals in Mast Cell Activation. Trends Immunol (2017) 38:657–67.  10.1016/j.it.2017.01.008 PubMed DOI

Malaviya R, Ross EA, MacGregor JI, Ikeda T, Little JR, Jakschik BA, et al. . Mast Cell Phagocytosis of FimH-expressing Enterobacteria. J Immunol (1994) 152:1907–14. PubMed

Malaviya R, Ikeda T, Ross E, Abraham SN. Mast Cell Modulation of Neutrophil Influx and Bacterial Clearance at Sites of Infection Through TNF-α. Nature (1996) 381:77–80.  10.1038/381077a0 PubMed DOI

Malaviya R, Gao Z, Thankavel K, van der Merwe PA, Abraham SN. The Mast Cell Tumor Necrosis Factor α Response to FimH-expressing Escherichia coli is Mediated by the Glycosylphosphatidylinositol-Anchored Molecule CD48. Proc Natl Acad Sci USA (1999) 96:8110–5.  10.1073/pnas.96.14.8110 PubMed DOI PMC

Malaviya R, Abraham SN. Mast Cell Modulation of Immune Responses to Bacteria. Immunol Rev (2001) 179:16–24.  10.1034/j.1600-065x.2001.790102.x PubMed DOI

Akira S, Takeda K, Kaisho T. Toll-Like Receptors: Critical Proteins Linking Innate and Acquired Immunity. Nat Immunol (2001) 2:675–80.  10.1038/90609 PubMed DOI

Marshall JS. Mast-Cell Responses to Pathogens. Nat Rev Immunol (2004) 4:787–99.  10.1038/nri1460 PubMed DOI

Echtenacher B, Mannel DN, Hultner L. Critical Protective Role of Mast Cells in a Model of Acute Septic Peritonitis. Nature (1996) 381:75–7.  10.1038/381075a0 PubMed DOI

Edelson BT, Li Z, Pappan LK, Zutter MM. Mast Cell-Mediated Inflammatory Responses Require the α2β1 Integrin. Blood (2004) 103:2214–20.  10.1182/blood-2003-08-2978 PubMed DOI

Matsui H, Sekiya Y, Takahashi T, Nakamura M, Imanishi K, Yoshida H, et al. . Dermal Mast Cells Reduce Progressive Tissue Necrosis Caused by Subcutaneous Infection With. Streptococcus Pyogenes Mice J Med Microbiol (2011) 60:128–34.  10.1099/jmm.0.020495-0[doi PubMed DOI

Gekara NO, Weiss S. Mast Cells Initiate Early anti-Listeria Host Defences. Cell Microbiol (2008) 10:225–36.  10.1111/j.1462-5822.2007.01033.x PubMed DOI

Dietrich N, Rohde M, Geffers R, Kroger A, Hauser H, Weiss S, et al. . Mast Cells Elicit Proinflammatory But Not Type I Interferon Responses Upon Activation of TLRs by Bacteria. Proc Natl Acad Sci USA (2010) 107:8748–53.  10.1073/pnas.0912551107 PubMed DOI PMC

Cunningham MW. Pathogenesis of Group A Streptococcal Infections. Clin Microbiol Rev (2000) 13:470–511.  10.1128/cmr.13.3.470-511.2000 PubMed DOI PMC

Bolz DD, Li Z, McIndoo ER, Tweten RK, Bryant AE, Stevens DL. Cardiac Myocyte Dysfunction Induced by Streptolysin O is Membrane Pore and Calcium Dependent. Shock (2015) 43:178–84.  10.1097/SHK.0000000000000266 PubMed DOI PMC

Marriott HM, Mitchell TJ, Dockrell DH. Pneumolysin: A Double-Edged Sword During the Host-Pathogen Interaction. Curr Mol Med (2008) 8:497–509.  10.2174/156652408785747924 PubMed DOI

Fritscher J, Amberger D, Dyckhoff S, Bewersdorf JP, Masouris I, Voelk S, et al. . Mast Cells are Activated by Streptococcus Pneumoniae In Vitro But Dispensable for the Host Defense Against Pneumococcal Central Nervous System Infection In Vivo . Front Immunol (2018) 9:550.  10.3389/fimmu.2018.00550 PubMed DOI PMC

Schlech WF. Epidemiology and Clinical Manifestations of Listeria Monocytogenes Infection. Microbiol Spectr (2019) 71–12.  10.1128/microbiolspec.GPP3-0014-2018 PubMed DOI PMC

Vazquez-Boland JA, Kuhn M, Berche P, Chakraborty T, Dominguez-Bernal G, Goebel W, et al. . Listeria Pathogenesis and Molecular Virulence Determinants. Clin Microbiol Rev (2001) 14:584–640.  10.1128/CMR.14.3.584-640.2001 PubMed DOI PMC

Flanagan J, Collin N, Timoney J, Mitchell T, Mumford JA, Chanter N. Characterization of the Haemolytic Activity of Streptococcus Equi . Microb Pathog (1998) 24:211–21.  10.1006/mpat.1997.0190 PubMed DOI

Sweeney CR, Timoney JF, Newton JR, Hines MT. Streptococcus Equi Infections in Horses: Guidelines for Treatment, Control, and Prevention of Strangles. J Vet Intern Med (2005) 19:123–34. 10.1111/j.1939-1676.2005.tb02671.x PubMed DOI

O’Brien DK, Melville SB. Effects of Clostridium Perfringens α-Toxin (PLC) and Perfringolysin O (PFO) on Cytotoxicity to Macrophages, on Escape From the Phagosomes of Macrophages, and on Persistence of C. Perfringens in Host Tissues. Infect Immun (2004) 72:5204–15.  10.1128/IAI.72.9.5204-5215.2004[doi PubMed DOI PMC

Verherstraeten S, Goossens E, Valgaeren B, Pardon B, Timbermont L, Haesebrouck F, et al. . Perfringolysin O: The Underrated Clostridium Perfringens Toxin? Toxins (Basel) (2015) 7:1702–21.  10.3390/toxins7051702 PubMed DOI PMC

Gelber SE, Aguilar JL, Lewis KL, Ratner AJ. Functional and Phylogenetic Characterization of Vaginolysin, the Human-Specific Cytolysin From Gardnerella Vaginalis . J Bacteriol (2008) 190:3896–903.  10.1128/JB.01965-07 PubMed DOI PMC

Mitchell J. Streptococcus Mitis: Walking the Line Between Commensalism and Pathogenesis. Mol Oral Microbiol (2011) 26:89–98.  10.1111/j.2041-1014.2010.00601.x PubMed DOI

Tenenbaum T, Asmat TM, Seitz M, Schroten H, Schwerk C. Biological Activities of Suilysin: Role in Streptococcus Suis Pathogenesis. Future Microbiol (2016) 11:941–54.  10.2217/fmb-2016-0028 PubMed DOI

Issa E, Salloum T, Tokajian S. From Normal Flora to Brain Abscesses: A Review of Streptococcus Intermedius . Front Microbiol (2020) 11:826.  10.3389/fmicb.2020.00826 PubMed DOI PMC

Yoshino M, Murayama SY, Sunaoshi K, Wajima T, Takahashi M, Masaki J, et al. . Nonhemolytic Streptococcus Pyogenes Isolates That Lack Large Regions of the Sag Operon Mediating Streptolysin S Production. J Clin Microbiol (2010) 48:635–8.  10.1128/JCM.01362-09 PubMed DOI PMC

Bernheimer AW, Davidson M. Lysis of Pleuropneumonia-Like Organisms by Staphylococcal and Streptococcal Toxins. Science (1965) 148:1229–31.  10.1126/science.148.3674.1229 PubMed DOI

Cowell JL, Bernheimer AW. Role of Cholesterol in the Action of Cereolysin on Membranes. Arch Biochem Biophys (1978) 190:603–10.  10.1016/0003-9861(78)90316-8 PubMed DOI

Giddings KS, Johnson AE, Tweten RK. Redefining Cholesterol’s Role in the Mechanism of the Cholesterol-Dependent Cytolysins. Proc Natl Acad Sci USA (2003) 100:11315–20.  10.1073/pnas.2033520100 PubMed DOI PMC

Hotze EM, Tweten RK. Membrane Assembly of the Cholesterol-Dependent Cytolysin Pore Complex. Biochim Biophys Acta (2012) 1818:1028–38.  10.1016/j.bbamem.2011.07.036 PubMed DOI PMC

Feil SC, Ascher DB, Kuiper MJ, Tweten RK, Parker MW. Structural Studies of Streptococcus Pyogenes Streptolysin O Provide Insights Into the Early Steps of Membrane Penetration. J Mol Biol (2014) 426:785–92.  10.1016/j.jmb.2013.11.020 PubMed DOI PMC

Tweten RK, Hotze EM, Wade KR. The Unique Molecular Choreography of Giant Pore Formation by the Cholesterol-Dependent Cytolysins of Gram-positive Bacteria. Annu Rev Microbiol (2015) 69:323–40.  10.1146/annurev-micro-091014-104233 PubMed DOI PMC

Dal PM, van der Goot FG. Pore-Forming Toxins: Ancient, But Never Really Out of Fashion. Nat Rev Microbiol (2016) 14:77–92.  10.1038/nrmicro.2015.3 PubMed DOI

Christie MP, Johnstone BA, Tweten RK, Parker MW, Morton CJ. Cholesterol-Dependent Cytolysins: From Water-Soluble State to Membrane Pore. Biophys Rev (2018) 10:1337–48.  10.1007/s12551-018-0448-x PubMed DOI PMC

Morton CJ, Sani MA, Parker MW, Separovic F. Cholesterol-Dependent Cytolysins: Membrane and Protein Structural Requirements for Pore Formation. Chem Rev (2019) 119:7721–36.  10.1021/acs.chemrev.9b00090 PubMed DOI

Thapa R, Ray S, Keyel PA. Interaction of Macrophages and Cholesterol-Dependent Cytolysins: The Impact on Immune Response and Cellular Survival. Toxins (Basel) (2020) 12:531.  10.3390/toxins12090531 PubMed DOI PMC

Heuck AP, Moe PC, Johnson BB. The Cholesterol-Dependent Cytolysin Family of Gram-Positive Bacterial Toxins. Subcell Biochem (2010) 51:551–77.  10.1007/978-90-481-8622-8_20 PubMed DOI

Park SA, Park YS, Bong SM, Lee KS. Structure-Based Functional Studies for the Cellular Recognition and Cytolytic Mechanism of Pneumolysin From Streptococcus Pneumoniae . J Struct Biol (2016) 193:132–40.  10.1016/j.jsb.2015.12.002 PubMed DOI

Koster S, van PK, Hudel M, Leustik M, Rhinow D, Kuhlbrandt W, et al. . Crystal Structure of Listeriolysin O Reveals Molecular Details of Oligomerization and Pore Formation. Nat Commun (2014) 5:3690.  10.1038/ncomms4690 PubMed DOI

Cheerla R, Ayappa KG. Molecular Dynamics Study of Lipid and Cholesterol Reorganization Due to Membrane Binding and Pore Formation by Listeriolysin O. J Membr Biol (2020) 253:535–50.  10.1007/s00232-020-00148-9 PubMed DOI

Ramachandran R, Tweten RK, Johnson AE. Membrane-Dependent Conformational Changes Initiate Cholesterol-Dependent Cytolysin Oligomerization and Intersubunit β-Strand Alignment. Nat Struct Mol Biol (2004) 11:697–705.  10.1038/nsmb793 PubMed DOI

Dowd KJ, Farrand AJ, Tweten RK. The Cholesterol-Dependent Cytolysin Signature Motif: A Critical Element in the Allosteric Pathway That Couples Membrane Binding to Pore Assembly. PloS Pathog (2012) 8:e1002787.  10.1371/journal.ppat.1002787 PubMed DOI PMC

Farrand AJ, LaChapelle S, Hotze EM, Johnson AE, Tweten RK. Only Two Amino Acids are Essential for Cytolytic Toxin Recognition of Cholesterol at the Membrane Surface. Proc Natl Acad Sci USA (2010) 107:4341–6.  10.1073/pnas.0911581107 PubMed DOI PMC

Kozorog M, Sani MA, Lenarcic ZM, Ilc G, Hodnik V, Separovic F, et al. . 19F NMR Studies Provide Insights Into Lipid Membrane Interactions of listeriolysin O, a Pore Forming Toxin From Listeria Monocytogenes. Listeria Monocytogen Sci Rep (2018) 8:6894.  10.1038/s41598-018-24692-6 PubMed DOI PMC

Farrand AJ, Hotze EM, Sato TK, Wade KR, Wimley WC, Johnson AE, et al. . The Cholesterol-Dependent Cytolysin Membrane-Binding Interface Discriminates Lipid Environments of Cholesterol to Support β-Barrel Pore Insertion. J Biol Chem (2015) 290:17733–44.  10.1074/jbc.M115.656769 PubMed DOI PMC

Shewell LK, Harvey RM, Higgins MA, Day CJ, Hartley-Tassell LE, Chen AY, et al. . The Cholesterol-Dependent Cytolysins Pneumolysin and Streptolysin O Require Binding to Red Blood Cell Glycans for Hemolytic Activity. Proc Natl Acad Sci USA (2014) 111:E5312–20.  10.1073/pnas.1412703111 PubMed DOI PMC

Shewell LK, Day CJ, Jen FE, Haselhorst T, Atack JM, Reijneveld JF, et al. . All Major Cholesterol-Dependent Cytolysins Use Glycans as Cellular Receptors. Sci Adv (2020) 6:eaaz4926.  10.1126/sciadv.aaz4926 PubMed DOI PMC

Tweten RK. Cholesterol-Dependent Cytolysins, a Family of Versatile Pore-Forming Toxins. Infect Immun (2005) 73:6199–209.  10.1128/IAI.73.10.6199-6209.2005 PubMed DOI PMC

Ramachandran R, Tweten RK, Johnson AE. The Domains of a Cholesterol-Dependent Cytolysin Undergo a Major FRET-Detected Rearrangement During Pore Formation. Proc Natl Acad Sci USA (2005) 102:7139–44.  10.1073/pnas.0500556102 PubMed DOI PMC

Savinov SN, Heuck AP. Interaction of Cholesterol With Perfringolysin O: What Have We Learned From Functional Analysis? Toxins (Basel) (2017) 91–17.  10.3390/toxins9120381 PubMed DOI PMC

van Pee K, Neuhaus A, D’Imprima E, Mills DJ, Kuhlbrandt W, Yildiz O. CryoEM Structures of Membrane Pore and Prepore Complex Reveal Cytolytic Mechanism of Pneumolysin. Elife (2017) 6:e23644.  10.7554/eLife.23644 PubMed DOI PMC

Gupta N, DeFranco AL. Visualizing Lipid Raft Dynamics and Early Signaling Events During Antigen Receptor-Mediated B-lymphocyte Activation. Mol Biol Cell (2003) 14:432–44.  10.1091/mbc.02-05-0078 PubMed DOI PMC

Duncan JL, Schlegel R. Effect of Streptolysin O on Erythrocyte Membranes, Liposomes, and Lipid Dispersions. A Protein-Cholesterol Interaction. J Cell Biol (1975) 67:160–74.  10.1083/jcb.67.1.160 PubMed DOI PMC

McNeil PL, Terasaki M. Coping With the Inevitable: How Cells Repair a Torn Surface Membrane. Nat Cell Biol (2001) 3:E124–9.  10.1038/35074652 PubMed DOI

Walev I, Palmer M, Martin E, Jonas D, Weller U, Hohn-Bentz H, et al. . Recovery of Human Fibroblasts From Attack by the Pore-Forming α-Toxin of Staphylococcus Aureus . Microb Pathog (1994) 17:187–201.  10.1006/mpat.1994.1065 PubMed DOI

Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI. Differential Activation of Transcription Factors Induced by Ca2+ Response Amplitude and Duration. Nature (1997) 386:855–8.  10.1038/386855a0 PubMed DOI

Repp H, Pamukci Z, Koschinski A, Domann E, Darji A, Birringer J, et al. . Listeriolysin of Listeria Monocytogenes Forms Ca2+-permeable Pores Leading to Intracellular Ca2+ Oscillations. Cell Microbiol (2002) 4:483–91.  10.1046/j.1462-5822.2002.00207.x PubMed DOI

Dramsi S, Cossart P. Listeriolysin O-mediated Calcium Influx Potentiates Entry of Listeria Monocytogenes Into the Human Hep-2 Epithelial Cell Line. Infect Immun (2003) 71:3614–8.  10.1128/iai.71.6.3614-3618.2003 PubMed DOI PMC

Gekara NO, Westphal K, Ma B, Rohde M, Groebe L, Weiss S. The Multiple Mechanisms of Ca2+ Signalling by Listeriolysin O, the Cholesterol-Dependent Cytolysin of Listeria Monocytogenes . Cell Microbiol (2007) 9:2008–21.  10.1111/j.1462-5822.2007.00932.x PubMed DOI

Romero M, Keyel M, Shi G, Bhattacharjee P, Roth R, Heuser JE, et al. . Intrinsic Repair Protects Cells From Pore-Forming Toxins by Microvesicle Shedding. Cell Death Differ (2017) 24:798–808.  10.1038/cdd.2017.11 PubMed DOI PMC

Carrero JA, Calderon B, Unanue ER. Listeriolysin O From Listeria Monocytogenes is a Lymphocyte Apoptogenic Molecule. J Immunol (2004) 172:4866–74.  10.4049/jimmunol.172.8.4866 PubMed DOI

Rai P, He F, Kwang J, Engelward BP, Chow VT. Pneumococcal Pneumolysin Induces DNA Damage and Cell Cycle Arrest. Sci Rep (2016) 6:22972.  10.1038/srep22972 PubMed DOI PMC

Pillich H, Loose M, Zimmer KP, Chakraborty T. Activation of the Unfolded Protein Response by Listeria Monocytogenes . Cell Microbiol (2012) 14:949–64.  10.1111/j.1462-5822.2012.01769.x PubMed DOI

Hancz D, Westerlund E, Valfridsson C, Aemero GM, Bastiat-Sempe B, Orning P, et al. . Streptolysin O Induces the Ubiquitination and Degradation of Pro-IL-1β. J Innate Immun (2019) 11:457–68.  10.1159/000496403 PubMed DOI PMC

Walev I, Hombach M, Bobkiewicz W, Fenske D, Bhakdi S, Husmann M. Resealing of Large Transmembrane Pores Produced by Streptolysin O in Nucleated Cells is Accompanied by NF-κB Activation and Downstream Events. FASEB J (2002) 16:237–9.  10.1096/fj.01-0572fje PubMed DOI

Gekara NO, Zietara N, Geffers R, Weiss S. Listeria Monocytogenes Induces T Cell Receptor Unresponsiveness Through Pore-Forming Toxin Listeriolysin O. J Infect Dis (2010) 202:1698–707.  10.1086/657145 PubMed DOI

Simons K, Toomre D. Lipid Rafts and Signal Transduction. Nat Rev Mol Cell Biol (2000) 1:31–9.  10.1038/35036052 PubMed DOI

Dráber P, Dráberová L, Kovárová M, Hálová I, Tolar P, Cerná H, et al. . Lipid Rafts and Their Role in Signal Transduction - Mast Cells as a Model. Trends Glycosci Glyc (2001) 13:261–79. 10.4052/tigg.13.261 DOI

Dráber P, Draberova L. Lipid Rafts in Mast Cell Signaling. Mol Immunol (2002) 38:1247–52. 10.1016/S0161-5890(02)00071-8 PubMed DOI

Gekara NO, Jacobs T, Chakraborty T, Weiss S. The Cholesterol-Dependent Cytolysin Listeriolysin O Aggregates Rafts Via Oligomerization. Cell Microbiol (2005) 7:1345–56.  10.1111/j.1462-5822.2005.00561.x PubMed DOI

Wilson BS, Steinberg SL, Liederman K, Pfeiffer JR, Surviladze Z, Zhang J, et al. . Markers for Detergent-Resistant Lipid Rafts Occupy Distinct and Dynamic Domains in Native Membranes. Mol Biol Cell (2004) 15:2580–92.  10.1091/mbc.e03-08-0574 PubMed DOI PMC

Dwyer DF, Barrett NA, Austen KF. Expression Profiling of Constitutive Mast Cells Reveals a Unique Identity Within the Immune System. Nat Immunol (2016) 17:878–87.  10.1038/ni.3445 PubMed DOI PMC

Cavalcante MC, Allodi S, Valente AP, Straus AH, Takahashi HK, Mourao PA, et al. . Occurrence of Heparin in the Invertebrate Styela Plicata (Tunicata) is Restricted to Cell Layers Facing the Outside Environment. An Ancient Role in Defense? J Biol Chem (2000) 275:36189–6.  10.1074/jbc.M005830200 PubMed DOI

Cavalcante MC, de Andrade LR, Du BS-P, Straus AH, Takahashi HK, Allodi S, et al. . Colocalization of Heparin and Histamine in the Intracellular Granules of Test Cells From the Invertebrate Styela Plicata (Chordata-Tunicata). J Struct Biol (2002) 137:313–21.  10.1016/s1047-8477(02)00007-2 PubMed DOI

Wong GW, Zhuo L, Kimata K, Lam BK, Satoh N, Stevens RL. Ancient Origin of Mast Cells. Biochem Biophys Res Commun (2014) 451:314–8.  10.1016/j.bbrc.2014.07.124 PubMed DOI PMC

Marshall JS, Portales-Cervantes L, Leong E. Mast Cell Responses to Viruses and Pathogen Products. Int J Mol Sci (2019) 201–18.  10.3390/ijms20174241 PubMed DOI PMC

Bugajev V, Bambousková M, Dráberová L, Dráber P. What Precedes the Initial Tyrosine Phosphorylation of the High Affinity IgE Receptor in Antigen-Activated Mast Cell? FEBS Lett (2010) 584:4949–55.  10.1016/j.febslet.2010.08.045 PubMed DOI

Draber P, Halova I, Levi-Schaffer F, Draberova L. Transmembrane Adaptor Proteins in the High-Affinity IgE Receptor Signaling. Front Immunol (2012) 2:95.  10.3389/fimmu.2011.00095 PubMed DOI PMC

Draber P, Draberova L. Lifting the Fog in Store-Operated Ca2+ Entry. Trends Immunol (2005) 26:621–4.  10.1016/j.it.2005.09.006 PubMed DOI

Putney JW. Capacitative Calcium Entry: From Concept to Molecules. Immunol Rev (2009) 231:10–22.  10.1111/j.1600-065X.2009.00810.x PubMed DOI

Boyce JA. Mast Cells and Eicosanoid Mediators: A System of Reciprocal Paracrine and Autocrine Regulation. Immunol Rev (2007) 217:168–85.  10.1111/j.1600-065X.2007.00512.x PubMed DOI

Ma HT, Beaven MA. Regulators of Ca2+ Signaling in Mast Cells: Potential Targets for Treatment of Mast Cell-Related Diseases? Adv Exp Med Biol (2011) 716:62–90.  10.1007/978-1-4419-9533-9_5 PubMed DOI

Gilfillan AM, Tkaczyk C. Integrated Signalling Pathways for Mast-Cell Activation. Nat Rev Immunol (2006) 6:218–30.  10.1038/nri1782 PubMed DOI

Iwaki S, Tkaczyk C, Satterthwaite AB, Halcomb K, Beaven MA, Metcalfe DD, et al. . Btk Plays a Crucial Role in the Amplification of Fcϵri-Mediated Mast Cell Activation by Kit. J Biol Chem (2005) 280:40261–70.  10.1074/jbc.M506063200 PubMed DOI

Heiman AS, Chen M. Activation-Secretion Coupling in 10P2 Murine Mast Cells Challenged With IgE-antigen, Ionophore A23187, Thapsigargin and Phorbol Ester. Pharmacology (1997) 54:153–61.  10.1159/000139482 PubMed DOI

Draberova L, Shaik GM, Volna P, Heneberg P, Tumova M, Lebduska P, et al. . Regulation of Ca2+ Signaling in Mast Cells by Tyrosine-Phosphorylated and Unphosphorylated non-T Cell Activation Linker. J Immunol (2007) 179:5169–80.  10.4049/jimmunol.179.8.5169 PubMed DOI

Hirasawa N, Sato Y, Yomogida S, Mue S, Ohuchi K. Role of Phosphatidylinositol 3-Kinase in Degranulation Induced by IgE-dependent and -Independent Mechanisms in Rat Basophilic RBL-2H3 (Ml) Cells. Cell Signal (1997) 9:305–10.  10.1016/s0898-6568(96)00189-1 PubMed DOI

Huber M, Hughes MR, Krystal G. Thapsigargin-Induced Degranulation of Mast Cells is Dependent on Transient Activation of Phosphatidylinositol-3 Kinase. J Immunol (2000) 165:124–33.  10.4049/jimmunol.165.1.124 PubMed DOI

Carafoli E, Krebs J. Why Calcium? How Calcium Became the Best Communicator. J Biol Chem (2016) 291:20849–57.  10.1074/jbc.R116.735894 PubMed DOI PMC

Usmani SM, von Einem J, Frick M, Miklavc P, Mayenburg M, Husmann M, et al. . Molecular Basis of Early Epithelial Response to Streptococcal Exotoxin: Role of STIM1 and Orai1 Proteins. Cell Microbiol (2012) 14:299–315.  10.1111/j.1462-5822.2011.01724.x PubMed DOI

Stassen M, Muller C, Richter C, Neudorfl C, Hultner L, Bhakdi S, et al. . The Streptococcal Exotoxin Streptolysin O Activates Mast Cells to Produce Tumor Necrosis Factor α by p38 Mitogen-Activated Protein Kinase- and Protein Kinase C-dependent Pathways. Infect Immun (2003) 71:6171–7.  10.1128/iai.71.11.6171-6177.2003 PubMed DOI PMC

Metz M, Magerl M, Kuhl NF, Valeva A, Bhakdi S, Maurer M. Mast Cells Determine the Magnitude of Bacterial Toxin-Induced Skin Inflammation. Exp Dermatol (2009) 18:160–6.  10.1111/j.1600-0625.2008.00778.x PubMed DOI

Cruse G, Fernandes VE, de Salort J, Pankhania D, Marinas MS, Brewin H, et al. . Human Lung Mast Cells Mediate Pneumococcal Cell Death in Response to Activation by Pneumolysin. J Immunol (2010) 184:7108–15.  10.4049/jimmunol.0900802 PubMed DOI

Ronnberg E, Guss B, Pejler G. Infection of Mast Cells With Live Streptococci Causes a Toll-Like Receptor 2- and Cell-Cell Contact-Dependent Cytokine and Chemokine Response. Infect Immun (2010) 78:854–64.  10.1128/IAI.01004-09 PubMed DOI PMC

von Beek C, Waern I, Eriksson J, Melo FR, Robinson C, Waller AS, et al. . Streptococcal Saga Activates a Proinflammatory Response in Mast Cells by a Sublytic Mechanism. Cell Microbiol (2019) 21:e13064.  10.1111/cmi.13064 PubMed DOI PMC

Mannel DN, Hultner L, Echtenacher B. Critical Protective Role of Mast Cell-Derived Tumour Necrosis Factor in Bacterial Infection. Res Immunol (1996) 147:491–3.  10.1016/s0923-2494(97)85212-1 PubMed DOI

Henderson B, Wilson M, Wren B. Are Bacterial Exotoxins Cytokine Network Regulators? Trends Microbiol (1997) 5:454–8.  10.1016/S0966-842X(97)01125-6 PubMed DOI

Barbuti G, Moschioni M, Censini S, Covacci A, Montecucco C, Montemurro P. Streptococcus Pneumoniae Induces Mast Cell Degranulation. Int J Med Microbiol (2006) 296:325–9.  10.1016/j.ijmm.2005.11.009 PubMed DOI

Jobbings CE, Sandig H, Whittingham-Dowd JK, Roberts IS, Bulfone-Paus S. Listeria Monocytogenes Alters Mast Cell Phenotype, Mediator and Osteopontin Secretion in a Listeriolysin-Dependent Manner. PloS One (2013) 8:e57102.  10.1371/journal.pone.0057102 PubMed DOI PMC

Kramer S, Sellge G, Lorentz A, Krueger D, Schemann M, Feilhauer K, et al. . Selective Activation of Human Intestinal Mast Cells by Escherichia Coli Hemolysin. J Immunol (2008) 181:1438–45.  10.4049/jimmunol.181.2.1438 PubMed DOI

Magassa N, Chandrasekaran S, Caparon MG. Streptococcus Pyogenes Cytolysin-Mediated Translocation Does Not Require Pore Formation by Streptolysin O. EMBO Rep (2010) 11:400–5.  10.1038/embor.2010.37 PubMed DOI PMC

Logsdon LK, Hakansson AP, Cortes G, Wessels MR. Streptolysin O Inhibits Clathrin-Dependent Internalization of Group a. Streptococcus mBio (2011) 2:e00332–10.  10.1128/mBio.00332-10 PubMed DOI PMC

Howell TW, Gomperts BD. Rat Mast Cells Permeabilised With Streptolysin O Secrete Histamine in Response to Ca2+ at Concentrations Buffered in the Micromolar Range. Biochim Biophys Acta (1987) 927:177–83.  10.1016/0167-4889(87)90132-7 PubMed DOI

Cockcroft S, Howell TW, Gomperts BD. Two G-proteins Act in Series to Control Stimulus-Secretion Coupling in Mast Cells: Use of Neomycin to Distinguish Between G-proteins Controlling Polyphosphoinositide Phosphodiesterase and Exocytosis. J Cell Biol (1987) 105:2745–50.  10.1083/jcb.105.6.2745 PubMed DOI PMC

Koffer A, Tatham PE, Gomperts BD. Changes in the State of Actin During the Exocytotic Reaction of Permeabilized Rat Mast Cells. J Cell Biol (1990) 111:919–27.  10.1083/jcb.111.3.919 PubMed DOI PMC

Brown AM, O’Sullivan AJ, Gomperts BD. Induction of Exocytosis From Permeabilized Mast Cells by the Guanosine Triphosphatases Rac and Cdc42. Mol Biol Cell (1998) 9:1053–63.  10.1091/mbc.9.5.1053 PubMed DOI PMC

Pinxteren JA, Gomperts BD, Rogers D, Phillips SE, Tatham PE, Thomas GM. Phosphatidylinositol Transfer Proteins and Protein Kinase C Make Separate But non-Interacting contributions to the Phosphorylation State Necessary for Secretory Competence in Rat Mast Cells. Biochem J (2001) 356:287–96.  10.1042/0264-6021:3560287 PubMed DOI PMC

Shaik GM, Draberova L, Heneberg P, Draber P. Vacuolin-1-modulated Exocytosis and Cell Resealing in Mast Cells. Cell Signal (2009) 21:1337–45.  10.1016/j.cellsig.2009.04.001 PubMed DOI

McNeil PL, Warder E. Glass Beads Load Macromolecules Into Living Cells. J Cell Sci (1987) 88( Pt 5):669–78. 10.1242/jcs.88.5.669 PubMed DOI

Schoenauer R, Atanassoff AP, Wolfmeier H, Pelegrin P, Babiychuk EB, Draeger A. P2X7 Receptors Mediate Resistance to Toxin-Induced Cell Lysis. Biochim Biophys Acta (2014) 1843:915–22.  10.1016/j.bbamcr.2014.01.024 PubMed DOI

Virginio C, MacKenzie A, Rassendren FA, North RA, Surprenant A. Pore Dilation of Neuronal P2X Receptor Channels. Nat Neurosci (1999) 2:315–21.  10.1038/7225 PubMed DOI

Uchiyama S, Dohrmann S, Timmer AM, Dixit N, Ghochani M, Bhandari T, et al. . Streptolysin O Rapidly Impairs Neutrophil Oxidative Burst and Antibacterial Responses to Group A Streptococcus. Front Immunol (2015) 6:581.  10.3389/fimmu.2015.00581 PubMed DOI PMC

Lam GY, Fattouh R, Muise AM, Grinstein S, Higgins DE, Brumell JH. Listeriolysin O Suppresses Phospholipase C-mediated Activation of the Microbicidal NADPH Oxidase to Promote Listeria Monocytogenes Infection. Cell Host Microbe (2011) 10:627–34.  10.1016/j.chom.2011.11.005 PubMed DOI PMC

Yang J, Wang J, Zhang X, Qiu Y, Yan J, Sun S, et al. . Mast Cell Degranulation Impairs Pneumococcus Clearance in Mice Via IL-6 Dependent and TNF-α Independent Mechanisms. World Allergy Organ J (2019) 12:100028.  10.1016/j.waojou.2019.100028 PubMed DOI PMC

van den Boogaard FE, Brands X, Roelofs JJ, de Beer R, de Boer OJ, van ‘t Veer C, et al. . Mast Cells Impair Host Defense During Murine Streptococcus Pneumoniae Pneumonia. J Infect Dis (2014) 210:1376–84.  10.1093/infdis/jiu285 PubMed DOI

Jacobs T, Darji A, Frahm N, Rohde M, Wehland J, Chakraborty T, et al. . Listeriolysin O: Cholesterol Inhibits Cytolysis But Not Binding to Cellular Membranes. Mol Microbiol (1998) 28:1081–9.  10.1046/j.1365-2958.1998.00858.x PubMed DOI

Kayal S, Lilienbaum A, Poyart C, Memet S, Israel A, Berche P. Listeriolysin O-dependent Activation of Endothelial Cells During Infection With Listeria Monocytogenes: Activation of NF-κ B and Upregulation of Adhesion Molecules and Chemokines. Mol Microbiol (1999) 31:1709–22.  10.1046/j.1365-2958.1999.01305.x PubMed DOI

Carrero JA, Calderon B, Unanue ER. Type I Interferon Sensitizes Lymphocytes to Apoptosis and Reduces Resistance to Listeria Infection. J Exp Med (2004) 200:535–40.  10.1084/jem.20040769 PubMed DOI PMC

Tran Van Nhieu G, Clair C, Grompone G, Sansonetti P. Calcium Signalling During Cell Interactions With Bacterial Pathogens. Biol Cell (2004) 96:93–101.  10.1016/j.biolcel.2003.10.006 PubMed DOI

Molloy EM, Cotter PD, Hill C, Mitchell DA, Ross RP. Streptolysin S-like Virulence Factors: The Continuing Saga. Nat Rev Microbiol (2011) 9:670–81.  10.1038/nrmicro2624 PubMed DOI PMC

Nizet V, Beall B, Bast DJ, Datta V, Kilburn L, Low DE, et al. . Genetic Locus for Streptolysin S Production by Group A Streptococcus . Infect Immun (2000) 68:4245–54.  10.1128/iai.68.7.4245-4254.2000 PubMed DOI PMC

Menestrina G, Serra MD, Prevost G. Mode of Action of β-Barrel Pore-Forming Toxins of the Staphylococcal α-Hemolysin Family. Toxicon (2001) 39:1661–72.  10.1016/s0041-0101(01)00153-2 PubMed DOI

Seeman P. Transient Holes in the Erythrocyte Membrane During Hypotonic Hemolysis and Stable Holes in the Membrane After Lysis by Saponin and Lysolecithin. J Cell Biol (1967) 32:55–70.  10.1083/jcb.32.1.55 PubMed DOI PMC

Lorent JH, Quetin-Leclercq J, Mingeot-Leclercq MP. The Amphiphilic Nature of Saponins and Their Effects on Artificial and Biological Membranes and Potential Consequences for Red Blood and Cancer Cells. Org Biomol Chem (2014) 12:8803–22.  10.1039/c4ob01652a PubMed DOI

Yang WS, Park SO, Yoon AR, Yoo JY, Kim MK, Yun CO, et al. . Suicide Cancer Gene Therapy Using Pore-Forming Toxin, Streptolysin O. Mol Cancer Ther (2006) 5:1610–9.  10.1158/1535-7163.MCT-05-0515 PubMed DOI

Pahle J, Walther W. Vectors and Strategies for Nonviral Cancer Gene Therapy. Expert Opin Biol Ther (2016) 16:443–61.  10.1517/14712598.2016.1134480 PubMed DOI

Chiarot E, Faralla C, Chiappini N, Tuscano G, Falugi F, Gambellini G, et al. . Targeted Amino Acid Substitutions Impair Streptolysin O Toxicity and Group A Streptococcus Virulence. mBio (2013) 4:e00387–12.  10.1128/mBio.00387-12 PubMed DOI PMC

Ho NI, Huis In ‘t Veld LGM, Raaijmakers TK, Adema GJ. Adjuvants Enhancing Cross-Presentation by Dendritic Cells: The Key to More Effective Vaccines? Front Immunol (2018) 9:2874.  10.3389/fimmu.2018.02874 PubMed DOI PMC

Fleck JD, Betti AH, da Silva FP, Troian EA, Olivaro C, Ferreira F, et al. . Saponins From Quillaja Saponaria and Quillaja Brasiliensis: Particular Chemical Characteristics and Biological Activities. Molecules (2019) 24:171.  10.3390/molecules24010171 PubMed DOI PMC

Tian JH, Patel N, Haupt R, Zhou H, Weston S, Hammond H, et al. . Sars-CoV-2 Spike Glycoprotein Vaccine Candidate NVX-CoV2373 Immunogenicity in Baboons and Protection in Mice. Nat Commun (2021) 12:372.  10.1038/s41467-020-20653-8 PubMed DOI PMC

Keyel PA, Roth R, Yokoyama WM, Heuser JE, Salter RD. Reduction of Streptolysin O (SLO) Pore-Forming Activity Enhances Inflammasome Activation. Toxins (Basel) (2013) 5:1105–18.  10.3390/toxins5061105 PubMed DOI PMC