[en] Allergies are considered to represent mal-directed type 2 immune responses against mostly innocuous exogenous compounds. Immunoglobulin E (IgE) antibodies are a characteristic feature of allergies and mediate hypersensitivity against allergens through activation of effector cells, particularly mast cells (MCs). Although the physiological functions of this dangerous branch of immunity have remained enigmatic, recent evidence shows that allergic immune reactions can help to protect against the toxicity of venoms. Because bacteria are a potent alternative source of toxins, we assessed the possible role of allergy-like type 2 immunity in antibacterial host defense. We discovered that the adaptive immune response against Staphylococcus aureus (SA) skin infection substantially improved systemic host defense against secondary SA infections in mice. Moreover, this acquired protection depended on IgE effector mechanisms and MCs. Importantly, our results reveal a previously unknown physiological function of allergic immune responses, IgE antibodies, and MCs in host defense against a pathogenic bacterium.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Starkl, Philipp
Watzenboeck, Martin L.
Popov, Lauren M.
Zahalka, Sophie
Hladik, Anastasiya
Lakovits, Karin
Radhouani, Mariem
Haschemi, Arvand
Marichal, Thomas ; Université de Liège - ULiège > Physiologie générale et des systèmes
Akahoshi, M., Song, C.H., Piliponsky, A.M., Metz, M., Guzzetta, A., Abrink, M., Schlenner, S.M., Feyerabend, T.B., Rodewald, H.R., Pejler, G., et al. Mast cell chymase reduces the toxicity of Gila monster venom, scorpion venom, and vasoactive intestinal polypeptide in mice. J. Clin. Invest. 121 (2011), 4180–4191.
Anderson, E., Stavenhagen, K., Kolarich, D., Sommerhoff, C.P., Maurer, M., Metz, M., Human Mast Cell Tryptase Is a Potential Treatment for Snakebite Envenoming Across Multiple Snake Species. Front. Immunol., 9, 2018, 1532.
Arifuzzaman, M., Mobley, Y.R., Choi, H.W., Bist, P., Salinas, C.A., Brown, Z.D., Chen, S.L., Staats, H.F., Abraham, S.N., MRGPR-mediated activation of local mast cells clears cutaneous bacterial infection and protects against reinfection. Sci. Adv., 5, 2019, eaav0216.
Badarau, A., Rouha, H., Malafa, S., Battles, M.B., Walker, L., Nielson, N., Dolezilkova, I., Teubenbacher, A., Banerjee, S., Maierhofer, B., et al. Context matters: The importance of dimerization-induced conformation of the LukGH leukocidin of Staphylococcus aureus for the generation of neutralizing antibodies. MAbs 8 (2016), 1347–1360.
Balbino, B., Conde, E., Marichal, T., Starkl, P., Reber, L.L., Approaches to target IgE antibodies in allergic diseases. Pharmacol. Ther. 191 (2018), 50–64.
Bankhead, P., Loughrey, M.B., Fernández, J.A., Dombrowski, Y., McArt, D.G., Dunne, P.D., McQuaid, S., Gray, R.T., Murray, L.J., Coleman, H.G., et al. QuPath: Open source software for digital pathology image analysis. Sci. Rep., 7, 2017, 16878.
Bruhns, P., Jönsson, F., Mouse and human FcR effector functions. Immunol. Rev. 268 (2015), 25–51.
Cassini, A., Högberg, L.D., Plachouras, D., Quattrocchi, A., Hoxha, A., Simonsen, G.S., Colomb-Cotinat, M., Kretzschmar, M.E., Devleesschauwer, B., Cecchini, M., et al., Burden of AMR Collaborative Group. Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis. Lancet Infect. Dis. 19 (2019), 56–66.
Cosmi, L., Maggi, L., Mazzoni, A., Liotta, F., Annunziato, F., Biologicals targeting type 2 immunity: Lessons learned from asthma, chronic urticaria and atopic dermatitis. Eur. J. Immunol. 49 (2019), 1334–1343.
Diep, B.A., Gill, S.R., Chang, R.F., Phan, T.H., Chen, J.H., Davidson, M.G., Lin, F., Lin, J., Carleton, H.A., Mongodin, E.F., et al. Complete genome sequence of USA300, an epidemic clone of community-acquired meticillin-resistant Staphylococcus aureus. Lancet 367 (2006), 731–739.
Dombrowicz, D., Flamand, V., Brigman, K.K., Koller, B.H., Kinet, J.P., Abolition of anaphylaxis by targeted disruption of the high affinity immunoglobulin E receptor alpha chain gene. Cell 75 (1993), 969–976.
Eden, E., Navon, R., Steinfeld, I., Lipson, D., Yakhini, Z., GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics, 10, 2009, 48.
Galli, S.J., Tsai, M., IgE and mast cells in allergic disease. Nat. Med. 18 (2012), 693–704.
Gause, W.C., Rothlin, C., Loke, P., Heterogeneity in the initiation, development and function of type 2 immunity. Nat. Rev. Immunol., 2020, 10.1038/s41577-020-0301-x Published online May 4, 2020.
Gowthaman, U., Chen, J.S., Zhang, B., Flynn, W.F., Lu, Y., Song, W., Joseph, J., Gertie, J.A., Xu, L., Collet, M.A., et al. Identification of a T follicular helper cell subset that drives anaphylactic IgE. Science, 365, 2019, eaaw6433.
Hahn, B.L., Sohnle, P.G., Direct translocation of staphylococci from the skin surface to deep organs. Microb. Pathog. 63 (2013), 24–29.
Hammad, H., Lambrecht, B.N., Barrier Epithelial Cells and the Control of Type 2 Immunity. Immunity 43 (2015), 29–40.
Harris, N.L., Loke, P., Recent Advances in Type-2-Cell-Mediated Immunity: Insights from Helminth Infection. Immunity, 48, 2018, 396.
Inoshima, I., Inoshima, N., Wilke, G.A., Powers, M.E., Frank, K.M., Wang, Y., Bubeck Wardenburg, J., A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice. Nat. Med. 17 (2011), 1310–1314.
Kim, J., Kim, B.E., Ahn, K., Leung, D.Y.M., Interactions Between Atopic Dermatitis and Staphylococcus aureus Infection: Clinical Implications. Allergy Asthma Immunol. Res. 11 (2019), 593–603.
Kobayashi, T., Naik, S., Nagao, K., Choreographing Immunity in the Skin Epithelial Barrier. Immunity 50 (2019), 552–565.
Langen, U., Schmitz, R., Steppuhn, H., [Prevalence of allergic diseases in Germany: results of the German Health Interview and Examination Survey for Adults (DEGS1)]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 56 (2013), 698–706.
Marichal, T., Gaudenzio, N., El Abbas, S., Sibilano, R., Zurek, O., Starkl, P., Reber, L.L., Pirottin, D., Kim, J., Chambon, P., et al. Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis. J. Clin. Invest. 126 (2016), 4497–4515.
Marichal, T., Starkl, P., Reber, L.L., Kalesnikoff, J., Oettgen, H.C., Tsai, M., Metz, M., Galli, S.J., A beneficial role for immunoglobulin E in host defense against honeybee venom. Immunity 39 (2013), 963–975.
Meindl, S., Schmidt, U., Vaculik, C., Elbe-Bürger, A., Characterization, isolation, and differentiation of murine skin cells expressing hematopoietic stem cell markers. J. Leukoc. Biol. 80 (2006), 816–826.
Metz, M., Piliponsky, A.M., Chen, C.C., Lammel, V., Abrink, M., Pejler, G., Tsai, M., Galli, S.J., Mast cells can enhance resistance to snake and honeybee venoms. Science 313 (2006), 526–530.
Miller, L.S., Simon, S.I., Neutrophils in hot pursuit of MRSA in the lymph nodes. Proc. Natl. Acad. Sci. USA 115 (2018), 2272–2274.
Mukai, K., Tsai, M., Saito, H., Galli, S.J., Mast cells as sources of cytokines, chemokines, and growth factors. Immunol. Rev. 282 (2018), 121–150.
Mukai, K., Tsai, M., Starkl, P., Marichal, T., Galli, S.J., IgE and mast cells in host defense against parasites and venoms. Semin. Immunopathol. 38 (2016), 581–603.
Musher, D.M., Thorner, A.R., Community-acquired pneumonia. N. Engl. J. Med. 371 (2014), 1619–1628.
Nakamura, Y., Oscherwitz, J., Cease, K.B., Chan, S.M., Muñoz-Planillo, R., Hasegawa, M., Villaruz, A.E., Cheung, G.Y., McGavin, M.J., Travers, J.B., et al. Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. Nature 503 (2013), 397–401.
Oettgen, H.C., Fifty years later: Emerging functions of IgE antibodies in host defense, immune regulation, and allergic diseases. J. Allergy Clin. Immunol. 137 (2016), 1631–1645.
Oettgen, H.C., Martin, T.R., Wynshaw-Boris, A., Deng, C., Drazen, J.M., Leder, P., Active anaphylaxis in IgE-deficient mice. Nature 370 (1994), 367–370.
Olsen, J.V., de Godoy, L.M., Li, G., Macek, B., Mortensen, P., Pesch, R., Makarov, A., Lange, O., Horning, S., Mann, M., Parts per million mass accuracy on an Orbitrap mass spectrometer via lock mass injection into a C-trap. Mol. Cell. Proteomics 4 (2005), 2010–2021.
Palm, N.W., Rosenstein, R.K., Yu, S., Schenten, D.D., Florsheim, E., Medzhitov, R., Bee venom phospholipase A2 induces a primary type 2 response that is dependent on the receptor ST2 and confers protective immunity. Immunity 39 (2013), 976–985.
Perez-Riverol, Y., Csordas, A., Bai, J., Bernal-Llinares, M., Hewapathirana, S., Kundu, D.J., Inuganti, A., Griss, J., Mayer, G., Eisenacher, M., et al. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res. 47:D1 (2019), D442–D450.
Piliponsky, A.M., Romani, L., The contribution of mast cells to bacterial and fungal infection immunity. Immunol. Rev. 282 (2018), 188–197.
Popov, L.M., Marceau, C.D., Starkl, P.M., Lumb, J.H., Shah, J., Guerrera, D., Cooper, R.L., Merakou, C., Bouley, D.M., Meng, W., et al. The adherens junctions control susceptibility to Staphylococcus aureus α-toxin. Proc. Natl. Acad. Sci. USA 112 (2015), 14337–14342.
Prabhakara, R., Foreman, O., De Pascalis, R., Lee, G.M., Plaut, R.D., Kim, S.Y., Stibitz, S., Elkins, K.L., Merkel, T.J., Epicutaneous model of community-acquired Staphylococcus aureus skin infections. Infect. Immun. 81 (2013), 1306–1315.
Profet, M., The function of allergy: immunological defense against toxins. Q. Rev. Biol. 66 (1991), 23–62.
Pundir, P., Liu, R., Vasavda, C., Serhan, N., Limjunyawong, N., Yee, R., Zhan, Y., Dong, X., Wu, X., Zhang, Y., et al. A Connective Tissue Mast-Cell-Specific Receptor Detects Bacterial Quorum-Sensing Molecules and Mediates Antibacterial Immunity. Cell Host Microbe 26 (2019), 114–122.e8.
Reber, L.L., Hernandez, J.D., Galli, S.J., The pathophysiology of anaphylaxis. J. Allergy Clin. Immunol. 140 (2017), 335–348.
Ritchie, M.E., Phipson, B., Wu, D., Hu, Y., Law, C.W., Shi, W., Smyth, G.K., limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res., 43, 2015, e47.
Rouha, H., Weber, S., Janesch, P., Maierhofer, B., Gross, K., Dolezilkova, I., Mirkina, I., Visram, Z.C., Malafa, S., Stulik, L., et al. Disarming Staphylococcus aureus from destroying human cells by simultaneously neutralizing six cytotoxins with two human monoclonal antibodies. Virulence 9 (2018), 231–247.
Schneider, L.A., Schlenner, S.M., Feyerabend, T.B., Wunderlin, M., Rodewald, H.R., Molecular mechanism of mast cell mediated innate defense against endothelin and snake venom sarafotoxin. J. Exp. Med. 204 (2007), 2629–2639.
Scholten, J., Hartmann, K., Gerbaulet, A., Krieg, T., Müller, W., Testa, G., Roers, A., Mast cell-specific Cre/loxP-mediated recombination in vivo. Transgenic Res. 17 (2008), 307–315.
Sintobin, I., Siroux, V., Holtappels, G., Pison, C., Nadif, R., Bousquet, J., Bachert, C., Sensitisation to staphylococcal enterotoxins and asthma severity: a longitudinal study in the EGEA cohort. Eur. Respir. J., 54, 2019, 1900198.
Starkl, P., Marichal, T., Gaudenzio, N., Reber, L.L., Sibilano, R., Tsai, M., Galli, S.J., IgE antibodies, FcepsilonRIalpha, and IgE-mediated local anaphylaxis can limit snake venom toxicity. J. Allergy Clin. Immunol. 137 (2016), 246–257.e11.
Stemeseder, T., Klinglmayr, E., Moser, S., Lueftenegger, L., Lang, R., Himly, M., Oostingh, G.J., Zumbach, J., Bathke, A.C., Hawranek, T., Gadermaier, G., Cross-sectional study on allergic sensitization of Austrian adolescents using molecule-based IgE profiling. Allergy 72 (2017), 754–763.
Stentzel, S., Teufelberger, A., Nordengrun, M., Kolata, J., Schmidt, F., van Crombruggen, K., Michalik, S., Kumpfmuller, J., Tischer, S., Schweder, T., et al. Staphylococcal serine protease-like proteins are pacemakers of allergic airway reactions to Staphylococcus aureus. J. Allergy Clin. Immunol. 139 (2017), 492–500.e8.
Sullivan, B.M., Liang, H.E., Bando, J.K., Wu, D., Cheng, L.E., McKerrow, J.K., Allen, C.D., Locksley, R.M., Genetic analysis of basophil function in vivo. Nat. Immunol. 12 (2011), 527–535.
Takai, T., Li, M., Sylvestre, D., Clynes, R., Ravetch, J.V., FcR gamma chain deletion results in pleiotrophic effector cell defects. Cell 76 (1994), 519–529.
Torres, A., Rello, J., Update in community-acquired and nosocomial pneumonia 2009. Am. J. Respir. Crit. Care Med. 181 (2010), 782–787.
Untersmayr, E., Diesner, S.C., Oostingh, G.J., Selzle, K., Pfaller, T., Schultz, C., Zhang, Y., Krishnamurthy, D., Starkl, P., Knittelfelder, R., et al. Nitration of the egg-allergen ovalbumin enhances protein allergenicity but reduces the risk for oral sensitization in a murine model of food allergy. PLoS ONE, 5, 2010, e14210.
Van Zele, T., Gevaert, P., Watelet, J.B., Claeys, G., Holtappels, G., Claeys, C., van Cauwenberge, P., Bachert, C., Staphylococcus aureus colonization and IgE antibody formation to enterotoxins is increased in nasal polyposis. J. Allergy Clin. Immunol. 114 (2004), 981–983.
Voehringer, D., Protective and pathological roles of mast cells and basophils. Nat. Rev. Immunol. 13 (2013), 362–375.
Voehringer, D., Liang, H.E., Locksley, R.M., Homeostasis and effector function of lymphopenia-induced “memory-like” T cells in constitutively T cell-depleted mice. J. Immunol. 180 (2008), 4742–4753.
Walch, M., Dotiwala, F., Mulik, S., Thiery, J., Kirchhausen, T., Clayberger, C., Krensky, A.M., Martinvalet, D., Lieberman, J., Cytotoxic cells kill intracellular bacteria through granulysin-mediated delivery of granzymes. Cell 157 (2014), 1309–1323.
Zhang, X., Smits, A.H., van Tilburg, G.B., Ovaa, H., Huber, W., Vermeulen, M., Proteome-wide identification of ubiquitin interactions using UbIA-MS. Nat. Protoc. 13 (2018), 530–550.