Allergic airway inflammation in a model of house dust mite-induced asthma
Mucus production in airway epithelium, as determined by Period-Acid Schiff staining
Division of labor among subpopulations of mononuclear phagocytes during chronic infection
Mammals are born sterile; the gradual acquisition of a diverse and balanced microbiota, inhabiting all mucosal surfaces of the gastrointestinal tract and upper airways, as well as the lower urogenital tract and skin, begins at birth. The intergenerational transmission of microbes -predominantly from mother to child- plays a particularly important role during the ordered assembly of the microbial ecosystem. Perturbations of this assembly due to common practices affecting early childhood, such as C-section delivery, group B streptococcal prophylaxis, formula instead of breast-feeding, therapeutic and subtherapeutic antibiotic exposures and certain other sanitary measures, are all believed to have consequences that manifest later in life. In particular, allergic and chronic inflammatory conditions are more common, and more severe in children who have undergone, or have been exposed to, one or more of the above-listed interventions.
In this project, we aim to better understand how microbes, especially those present in early life, affect long-term health in models of allergic airway inflammation, food allergy, and acute and chronic intestinal infection. We test the idea that certain microbial immunomodulators, which can be both metabolites or protein products deployed to evade or counteract immunity, benefit the host by suppressing inappropriate or excessive T-cell responses to harmless food and environmental antigens. We further propose that the negative consequences of early-life interventions can be reversed by regular administration of rationally selected microbial products, with the goal of normalizing or fortifying gut homeostasis and barrier function, preventing damage cause by allergic responses at distant and systemic sites in the body, and reversing dysbiosis.
We have a long-standing interest in the immunomodulatory properties of the gastric pathobiont Helicobacter pylori, which can be exploited for the prevention and treatment of allergic disorders (food allergy, allergic airway inflammation) and of chronic intestinal inflammation. We have shown both Treg-dependent and -independent modes of action of H. pylori’s immunomodulators vacuolating cytotoxin (VacA) and g-glutamyl-transpeptidase (GGT) and of H. pylori extract in experimental models of allergic asthma, food allergy and of intestinal inflammation. We aim to now understand in more detail which cell types are targeted by H. pylori to suppress not only pathogen-specific, but also bystander immune responses; we focus on myeloid lineages and eosinophils at the interface of host and microbe. We further seek to investigate whether specific immunomodulators are suited to reverse Treg deficiencies associated with antibiotic exposures in early life, and aim to identify the time window of opportunity, administration route and dosing regimen that is most suitable for achieving long-lasting beneficial effects.
Altobelli, A., Bauer, M., Velez, K., Cover, T.L., Müller, A. Helicobacter pylori VacA Targets Myeloid Cells in the Gastric Lamina Propria To Promote Peripherally Induced Regulatory T-Cell Differentiation and Persistent Infection. MBio. 10:2 (2019).
Borbet, T.C., Zhang, X., Müller, A. and Blaser, M.J. The role of the changing human microbiome in the asthma pandemic. J Allergy Clin Immunol 144:1457-1466 (2019).
Kyburz, A., Fallegger, A., Zhang, X., Altobelli, A., Artola-Boran, M., Borbet, T., Urban, S., Paul, P., Münz, C., Floess, S., Huehn, J., Cover, T.L., Blaser, M.J., Taube, C., and Müller A. Transmaternal Helicobacter pylori exposure reduces allergic airway inflammation in offspring through regulatory T cells. J Allergy Clin Immunol. 143:1496-1512.e11 (2019).
Kyburz, K., Urban, S., Djekic, A., Floess, S., Huehn, J. Cover, T.L., and Müller, A. Helicobacter pylori and its secreted immunomodulator VacA protect against anaphylaxis in experimental models of food allergy. Clinical and Experimental Allergy. 47(10):1331-1341 (2017).
Smits, H.H., Hiemstra, P.S., Prazeres da Costa, C., Ege, M., Edwards, M., Garn, H., Howarth, P.H., Jartti, T., de Jong, E.C., Maizels, R.M., Marsland, B.J., McSorley, H.J., Müller, A., Pfefferle, P.I., Savelkoul, H., Schwarze, J., Unger, W.W., von Mutius, E., Yazdanbakhsh, M., and Taube, C. Microbes and asthma: Opportunities for intervention. J Allergy Clin Immunol. 137:690-7 (2016).
Engler, D.B., Reuter, S., van Wijck, Y., Urban, S., Kyburz, A., Maxeiner, J., Martin, H., Yogev, N., Waisman, A., Gerhard, M., Cover, T.L., Taube, C., and Müller, A. Effective treatment of allergic airway inflammation by tolerization with Helicobacter pylori-derived immunomodulators requires BATF3-dependent dendritic cell lineages and IL-10. PNAS, 111:11810-5 (2014).
Oertli, M., Noben, M., Engler, D.B., Taube, C., Gerhard, M., and Müller, A. The Helicobacter pylori virulence determinants g-glutamyl transpeptidase and vacuolating cytotoxin promote gastric colonization through tolerogenic re-programming of dendritic cells. PNAS, 110:3047-52 (2013).
Arnold, I.C., Dehzad, N., Reuter, S., Martin, H., Becher, B., Taube, C. and Müller, A. Neonatal infection with Helicobacter pylori prevents asthma through impaired dendritic cell maturation and induction of regulatory T-cells. Journal of Clinical Investigation 121:3088–3093 (2011).