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Exploiting the Intergenerational Immunomodulatory Properties of Helicobacter Pylori for the Treatment of Allergic Disorders


Kyburz, Andreas. Exploiting the Intergenerational Immunomodulatory Properties of Helicobacter Pylori for the Treatment of Allergic Disorders. 2017, University of Zurich, Faculty of Science.

Abstract

Helicobacter pylori is a Gram-negative, helical-shaped, flagellated and microaerophilic bacterium colonizing the human stomach of about 50 % of the world's population. During several thousand years of co-existence with humans, H. pylori has acquired abilities that allow it to evade and hijack both innate and adaptive branches of the immune system in order to persist in its host. Recently, we and others have shed light on the beneficial allergy-preventing potential of this bacterium, which is rather infamous for its pathogenic role in promoting gastritis, gastric ulcers and eventually gastric cancer. Epidemiological data showed the putative protective effects of H. pylori infection on the course of immunological diseases, including asthma, other allergic diseases, and inflammatory bowel disease (IBD). Moreover, we confirmed that in murine experimental models, H. pylori infection prevents the development of atopic asthma and IBD. Interestingly, tolerizing vaccination with H. pylori-extract, VacA or GGT, which both are immunomodulators of H. pylori, is as efficient as live infection in preventing asthma and IBD. The protective effects are particularly evident in mice infected or treated at an early age, and depend on H. pylori-mediated induction of regulatory T cells (Tregs) with highly suppressive activity as well as on IL-10 produced by specific dendritic cell (DC) subsets that are controlled by the transcription factor BATF3.
Herein, I aimed to further develop and extend these findings by using a more robust and translatable house dust mite-induced murine asthma model and by investigating the effects of maternal pre- and postnatal H. pylori exposure and its implication on asthma outcome in the murine offspring. Furthermore, I sought to assess whether food allergy, another typical TH2-dominated disease, might as well be prevented by neonatal H. pylori-specific interventions. Finally, we strived to identify the underlying mechanism of these potential H. pylori-dependent immunomodulations.
In this work, I further extended the protective effects to a range of experimental food allergy models. I could show that neonatal infection, extract and VacA treatment prevents, although less efficient and robust than in the asthma model, food allergy development through a Treg-dependent mechanism. These treatments led to a higher frequency of Tregs as well as to an increased demethylation of the Treg-specific demethylated region (TSDR) and thus, more stable and committed Tregs. Additionally, I was able to show that prenatal and postnatal transmaternal H. pylori-treatments efficiently prevent allergic asthma development in the progeny. I characterized the associated altered immune correlates such as a decreased frequency of DCs and bulk CD4+ T cells and increased frequencies of specialized RORγt+ and CXCR3+ Treg subsets in the lungs. Furthermore, these effects were linked to shifts in the microbiota composition, as well as the epigenetic signature of Tregs (i.e. the TSDR) indicating qualitative and/or quantitative differences in the stability and functionality of Tregs. Notably, transmaternal H. pylori exposure did not lead to a generalized immunosuppression due to the fact that acute infection with influenza A virus readily broke the tolerance. Most strikingly, I was able to show that the asthma-protective effects were propagated to the second generation without any further treatments, demonstrating H. pylori's ability to beneficially impact allergy susceptibility of several generations.

Abstract

Helicobacter pylori is a Gram-negative, helical-shaped, flagellated and microaerophilic bacterium colonizing the human stomach of about 50 % of the world's population. During several thousand years of co-existence with humans, H. pylori has acquired abilities that allow it to evade and hijack both innate and adaptive branches of the immune system in order to persist in its host. Recently, we and others have shed light on the beneficial allergy-preventing potential of this bacterium, which is rather infamous for its pathogenic role in promoting gastritis, gastric ulcers and eventually gastric cancer. Epidemiological data showed the putative protective effects of H. pylori infection on the course of immunological diseases, including asthma, other allergic diseases, and inflammatory bowel disease (IBD). Moreover, we confirmed that in murine experimental models, H. pylori infection prevents the development of atopic asthma and IBD. Interestingly, tolerizing vaccination with H. pylori-extract, VacA or GGT, which both are immunomodulators of H. pylori, is as efficient as live infection in preventing asthma and IBD. The protective effects are particularly evident in mice infected or treated at an early age, and depend on H. pylori-mediated induction of regulatory T cells (Tregs) with highly suppressive activity as well as on IL-10 produced by specific dendritic cell (DC) subsets that are controlled by the transcription factor BATF3.
Herein, I aimed to further develop and extend these findings by using a more robust and translatable house dust mite-induced murine asthma model and by investigating the effects of maternal pre- and postnatal H. pylori exposure and its implication on asthma outcome in the murine offspring. Furthermore, I sought to assess whether food allergy, another typical TH2-dominated disease, might as well be prevented by neonatal H. pylori-specific interventions. Finally, we strived to identify the underlying mechanism of these potential H. pylori-dependent immunomodulations.
In this work, I further extended the protective effects to a range of experimental food allergy models. I could show that neonatal infection, extract and VacA treatment prevents, although less efficient and robust than in the asthma model, food allergy development through a Treg-dependent mechanism. These treatments led to a higher frequency of Tregs as well as to an increased demethylation of the Treg-specific demethylated region (TSDR) and thus, more stable and committed Tregs. Additionally, I was able to show that prenatal and postnatal transmaternal H. pylori-treatments efficiently prevent allergic asthma development in the progeny. I characterized the associated altered immune correlates such as a decreased frequency of DCs and bulk CD4+ T cells and increased frequencies of specialized RORγt+ and CXCR3+ Treg subsets in the lungs. Furthermore, these effects were linked to shifts in the microbiota composition, as well as the epigenetic signature of Tregs (i.e. the TSDR) indicating qualitative and/or quantitative differences in the stability and functionality of Tregs. Notably, transmaternal H. pylori exposure did not lead to a generalized immunosuppression due to the fact that acute infection with influenza A virus readily broke the tolerance. Most strikingly, I was able to show that the asthma-protective effects were propagated to the second generation without any further treatments, demonstrating H. pylori's ability to beneficially impact allergy susceptibility of several generations.

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Additional indexing

Item Type:Dissertation
Referees:Müller Anne, van den Broek Maries, Marsland Benjamin, Rogler Gerhard
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2017
Deposited On:09 Jan 2018 14:23
Last Modified:09 Jan 2018 14:23

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