The mucosal immunity of the gastrointestinal (GI) tract is constituted by a complex, highly specialized and dynamic system of immune components that aim to protect the gut from external threats. The sustained exposure of the mucosal immune system of the GI tract to an enormous number of lumen antigens, requires the constant upkeep of a highly regulated balance between initiation of immune responses against harmful agents and the generation of immune tolerance towards innocuous antigens. Therefore, the regulatory component is key to preserve tissue homeostasis and a normal functioning of the system. Indeed, defective regulatory responses lead to the development of pathological conditions, including unresolved infections, and inflammatory diseases. In this study, we aim to elucidate novel mechanisms involved in host-pathogen interactions during Helicobacter pylori and Clostridium difficile infections. Indeed, this work integrates preclinical in vivo and in vitro experimental approaches together with a bioinformatics pipeline to identify and characterize novel regulatory mechanisms and molecular targets of the mucosal immune system during enteric infections. Firstly, we identified a novel regulatory mechanism during H. pylori infection mediated by a specific subset of IL10-producing tissue resident macrophages. Secondly, we employed an ex vivo H. pylori co-culture with bone marrow derived macrophages, that together with a global transcriptomic analysis and a bioinformatics pipeline, lead to the discovery of promising regulatory genes based on expression kinetics. Lastly, we characterized the innate inflammatory responses induced during the course of C. difficile infection and identified IL-1ß, and its subsequent induction of neutrophil recruitment, as a key mediator of C. difficile-induced effectors responses. The characterized regulatory mechanisms in this work show promise to lead the generation of new host-centered therapeutics through the modulation of the immune response as promising alternative treatments for infectious diseases. / Doctor of Philosophy / The immune system is responsible for protecting the human body from external threats. To achieve this goal, it must differentiate between harmless and harmful agents to only fight the latter. To combat these dangerous agents, the immune system induces highly controlled, inflammatory processes that aim to eliminate the external threat while minimizing the damage of human tissues and organs. The gastrointestinal tract is exposed to an enormous number of molecules, mostly harmless molecules from both the ingested food and the beneficial bacteria inhabiting the gut, but also from harmful bacteria and agents, only separated from the internal body structures by a thin layer called the epithelial barrier of the gut. The immune system responsible for the protection of the gastrointestinal tract includes an important regulatory component critical to maintain a proper gut function. This regulatory component regulates the generation of inflammatory processes to fight the dangerous agents, while blocking the responses against the inoffensive agents and preventing excessive tissue damage to maintain the integrity of the epithelial barrier. Indeed, a failure in the regulatory component results in severe consequences for the body's health, such as the inability to resolve infections. In this study, we aim to investigate the interaction between the human body and the enteric bacteria Helicobacter pylori and Clostridium difficile, to bring new insights in the regulatory component of the immune system of the gut. Moreover, the new mechanisms discovered in the regulatory system, might allow the development of new treatments for infectious diseases.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/104250 |
| Date | 28 January 2020 |
| Creators | Tubau Juni, Nuria |
| Contributors | Genetics, Bioinformatics, and Computational Biology, Bassaganya-Riera, Josep, Hontecillas-Magarzo, Raquel, Bevan, David R., Abedi, Vida |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf, application/x-zip-compressed |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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