Transdisciplinary Strategies for the Characterization of Mucosal Immune Responses to Enteric Pathogens

The gastrointestinal mucosal immune system has the daunting task of maintaining immune homeostasis by eliminating potentially harmful microorganisms and limiting tissue injury while inducing tolerogenic responses to luminal antigens including innocuous food, commensal bacteria and self-antigens. This carefully orchestrated system depends on elaborate down-regulating mechanisms that mediate and maintain a state of tolerance under normal conditions. Changes in such delicate balance are linked to the development of gastrointestinal pathology as well as systemic disease states. Despite the rapid increase in our appreciation of the gastrointestinal immune system, there is still a major disconnect between the description of how mucosal immune responses are organized and controlled and an insufficient mechanistic understanding of how such responses shape and influence disease outcome and pathogenesis. By using model enteric microorganisms Helicobacter pylori and Clostridium difficile, this dissertation presents a systematic effort to generate novel mechanistic hypothesis based on computational predictions and experimentally elucidate the mechanisms of action underlying mucosal immune responses and pathology in the gut. In this thesis I present i) an overview on mucosal immunology and the need to develop novel therapeutics that limit the pathogenic effects of invading bacteria while maintaining their protective functions, ii) the role of miRNAs in the modulation of immune responses to enteric pathogens, iii) the mechanisms by which Helicobacter pylori is able to limit effector inflammatory responses required for bacterial clearance thus favoring tolerance over immunity, iv) intracellular mechanisms of immune evasion that contribute to bacterial persistence and chronic infection. The knowledge generated throughout this dissertation exemplifies how a combination of computational modeling, immunoinformatics and experimental immunology holds enormous potential for discovering unforeseen targets and developing novel vaccines and cures for infectious, allergic and immune-mediated diseases.

Name thesis:degree_name

Ph. D.

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Genetics, Bioinformatics, and Computational Biology

Department dc:contributor.department

Animal and Poultry Sciences

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2015

Author dc:creator

• Viladomiu Pujol, Monica

Chairs dc:contributor.committeechair

• Bassaganya-Riera, Josep
• Hontecillas-Magarzo, Raquel

Committee members dc:contributor.committeemember

• Bevan, David R.
• Michalak, Pawel

• mucosal immunology
• bioinformatics
• helicobacter pylori
• clostridium difficile
• miRNA

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Dc Identifier Other

vt_gsexam:6057

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/74404