Date of Completion

4-27-2018

Embargo Period

4-26-2020

Keywords

microbiome, asthma, immune system, allergy, treg, regulatory t cells, house dust mite

Major Advisor

Roger S. Thrall

Associate Advisor

Joerg Graf

Associate Advisor

Craig M. Schramm

Associate Advisor

Kamal M. Khanna

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Asthma is a complex and highly heterogeneous disease characterized by inflammation of the airways, leading to a host of respiratory symptoms including wheeze and dyspnea. Asthma is the product of multiple interconnected immunological processes and represents a constellation of related, but distinct, disease phenotypes. Disturbingly, the prevalence of the disease has more than doubled since the 1980s, and efforts to understand this increase have led to the consideration of the microbiome, or the communities of microorganisms that dwell on and within us, as a key player in the pathology and regulation of this disease. While recent years have seen an explosion of new research in this area, we are only beginning to untangle to mechanisms by which the microbiome may influence asthma. Utilizing a house dust mite-induced model of experimental asthma, we explored the relationship between the microbiome and the development of both allergic airway disease and the development of tolerance and disease resolution. Herein, we report that HDM exposure has can alter the gut microbiome, producing distinct changes in the microbial community over the course of HDM exposure, but that these effects are not consistent between treatment groups. We demonstrate that oral tolerance is not inducible for HDM, in contrast to a large body of evidence in other experimental allergens such as ovalbumin, suggesting that the inhalational tolerance seen with this allergen forms by independent mechanisms within the lungs. We describe a new, clinically-relevant model of early-life antibiotic exposure that produces heightened asthma severity, including the first evidence that brief exposure to antibiotics after weaning is sufficient to alter the pathophysiology of asthma later in life. Furthermore, we demonstrate that the enhanced disease seen in this model may arise from deficiencies in pulmonary regulatory T Cells driven by loss of diversity in the microbiome. Finally, we explore the ability of antibiotic treatment to influence the development of inhalational tolerance, reporting that lifelong exposure to antibiotics can impair tolerance development through mechanisms that may be mediated by a loss of regulatory T and B Cells.

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