Allergic diseases affect an increasing number of people in the United States and worldwide. Among these diseases, allergic asthma is particularly concerning because of its high morbidity and financial burden. While medical science has made profound advances in the treatment of asthma symptoms, a true cure for the disease remains elusive. Many researchers seeking a cure for asthma have focused their attention on the immune system. In asthma, the immune system reacts inappropriately to common, harmless products (allergens) in the environment, such as house dust mite (HDM). Normal individuals do not experience an immune response when encountering such allergens and are said to be tolerant to the allergen. However, asthma suffers lack this tolerance and experience a damaging inflammatory response. Understanding how tolerance develops and why it is lacking in asthma is critical for development of a true cure. The immune system possesses regulatory elements that help control immune responses. Previous work has shown that one of these, the regulatory T cell (Treg), plays a key role in the establishment of tolerance to allergens. However, the mechanisms by which Tregs are generated and prevent asthma in healthy people remains unknown. One possible influence on the immune system is the microbiome, the community of microorganisms that live on and within each of us. Over the past decade, researchers have discovered that the microbiome can exert regulatory effects on the immune system, including induction of Tregs. Many studies have shown that loss or disruption of the microbiome promotes allergy and asthma; thus, the microbiome may have a key influence on tolerance development. This proposal hypothesizes that the microbiome promotes tolerance to allergens like house dust mite (HDM) through promotion of Treg formation. The overall goal of this proposal is to determine the effect of HDM exposure on the microbiome and the relationship of the microbiome to allergic disease and tolerance. Overall Impact: Completion of the proposed aims may reveal new opportunities for microbiome-based therapies that could provide curative treatments for asthma.

Public Health Relevance

Asthma is a chronic disorder of the lungs that leads to decreased quality of life and major economic burden in both developed and undeveloped nations alike. This proposal aims to identify the role of the microbiome in the acute inflammatory and resolution stages of house dust mite-induced asthma using a mouse model of allergic airway disease. As a result, these studies may provide insight into the disease processes of asthma and aid in the development of novel, microbiome-targeted therapies to treat asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30HL126324-03
Application #
9187045
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Tigno, Xenia
Project Start
2014-12-01
Project End
2018-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06032
Fox, Brandon M; Adami, Alexander J; Hull, Travis D (2018) Reinforcing our pipeline: trainee-driven approaches to improving physician-scientist training. J Clin Invest 128:3206-3208
Zelin, Nicole Sitkin; Hastings, Charlotte; Beaulieu-Jones, Brendin R et al. (2018) Sexual and gender minority health in medical curricula in new England: a pilot study of medical student comfort, competence and perception of curricula. Med Educ Online 23:1461513
Adami, Alexander J; Bracken, Sonali J; Guernsey, Linda A et al. (2018) Early-life antibiotics attenuate regulatory T cell generation and increase the severity of murine house dust mite-induced asthma. Pediatr Res 84:426-434
Bracken, Sonali J; Adami, Alexander J; Rafti, Ektor et al. (2018) Regulation of IgE activity in inhalational tolerance via formation of IgG anti-IgE/IgE immune complexes. Clin Mol Allergy 16:13
Adami, Alexander J (2017) Lessons in leadership and the impact of trainee leaders. J Clin Invest 127:3571-3574
Adami, Alexander J; Bracken, Sonali J (2016) Breathing Better Through Bugs: Asthma and the Microbiome. Yale J Biol Med 89:309-324
Hong, Bo-Young; Maulén, Nancy Paula; Adami, Alexander J et al. (2016) Microbiome Changes during Tuberculosis and Antituberculous Therapy. Clin Microbiol Rev 29:915-26
Adami, Alexander J; Cervantes, Jorge L (2015) The microbiome at the pulmonary alveolar niche and its role in Mycobacterium tuberculosis infection. Tuberculosis (Edinb) 95:651-658