Asthma is a common allergic disorder characterized airway inflammation and obstruction. Though the prevalence of allergic diseases such as asthma is increasing, the reasons are incompletely understood. Environmental, rather than genetic, factors are thought to be primarily responsible, in part because of the association of allergy with Western lifestyles. This project will examine the hypothesis that the respiratory trac and gut microbiota is a key factor in conferring susceptibility or protection to allergic diseases, including asthma. Conventionally-raised and gnotobiotic mouse models of asthma will be used to test the hypothesis that a subset of bacteria, recognized by the immune system, is responsible for modulating susceptibility to asthma. The microbiota has previously been demonstrated to play a role in asthma pathogenesis in mice, but little is known about which microbes are responsible or even where (which body habitat) these organisms reside. In the first aim of this grant, mice from various vendors with different microbiota will be screened for microbial communities that predispose to allergic inflammation of their airways. Asthma will be induced by ovalbumin sensitization followed by antigen challenge. Severity of asthma in these animals will be determined by the degree of airway obstruction and tissue inflammation in their lungs. Their respiratory and intestinal microbiota will then be characterized by bacterial 16S rRNA sequencing, and BugFACS, a technique that allows isolation and identification of viable bacteria based on their binding to immunoglobulin A (IgA), the major antibody produced at mucosal surfaces. I will identify candidate bacterial strains that impact asthma phenotypes, initially by co-housing two types of mice - those harboring a microbiota associated with severe asthma and those with a microbiota associated with mild disease. Microbial source tracking algorithms, applied to 16S rRNA datasets generated from gut and respiratory tract microbiota, will be used to correlate observed changes in asthma severity upon co-housing with uni- or bilateral invasion of bacterial strains between cagemates. I will then transplant cultured invasive strains into the respiratory tract and/or gut of germ-free mice to establish whether these strains are causally related to asthma severity. In the second aim, a small group of well phenotyped 6-8 year old children, with and without asthma, will be sampled to characterize their respiratory and fecal microbiota by 16S rRNA sequencing and BugFACS. Representative respiratory tract and gut microbial communities will be transplanted from a) a representative asthmatic donor during an acute exacerbation, b) the same asthmatic at baseline, and c) a representative healthy non-asthmatic patient, into germ-free mice. Asthma will be induced in the recipient gnotobiotic mice that will then be characterized as described above.
These aims will help dissect the relative contributions of respiratory tract and gut microbiota to disease pathogenesis and provide an approach for identifying bacterial strains that may have diagnostic and therapeutic utility.

Public Health Relevance

Asthma is a common immune disorder caused by allergic sensitization to antigens within the environment leading to airway inflammation and obstruction. The microbiota, or the collection of microbes that live in association with the mucosal surfaces, has been proposed as an important environmental factor that predisposes to allergic sensitization. To test this notion, I will characterize gnotobiotic mice colonized with the microbiota of allergic and non-allergic individuals to explore its role in modulating allergic inflammation, with the expectation that data generated from this mouse model will reveal new mechanisms of asthma pathogenesis and lead to new treatment and prevention strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI113184-03
Application #
9211283
Study Section
Allergy, Immunology, and Transplantation Research Committee (AITC)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2015-02-01
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
$162,920
Indirect Cost
$12,068
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Planer, Joseph D; Peng, Yangqing; Kau, Andrew L et al. (2016) Development of the gut microbiota and mucosal IgA responses in twins and gnotobiotic mice. Nature 534:263-6
Xu, Amy Z; Tripathi, Shivani V; Kau, Andrew L et al. (2016) Immune dysregulation underlies a subset of patients with chronic idiopathic pruritus. J Am Acad Dermatol 74:1017-20