Lung transplantation is the only long-term option for many end stage lung diseases, but chronic allograft dysfunction manifest as bronchiolitis obliterans syndrome (BOS) develops in e50% of recipients by 5 years and is the principal barrier to long term survival. Microbial factors are believed to play an important role in BOS pathogenesis, based on associations with certain microbial agents, linkage to host genes involved in microbial defense, and other factors. However, current understanding of the relationship between lung microbes and transplant outcome is limited by reliance on traditional methods requiring culture or a priori knowledge of specific pathogens, focus on single agents rather than communities, and an absence of comprehensive and systematic information on allograft microbial populations in lung transplant recipients in general and specifically in those with vs without BOS. Recent advances using culture-independent molecular approaches are revealing remarkable insights into microbial populations in multiple ecological niches and their roles in health and disease, but have not been applied to lung transplantation. Our group has applied this emerging technology to complex bacterial, fungal &viral populations in gut, blood and, recently, the respiratory tract. We have developed novel high stringency sampling, sequencing &analytic approaches to define microbial populations in the lower respiratory tract (LRT) by bronchoscopy, including methods to account for challenges in LRT analysis such as upper respiratory tract carryover &environmental source admixture;tools to identify lung-enriched or unique organisms;and preliminary data revealing aberrant communities and specific taxa enriched in lung transplant allografts. Our hypothesis is that an abnormal LRT microbiome is established following lung transplant, and that specific features of community composition are associated with the development of BOS, which can be identified through systematic culture-independent methodology utilizing high stringency approaches.
Our specific aims are to: (1) Define the respiratory tract microbiome established in lung transplant recipients over the first year post-transplant;(2) Determine prospectively the relationship between the allograft microbiome populations and subsequent development of BOS;(3) Define the lower respiratory tract microbiome at the time of graft dysfunction in a case-control of transplant recipients experiencing BOS compared with recipients without BOS. The proposal leverages two highly synergistic programs - lung transplant clinical research, and deep sequencing microbiome studies - with the long-term goal of providing critical understanding of microbial populations in the lung transplant respiratory tract and its role in BOS, the major impediment to long-term transplant success.

Public Health Relevance

Lung transplantation is the only option for many people with end stage lung diseases, but long term survival is limited mainly by a syndrome of late transplant failure called Bronchiolitis Obliterans Syndrome (BOS). Research suggests that microbes (bacteria, fungi, viruses) play an important role in the development of BOS, but how they colonize the transplanted lung and are related BOS is not understood. New technology now enables comprehensive study of all the microbes at a site (the microbiome), and we have developed methods to apply them to the lung. We will use these new technologies, combined with our active lung transplant research program, to understand the lung microbes (lung microbiome) in lung transplant recipients, and role leading to BOS and late transplant failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL113252-01A1
Application #
8505677
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Eu, Jerry Pc
Project Start
2013-06-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$742,869
Indirect Cost
$275,474
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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