BSc, MD, PhD, FRCPC
Our laboratory is studying the impact of the microbial communities (i.e. the microbiome) in the lungs of patients with cystic fibrosis and other chronic lung diseases. We also participate in collaborative research investigating various aspects of lung injury, repair, and transplantation.
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane regulator (CFTR) and is characterized in the lungs by deterioration of pulmonary function resulting from repetitive episodes of bacterial infection of the airways. There has been growing awareness in recent years that the lungs in CF are infected by multiple microorganisms, and that interspecies interactions impact on clinical course, for example, by altering the virulence of CF-related pathogens.
Differences in the composition of pulmonary microbial communities may therefore account in part for the different clinical outcomes seen in patients infected by the same presumed pathogen. The structure and dynamics of these communities, however, remain largely unknown. A thorough characterization of these communities and how they change over the course of disease progression and treatment is a crucial first step to understanding how interactions within these communities and between the communities and their hosts impact on clinical outcomes.
Metagenomics is the study of communities of organisms using genetic material taken directly from their natural environment. Metagenomics' power comes from its ability to assess community structure and dynamics without needing first to isolate and propagate organisms in the laboratory. Free of the constraints and limitations imposed by culture-based methods, it provides a largely unbiased and semi-quantitative assessment of the diversity of the microbial community (i.e. microbiome) of interest.
Communities can be studied without any prior knowledge and without the need for specific selective conditions, by isolating and characterizing DNA (and/or RNA) directly from the metagenome (and/or metatranscriptome) – that is, the combined genomes of all species present in the specimen of interest.
Together with other members of a multidisciplinary CIHR Emerging Team, and as part of the Canadian Microbiome Initiative, we are investigating the impact of the microbiome of the lungs of patients with CF and other chronic lung diseases, using a combination of microbiologic culture-based studies and next-generation sequencing based metagenomic and metatranscriptomic approaches. Our laboratory is focused in particular on studying inter- and intra-species diversity of pulmonary bacterial communities in CF patients, and how such diversity affects antibiotic response and resistance. This work will shed light on why seemingly appropriate antibiotic treatments often fail in this patient population, and should help in the development of more individualized therapies for patients with CF and other polymicrobial lung infections
Maughan H, Wang PW, Diaz-Caballero J, Fung P, Gong Y, Donaldson SL, Yuan L, Keshavjee S, Zhang Y, Tullis DE, Hwang DM, Guttman DS (2012) Microbiome analysis of the cystic fibrosis lung by serial Illumina sequencing of bacterial 16S rRNA hypervariable regions. PLoS One, 7(10):e45791.
Maughan H, Cunningham KS, Wang PW, Zhang Y, Cypel M, Chaparro C, Tullis DE, Waddell TK, Keshavjee S, Liu M, Guttman DS, Hwang DM. Pulmonary bacterial communities in surgically resected noncystic fibrosis bronchiectasis lungs are similar to those in cystic fibrosis. Pulm Med. 2012;2012:746358.
Sato M, Hwang DM, Ohmori-Matsuda K, Chaparro C, Waddell TK, Singer LG, Hutcheon MA, Keshavjee S. Revisiting the pathologic finding of diffuse alveolar damage after lung transplantation. J Heart Lung Transplant. 2012; 31:354-363.
Sato M, Hwang DM, Guan Z, Yeung JC, Anraku M, Wagnetz D, Hirayama S, Waddell TK, Liu M, Keshavjee S. Regression of allograft airway fibrosis: the role of MMP-dependent tissue remodeling in obliterative bronchiolitis after lung transplantation. Am J Pathol. 2011; 179:1287-1300.