Abstract
Despite insights gained through experimental models, the set of bacterial genes important for human infection is unclear for many of our most threatening pathogens. Klebsiella pneumoniae is a leading cause of health care-associated infections (HAIs) and commonly colonizes hospitalized patients, but the factors that determine whether a particular isolate causes disease or remains a colonizer are poorly understood. To identify bacterial genes associated with K. pneumoniae infection, a case-control study was performed comparing infected and asymptomatic colonized patients. Comparative bacterial genomics was combined with a conditional logit model that identified patient factors differentiating cases from controls. This method identified five gene loci associated with infection after adjustment for patient factors, including a psicose sugar utilization locus that was validated as a fitness factor during mouse lung infection. These results indicate that bacterial genome-wide association studies of patients can identify loci associated with HAIs and important in infection models. IMPORTANCE Klebsiella pneumoniae is a common cause of infections in the health care setting. This work supports a paradigm for K. pneumoniae pathogenesis where the accessory genome, composed of genes present in some but not all isolates, influences whether a strain causes infection or asymptomatic colonization, after accounting for patient-level factors. Identification of patients at high risk of infection could allow interventions to prevent or rapidly treat K. pneumoniae infections.
Original language | English (US) |
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Article number | e00015-18 |
Journal | mSystems |
Volume | 3 |
Issue number | 3 |
DOIs | |
State | Published - Jun 2018 |
Funding
This project was funded by the Michigan Institute for Clinical and Translational Research (UL1TR000433 and UL1TR002240) and the National Institutes of Health (R01AI125307) to M.A.B. R.M.M. and M.A.B. thank Eric Martens and Maria Sandkvist for the use of reagents and instrumentation for substrate identification and Eric Martens and Robert Glowacki for assistance analyzing growth curves. This project was funded by the Michigan Institute for Clinical and Translational Research (UL1TR000433 and UL1TR002240) and the National Institutes of Health (R01AI125307) to M.A.B. R.M.M., W.W., K.R., P.N.M., and M.A.B. conceived and designed the study. R.M.M. acquired patient isolates, acquired MLST data, and performed in vitro and in vivo experiments. J.C., D.M.M., and K.R. acquired patient demographic data. W.W. performed bioinformatic analysis of sequenced isolates. A.P. assembled sequenced genomes and generated the WGS phylogenetic tree. R.M.M., W.W., A.P., E.S., L.Z., and K.R. analyzed the data. R.M.M. wrote the manuscript draft. J.C., W.W., L.Z., D.M.M., K.R., P.N.M., and M.A.B. critically revised the manuscript. M.A.B. supervised the study. We declare that we have no conflicts of interest.
Keywords
- Comparative genomics
- Intestinal colonization
- Klebsiella
- Pathogenesis
- Psicose
- Tellurite
ASJC Scopus subject areas
- Microbiology
- Physiology
- Biochemistry
- Ecology, Evolution, Behavior and Systematics
- Modeling and Simulation
- Molecular Biology
- Genetics
- Computer Science Applications