100. Shared genetic variants among Streptococcus pneumoniae isolates causing complicated pneumonia and empyema in children
Session: Oral Abstract Session: Diagnostics: Typing/Sequencing
Thursday, October 8, 2015: 10:45 AM
Room: 7--AB
Background: Pneumococcal conjugate vaccines (PCV) have reduced the incidence of invasive pneumococcal disease (IPD) in the US. However, complicated pneumonia with parapneumonic empyema (PPE) increased after the introduction of PCV7. In Utah, PPE was primarily associated with Streptococcus pneumoniae serotype 1 infection before PCV7 introduction, whereas after PCV7 licensure serotypes 3, 7F, and 19A emerged as important causes of PPE and produced a clinical phenotype similar to serotype 1.

Methods: To examine bacterial genetic factors associated with PPE, and investigate whether a propensity to cause PPE is related to shared genetic factors across pneumococcal serotypes, we performed whole-genome sequencing of 214 invasive S. pneumoniae isolates from Utah children collected pre and post PCV licensure (1996-2000 and 2001-2013 respectively). We mapped our sequences against a number of published S. pneumoniae genomes (R6, Spn23F and INV104B). To find variants associated with PPE we used a probabilistic Fst approach to measure genetic differentiation between PPE and non-PPE causing strains.

Results: We identified a total of 5.9-7.8x10^4 single nucleotide polymorphisms and 2.5-2.6x10^5 putative structural variants (minor allele frequency > 5%) across strains. We identified genetic differentiation at a number of regions throughout the S. pneumoniae genome, including previously identified and putative virulence factors such as zmpB, cpbF, and pspA. Other areas of differentiation correspond to novel putative PPE virulence genes such as ABC-MSP. Both point mutations and larger structural variants were associated with PPE. To ensure that differential strain enrichment did not confound our results, we performed genetic analyses between PPE and non-PPE causing strains within single serotypes (1, 3, 7F, and 19A) with similar results.

Conclusion: Our study demonstrates genomic variation in S. pneumoniae associated with PPE, and presents new candidate genes for functional screens in PPE disease models. Identification of genetic variants enriched in pneumococcal isolates causing PPE is a critical step in evaluating potential new targets for treatment and prevention of complicated pneumonia in children.

Edward Osborne, PhD1,2, Anne J. Blaschke, MD, PhD, FIDSA, FPIDS3, Krow Ampofo, MD, FIDSA, FPIDS3, Hillary Crandall, MD, PhD4, Jarrett Killpack, BSc3, Chris R. Stockmann, MSc3, Andrew P. Farrell, PhD1,2, Kael F Fischer, PhD5, Andrew Pavia, MD, FIDSA, FSHEA, FPIDS3, Karen Eilbeck, PhD6, Robert Schlaberg, MD, MPH7, Mark Yandell, PhD1,2 and Carrie L. Byington, MD, FIDSA8, (1)Human Genetics, University of Utah, Salt Lake City, UT, (2)Utah Center for Genetic Discovery, Salt Lake City, UT, (3)Department of Pediatrics, Division of Pediatric Infectious Diseases, University of Utah School of Medicine, Salt Lake City, UT, (4)Department of Pediatrics, Salt Lake City, UT, (5)Pathology, University of Utah School of Medicine, Salt Lake City, UT, (6)Department of Biomedical Informatics, University of Utah, Salt Lake City, UT, (7)Department of Pathology, University of Utah, Salt Lake City, UT, (8)Pediatrics, University of Utah, Salt Lake City, UT

Disclosures:

E. Osborne, None

A. J. Blaschke, BioFire Diagnostics, LLC: Collaborator , Consultant and Scientific Advisor , Consulting fee , Licensing agreement or royalty and Research support
bioMerieux, Inc: Collaborator , Investigator and Scientific Advisor , Consulting fee and Research support
Merck: Investigator , Research grant

K. Ampofo, None

H. Crandall, None

J. Killpack, None

C. R. Stockmann, None

A. P. Farrell, None

K. F. Fischer, None

A. Pavia, None

K. Eilbeck, None

R. Schlaberg, IDbyDNA: Consultant and Shareholder , Licensing agreement or royalty

M. Yandell, IDbyDNA: Shareholder , Licensing agreement or royalty

C. L. Byington, NIH: Grant Investigator , Grant recipient
BioFire Diagnostics: Intellectual Property for the FilmArray , Intellectual Property

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