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NIH

Julie A. Segre, Ph.D.

Chief & Senior Investigator, Translational and Functional Genomics Branch
Head, Microbial Genomics Section

Scientific Summary

The Microbial Genomics Section (MGS) explores the full genetic diversity of human-associated microbiota (bacteria, fungi, viruses) which contribute to both health and disease. We study and understand health with the perspective that humans coexist with billions of microbiota in our guts, on our skin and covering all epithelial surfaces. Pathogenic bacteria flourish and compete within a larger symbiotic microbial community, whose DNA is collectively referred to as the microbiome. The Microbial Genomics Section developed methods to characterize microbial communities with genomic sequencing and analysis, which offer significant advantages over traditional culture-based studies to capture microbial diversity.

The Section explores two major areas of clinical microbial genomics: foundational studies of the human skin microbiome and tracking hospital-associated bacterial pathogens. We performed the first skin bacterial survey, characterizing the diversity of microbes that live on normal volunteers, and determined that humans are ecosystems with niche-dependent bacterial populations (dry, moist or oily regions). Fungal diversity, by contrast, is more topographically driven with the greatest diversity observed on feet (toenails, toeweb, plantar heel).

Klebsiella pneumonaeTogether with clinical collaborators, we extended these studies to patient populations with common atopic dermatitis (AD, eczema; OMIM 603165) and rare primary immune deficiencies. We focus our studies on AD because these patients typically respond to various antimicrobial therapies, but there are no biomarkers to direct an individual patient's treatment. Our longitudinal study of pediatric AD patients shows a drop in skin microbial diversity and an increase in Staphylococcus aureus with disease flare. Our current efforts are directed at defining and assessing the role of specific strains of Staphylococcus aureus in the progression to disease flare.  Mechanistically, we are assessing the function of skin-associated bacteria in priming the immune system and driving AD with animal models.

Future microbiome studies transition from survey-based studies of microbes to full metagenomic sequencing. To build the resources needed for skin microbiome analysis, we sequenced reference skin microbes, such as the commensal Staphylococcus epidermidis.  We have determined that the S. epidermidis pan-genome is quite large with 80 percent core genes (~2,000 total) and the remaining 20 percent of genes selected from a large pool of ~5000 genes. These sequenced reference genomes enabled us to fully harness the power of strain tracking across individuals and between skin body sites. 

As a second area of focus for the Microbial Genomics Section, we developed pipelines to tracking hospital-associated bacterial pathogens with whole-genome sequencing.  We retrospectively reconstructed a polymicrobial outbreak of multi-drug resistant Acinetobacter baumannii that swept through the NIH Clinical Center in 2007 to elucidate the role of recombination in diversification. The last line of antibiotic defense against A. baumannii is colistin, a polymixin peptide.  Therefore, we followed up the outbreak tracking with genomic sequence studies to identify molecular changes that conferred colistin resistance.  Genomic studies are complemented by microbiological growth studies to assess variants' effects on the organism's overall fitness. Our long-term goal is to create a drug strategy that capitalizes on the bacterium's loss of fitness typically associated with acquisition of antibiotic resistance. 

While our genomic studies of A. baumannii were performed retrospectively, our carbapenem-resistant Klebsiella pneumonaie studies were carried out prospectively.  In 2011, 17 patients were infected with a single K. pneumonaie isolate that is highly virulent and has now evolved resistance to all known antibiotics.  For the first time, our real-time genomic sequencing tracked exact patient-to-patient routes of transmission within the NIH Clinical Center and informed epidemiologists' actions to monitor and control this outbreak.  We have now extended these studies to explore transfer between bacterial species of the plasmid that encodes carbapenemase. The section's mission is to use genomic information to model outbreaks, monitor evolution of antibiotic resistance and develop risk assessment strategies.

Microbial Genomics Section Members

Allyson Byrd, B.A., Graduate Student
Sean Conlan, Ph.D. Staff Scientist
Clay Deming, M.S. Biologist
Cynthia Ng, B.A. Biologist
Julia Oh, Ph.D. Postdoctoral Fellow
Evan Snitkin, Ph.D. Postdoctoral Fellow
Alex Valm, Ph.D. Postdoctoral Fellow

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Last Updated: October 19, 2015