Chronic Bacterial Pathogenesis
We are interested in how chronic bacterial pathogens persist in the face of antimicrobial therapy and the adaptive host response. To understand this complex phenomenon, we have promulgated the rubric of “Bacterial Plurality” which embodies the concept that chronic pathogens display enormous heterogeneity at many levels including: phenotypic, metabolic, and genotypic. The reasoning behind the development of this theoretical construct was to provide a paradigm that more accurately models chronic pathogenic processes so that it will be possible to develop rational therapies for these recalcitrant diseases. It is our belief that the extant paradigms of bacterial pathogenesis passed down to us from Robert Koch and developed for acute epidemic infections, although powerful and useful for clonal planktonic infections, acted for decades as blinders towards our understanding of chronic infections.
As part of our studies of bacterial plurality we have participated in the development of a new understanding of bacterial ecology, which includes the realization that bacteria have a developmental life cycle, can exist as solitary organisms or as part of a complex interacting multicellular community, and can phenotypically adapt to changing environmental conditions. Phenotypic heterogeneity is explained by the fact that nearly all bacteria can form biofilms or even more complex ordered large-scale structures for protection, generation of reducing power, and dispersal; metabolic heterogeneity by the understanding of limiting nutrient fluxes into a biofilm, and genotypic heterogeneity by the distributed genome hypothesis (DGH) which we advanced in 2001. The DGH states that chronic bacterial pathogens utilize a survival strategy wherein a large set of genes are distributed among a population and are not found in all members of a species; thus there exists a supra-genome at the population level which is far greater in size than the genome of any one organism. The DGH includes the concept that energetic methods of horizontal gene transfer (HGT) are population-based virulence factors that evolved specifically to create diversity and drive strain evolution and that the distribution of contingency genes among a population serves as a supra-virulence factor that provides for improved population survival through increased rates of horizontal gene transfer which provides the engine for rapid adaptation to environmental conditions through the reassortment of genes among strains.
Using the massively parallel pyrosequencing technology of 454 LifeSciences and a suite of bioinformatic and mathematical modeling tools developed in-house we have: 1) performed whole genome sequencing on over 100 clinical strains of pathogenic bacteria representing six species; and 2) performed comparative genomics on over 400 bacterial strains representing 24 species. The data from these studies have demonstrated that the DGH holds for all bacterial species examined including pathogens and nonpathogens alike; and that the supragenomes for most of these species are several times the size of the species’ core genomes. Importantly the species examined cover gram-negatives, gram-positives, gram-indeterminates, spirochetes, professional pathogens, opportunistic pathogens, and free-living environmental and commensal organisms. We therefore feel comfortable in stating that the DGH is broadly applicable across the entire spectrum of free-living bacteria and that bacterial diversity provides bacterial species, as a whole – regardless of their individual environmental niches, with the ability to persist in the face of multi-faceted attacks.
More recently we have been expanding the concept of population-based virulence factors which include phenomena that exist only at the population-level and are thus nonobservable at the level of the individual bacterium. These include biofilm formation, caserna construction, and other complex cellular organizations such as nanowires; bacterial communication systems such as quorum sensing and vesicle formation and dispersement; and horizontal gene transfer mechanisms. Collectively these systems imbue bacteria with a type of intelligence analogous to cellular automation.
Human Disease, Susceptibility, and Performance Gene Mapping and Cloning
We are involved in a number of human gene identification projects which utilize microsatellite-based mapping, SNP-based mapping and gene association studies, and candidate gene cloning technologies. Toward this end we have heavily invested in high throughput genomic and expressomic technologies and the bioinformatic infrastructure to support these endeavors. Our laboratory has mapped genes for Crouzon syndrome, hereditary pancreatitis, DAIA, ectrodactyly, severe pediatric GERD, and Dupuytren’s contracture; and cloned genes for Crouzon and Jackson-Weiss syndromes and hereditary pancreatitis. Ongoing studies include cloning the Dupuytren’s gene, and mapping genes associated with human performance through a grant from the United States Air Force.
Selected Publications (See all Garth Ehrlich's publications in PubMed.)
"Chronic surgical site infection due to suture-associated polymicrobial biofilm"
Kathju S, Nistico L, Hall-Stoodley L, Post JC, Ehrlich GD, and Stoodley P
Surgical Infections, Accepted, 2009
"Biofilm formation by ica-positive and ica-negative strains of Staphylococcus epidermidis in vitro"
Dice B, Stoodley P, Buchinsky F, Metha N, Ehrlich GD and Hu FZ
Biofouling, 25(4):367-375, 2009
"Medical treatment of craniosynostosis: recombinant Noggin inhibits coronal suture closure in the rat craniosynostosis model"
Shen K, Krakora SM, Cunningham M, Singh M, Wang X, Hu FZ, Post JC, and Ehrlich GD
Orthodontics & Craniofacial Research, 12:254-262, 2009
"Gene expression differences in infected and non-infected middle ear complementary DNA libraries"
Kerschner JE, Horsey E, Ahmed A, Erbe C, Khampang P, Cioffi J, Hu FZ, Post JC, and Ehrlich GD
Archives of Otolaryngology-Head & Neck Surgery, 135(1):33-39, 2009
"Characterization of biofilm matrix, degradation by DNase treatment and evidence of capsule downregulation in Streptococcus pneumoniae clinical isolates"
Hall-Stoodley L, Nistico L, Sambanthamoorthy K, Dice B, Nguyen D, Mershon WJ, Johnson C, Hu FZ, Stoodley P, Ehrlich GD, and Post JC
BMC Microbiology, 8:173, 2008
"What makes pathogens pathogenic"
Ehrlich GD, Hiller NL, and Hu FZ
Genome Biology, 9;6:225, 2008
"Age of child, more than HPV type, is associated with clinical course in recurrent respiratory papillomatosis"
Buchinsky FJ, Donfack J, Derkay CS, Choi SS, Conley SF, Myer III CM, McClay JE, Campisi P, Wiatrak BJ, Sobol SE, Schweinfurth JM, Tsuji DH, Hu FZ, Rockette HE, Ehrlich GD, and Post JC
PLoS ONE, 3(5):e2263, 2008
"Differential expression of chaperonin containing T-complex polypeptide (CCT) subunits during fetal and adult skin wound healing"
Satish L, Abdulally A, Oswald D, Johnson S, Hu FZ, Post JC, Ehrlich GD, and Kathju S
Cell Stress Chaperones, 13:527-533, 2008
"Identification of differentially expressed genes in fibroblasts derived from patients with Dupuytren's Contracture"
Satish L, Laframboise WA, O'Gorman DB, Johnson S, Janto B, Gan BS, Baratz ME, Hu FZ, Post JC, Ehrlich GD, and Kathju S
BMC Medical Genomics, 1:10, 2008
"Strain-specific virulence phenotypes of Streptococcus pneumoniae assessed using the Chinchilla laniger model of otitis media"
Forbes ML, Horsey E, Hiller NL, Buchinsky FJ, Hayes JD, Compliment JM, Hillman T, Ezzo S, Shen K, Keefe R, Barbadora K, Post JC, Hu FZ, and Ehrlich GD
PLoS ONE, 3(4):e1969, 2008
"Population-level virulence factors amongst pathogenic bacteria: relation to infection outcome"
Hu FZ and Ehrlich GD
Future Microbiology, 3(1):31-42, 2008
"The role of biofilms in otolaryngologic infections: update 2007"
Post JC, Hiller NL, Nistico L, Stoodley P, and Ehrlich GD
Current Opinion in Otolaryngology & Head and Neck Surgery, 15(5):347-351, 2007
"Insights into the genome of large sulfur bacteria revealed by analysis of single filaments"
Mussmann M, Hu FZ, Richter M, de Beer D, Preisler A, Jørgensen BB, Huntemann M, Glöckner FO, Amann R, Koopman WJ, Lasken RS, Janto B, Hogg J, Stoodley P, Boissy R, and Ehrlich GD
PLoS Biology, 5(9):e230, 2007
"Comparative genomic analyses of seventeen Streptococcus pneumoniae strains: insights into the pneumococcal supragenome"
Hiller NL, Janto B, Hogg JS, Boissy R, Yu S, Powell E, Keefe R, Ehrlich NE, Shen K, Hayes J, Barbadora K, Klimke W, Dernovoy D, Tatusova T, Parkhill J, Bentley SD, Post JC, Ehrlich GD, and Hu FZ
Journal of Bacteriology, 189(22):8186-8195, 2007
"Virulence phenotypes of low-passage clinical isolates of nontypeable Haemophilus influenzae assessed using the chinchilla laniger model of otitis media"
Buchinsky FJ, Forbes ML, Hayes JD, Shen K, Ezzo S, Compliment J, Hogg J, Hiller NL, Hu FZ, Post JC, and Ehrlich GD
BMC Microbiology, 7:56, 2007