Garth D. Ehrlich Professor Microbiology and Immunology Executive Director, Center for Genomic Sciences, ASRI 320 East North Avenue Pittsburgh, PA 15212 Tel: (412) 359-4228 Fax: (412) 359-6995 Email: gehrlich@wpahs.org Ph.D., 1987, Syracuse University, Syracuse, New York

Bacteria, chronic bacterial pathogenesis, Haemophilus, Streptococcus, otitis media, DNA sequencing, whole genome sequencing, genetics, genomics, bioinformatics, gene mapping, gene cloning, wound healing

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 performed whole genome sequencing and comparative genomics on over 40 clinical strains of pathogenic bacteria. The data from these studies have demonstrated that the DGH holds for Haemophilus influenzae, Streptococcus pneumoniae and Pseudomonas aeruginosa; and that the supragenomes for each of these species is at least three times the size of the genome for any single strain.  Importantly these three organisms cover gram-negatives, gram-positives, professional pathogens, and opportunistic pathogens, and we therefore feel comfortable that the DGH is broadly applicable across the entire spectrum of chronic free-living bacterial pathogens and that bacterial diversity provides bacterial populations, as a whole, the ability to persist in the face of multi-faceted attacks.

Human Disease, Susceptability, 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:

1. Ehrlich GD, Stoodley P, Kathju S, Zhao Y, McLeod BR, Balaban N, Hu FZ, Sotereanos NG, Costerton JW, Stewart PS, Post JC, Lin Q. Engineering Approaches for the Detection and Control of Orthopaedic Biofilm Infections. Clin Orthop Relat Res. 437:59-66, 2005
   
   
2. Gladitz, J., Antalis, P., Hu, F.Z. Post, J.C. and  Ehrlich, G.D.   Codon usage comparison of novel genes in clinical isolates of Haemophilus influenzae.  Nucleic Acids Research 33:3644-58, 2005
   
   
3. Dohar, J.E., Hebda, P.A., Veeh, R., Awad, M., Costerton, J.W., Hayes, J., Ehrlich, G.D.  Mucosal biofilm formation on middle-ear mucosa in a non-human primate model of chronic suppurative otitis media.  Laryngoscope 115:1469-72, 2005
   
   
4. F.Z. Hu, A. Nyström, A. Ahmed, R. Dopico, I. Mossberg, M. Palmquist, J. Gladitz, M. Rayner, J.C. Post, R.A. Preston, and  E hrlich, G.D.  Mapping a Gene for Dupuytren contracture to chromosome 16 in a Swedish family.  Clinical Genetics 68:424-29, 2005 
   
   
5. Kathju, S., Satish, L., Rabik, C., Rupert, T., Oswald, D., Johnson, S., Hu,  F.Z., Post, J.C., and Ehrlich, G.D.  Identification of differentially expressed genes in scarless wound healing utilizing PCR suppression subtractive hybridization.   Wound Repair and Regeneration 14(4):413-20, 2006
   
   
6. Shen, K., Antalis, P., Gladitz, J., Dice, B., Janto, B., Keefe, R., Hayes, J., Ahmed, A., Dopico, R.,  Ehrlich, N., Jocz, J., Kropp, J., Yu, S., Nistico, L., Greenberg, D. P., Barbadora, K., Post, J.C.,   Ehrlich, G.D., and Hu, F.Z.  Characterization, Distribution and Expression of Novel Genes Among Eight Clinical Isolates of Streptococcus pneumoniae.   Infection and Immuity 74(1):321-30, 2006
   
   
7. Borriello, G., Richards, L., Ehrlich, G.D., and Stewart, P.S.   Arginine or Nitrate Enhance Antibiotic Susceptibility of Pseudomonas aeruginosa in Biofilms.  Antimicrobial Agents and Chemotherapy 50(1):382-4, 2006
   
   
8. Donfack, J., Buchinsky, F.J., Derkay, C.S., Steinberg, B.M., Choi, S.S., Conley, S.F., Meyer III, C.M., McClay, J.E., Campesi, P., Hu, F.Z., Preston, R.A., Abramson, A.L., Ehrlich, G.D., and Post, J.C.   Four Mutations in Epidermodysplasia Verruciformis 1 (EVER1) Gene Are Not Contributors to Susceptibility in RRP   Int. J.Ped Oto 70(7):1235-40, 2006.
   
   
9. Fux, C., Quigley, A.M., Worel, A. Post, J.C., Zimmerli, S., Ehrlich, G.D., Veeh R.H.  Biofilm-related infections of cerebro-spinal fluid shunts.  Clinical Microbiology and Infection 12:326-332. 2006
   
   
10. Allegrucci, M.,  Hu, F.Z., Shen, K., Hayes, J., Ehrlich, G.D., Post, J.C., and Sauer, K.  Phenotypic Characterization of Streptococcus pneumoniae Biofilm Development.  J Bacteriol. 188:2325-35, 2006.
    
    
11. Sherwood ML, Buchinsky FJ, Quigley MR, Donfack J, Choi SS, Conley SF, Derkay CS, Myer CM, Ehrlich GD and Post JC.  Unique challenges of obtaining regulatory approval for a multicenter protocol to study the genetics of RRP and suggested remedies.  Otolaryngol Head Neck Surg.  135(2):189-96, 2006 
    
    
12. Kerschner, J.E., Meyers, T., Burrows, A., Ehrlich, G.D. and Post, J.C.  Mucin gene cDNA sequence characterization from the chinchilla middle ear epithelium Intl J. Pediatric Otolaryngol. 70(8):1449-1456, 2006.
    
    
13. Shen, K., Sayeed, S., Antalis, P., Gladitz, J., Ahmed, A., Dice, B., Janto, B., Dopico, R., Keefe, R., Hayes, J.,  Johnson, S., Yu, S., Ehrlich, N., Jocz, J., Kropp, L., Tadique, E., Wong, R., Wadowsky, R.M., Slifkind, M., Preston, R.A., Erdos, G., Post, J.C., Ehrlich, G.D., Hu, F.Z.   Extensive genomic plasticity in Pseudomonas aeruginosa revealed by identification and distribution studies of novel (nonPAO1) genes among  clinical isolates. Infection and Immunity. 74(9):5272-83, 2006.
    
    
14. Erdos, G., Sayeed, S., Hu, F.Z., Antalis, P.T., Shen, K., Hayes, J.,  Dopico, R., Johnson, S., Post, J.C., and   Ehrlich, G.D.  Construction and characterization of a highly redundant Pseudomonas aeruginosa genomic library prepared from 12 clinical isolates: application to studies of gene distribution among populations. Int. J.Ped Oto  70(11):1891-900, 2006. 
    
    
15. Hall-Stoodley, L., Hu, F.Z., Stoodley, P., Nistico, L., Link, T.R.,  Burrows, A., Post, J.C. Ehrlich, G.D.,  and Kerschner, K.E.  Direct Evidence that Otitis Media with Effusion is a Biofilm Disease.  JAMA 296:202-211, 2006.