Bruce Geller

Mucosal Vaccine Delivery, Antisense Antibiotics, Bacteriophage Receptors

Research Interests:

Mucossal Vaccine Delivery System, Antisense Antibiotics, Phage Infections of Lactococcus lactis

Office: 354 Nash Hall

Courses taught: MB 311, Molecular Microbiology Lab: A Writing Intensive Course; MB 312, Bacterial Physiology and Metabolism; MB 479/579, Food Biotechnology

Degrees: Ph.D. University of Utah

Research

Mucosal Vaccine Delivery. My lab is developin an oral vaccine for strep throat in collabora with a pharmaceutical company. we have expressed a conserved sequence of the M protein (CRR) on the suface of Lactococcus lactis. Mice vaccinated nasally with the engineered lactococcal strain develop CRR-specific sIgA and serum IgA responses. Moreover, the vaccinated mice are protected from an infectious challenge with the causative agent of strep throat, Streptococcus pyogenes.

Antisense Antibiotics. In collaboration with AVI BioPharma, we are developin an antisense antibiotic. Phosphorodiamidate morpholino oligomers (PMOs) are DNA mimics that inhibit expression of specific mRNA. They are synthesized using the four natural bases, with a base sequence different than DNA in the chemical structure that links the bases together. Ribose has been replaced with a mopholine group, and the phosphodiester is substituted with a phosphordiamidate. These alterations make the antisense molecule resistant to nucleases, which is required for in vivo therapeutics. PMOs targeted to essential genes of E. coli reduce viability about 505 in pur cultures and about 90% in infected mice. Efficacy is limited by penetration of the outer membrane. We have covalently coupled membrane-penetrating peptides to the end of PMOs and found that low micromolar concentrations of these conjugates reduce viability of E. coli by up to 7 orders of magnitude.

Bacteriophage Infections of Lactococcus. Bacteriophage infection of Lactococcus lactis, L. cremoris, and other commercially important strains of gram positive bacteria is a major problem in the dairy industry. we have cloned a gene (pip) that is the phage receptors for one of three main species of lactococcal phages. We have constructed pip null mutants of Lactococcus lactis and found that they are completely reisistant to all phages that use Pip as a receptor. Our goal is to provide genetically engineered receptors that would delay or prevent bacteriophage infection. Moreover, pip mutants grow normally and make excellent cheese.

Selected Publications

Pub Med

Tilley, L., B. Mellbye, S. E. Puckett, P. L. Iversen, and B. L. Geller. 2007. Antisense Phosphorodiamidate Morpholino Oligomer-Peptide Conjugate: Dose-Response in Mice Infected with Escherichia coli. J. Antimicrob. Chemother 59:66-73.

Tilley, L., O.S. Hine, J.A. Kellogg, J.N. Hassinger, D. Weller, P.L. Iversen, and B.L. Geller. 2006. Gene-Specific Effects of Antisense Phosphorodiamidate Morpholino Oligomer-Peptide Conjugates on Escherichia coli and Salmonella typhimurium in Pure Culture and in Tissue Culture. Antimicrob, Agents Chemother. 50: 2789-2796.

Mooney, D.T., M. Jann, and B.L. Geller. 2006 Subcellular Location of Phage Infection Protein (Pip) in Lactococcus lactis. Can J. Microbiol. 52:664-672.

Geller, B.L., J. Deere, L. Tilley, and P.L. Iversen. 2005. Antisense phosphorodiamidate morpholino oligomer inhibits viability of Escherichia coli in pure culture and in mouse peritonitis. J. Antimicrob. Chemother. 55:983-988.

Deere, J., P. Iversen, and B.L. Geller. 2005 Antisense phosphorodiamidate morpholino oligomer length and target position effect on gene-specific inhibition in Escherichia coli. Antimicrob. Agents Chemother. 49:249-255.

Geller, B.L., H.t. Ngo, D.T. Mooney, P.Su, N. Dunn. 2005. Lactococcal 936-species phage attachment to surface of Lactococcus lactis. J. Dairy Sci. 88:900-7.

Mannam, P., K.F. Jones, and B.L. Geller, 2004. Mucosal vaccine made from live, recombinant Lactococcus lactis protects mice agains pharyngeal infection with Streptococcus pyogenes. Infect. Immun. 72:3444-50.

Geller, B.L., J.D. Deere, D.A. Stein, A.D. Kroeker, H.M. Moulton, and P.L. Iversen. 2003. Inhibition of gene expression in Escherichia coli by antisense phophorodiamidate morpholino oligomers. Antimicrob. Agents Chemother. 47:3233-3239.

Kraus, J.,B.L. Geller, 2001. Cloning of genomic DNA of Lactococcus lactis that restores phage sensitivity to an unusual bacteriophage sk 1-resistant mutant. Appl. Environ. Microbiol. 67:791-8.

Garbutt, K.C., J. Kraus, and B.L. Geller. 1997. Bacteriophage-resistance in Lactocopccus lactis engineered by Replacement of a gene for a bacteriophage receptor. J. Dair Sci., in press (Aug).

Babu, K.S., W.S. Spence, M.M. Monteville, and B.L. Geller (1995) Characterizationof a cloned gene (pip) from Lactococcus lactis requried for phage infection. In Genetics of Streptococci, Enterococci, and Lactococci (J. Ferretti, ed.). Proceedings of the IVth International ASM Conference on Streptococcal Genetics. Developments in Biological Standardization (Geneve, Switzerland), vol 85, pp. 569-575.

Monteville, M.M., B. Ardestani, and B.L. Geller (1994) Lactococcal bacteriophages require a host cell wall carbohydrate and a plasma membrance protein for absorption and ejection of DNA. Appl. Environ. Microbiol. 60:3204-3211.

Valyasevim, R., W.E. Sandine, and B.L. Geller (1994) Lactococcus lactis subsp. lactis C2 bacteriophage sk1 receptor involves rhamnose and glucose moieties int he cell wall. J. Dair Sci. 77:1-6.

Geller, B.L., R.G. Ivey, J.E. Trempy, and B. Hettinger-Smith (1993) Cloning of a chromosomal gene required for Phage infection of Lactococcus lactis subsp. lactis C2. J. Bacteriol. 175:5510-5519.

Valyasevi, R., W.E. Sandine, and B.L. Geller (1991) A membrane protein of Lactococcus lactis subsp. lactis C2 is required for phage infection. J. Bacteriol. 173:6095-6100.