Microbiologist, Department of Medicine
Brigham and Women's Hospital

gpier@channing.harvard.edu

The major research interests include studies of the following bacterial pathogens: Pseudomonas aeruginosa, Staphylococcus epidermidis, and Staphylococcus aureus. The research for all of these pathogens encompasses identification of the molecular basis for the interactions of these bacteria with mammalian hosts, with the primary goal being identification of surface antigens eliciting protective innate and adaptive immunity and also essential for full virulence of the organism. These studies involve basic molecular biologic process the bacteria use to produce and regulate virulence factor expression, isolation, chemical characterization and evaluation of surface antigens as vaccines, and production and maximization of the biologic properties of human monoclonal antibodies that can be used as passive therapeutic agents to prevent or treat infections with these microbes.

In regard to P. aeruginosa we are producing and testing live, attenuated vaccines to determine if they can prevent infections of the lung, eye and blood. The focus of these studies is to characterize the safety and immunogenicity of these strains and carry out detailed studies on immunologic factors, such as antibody and T-cell responses that prevent P. aeruginosa infection. In addition, studies on virulence factors that allow P. aeruginosa to cause infections are also a key part of the laboratory investigations.

Additional work has focused on the mechanisms whereby P. aeruginosa initiates infection in cystic fibrosis (CF) patients. We have shown that airway epithelial cells from CF patients are defective in their ability to ingest P. aeruginosa, and postulate that normal cellular uptake of P. aeruginosa is involved in bacterial elimination by initiating an inflammatory response that clears P. aeruginosa from the airway epithelium. The epithelial cellular receptor for P. aeruginosa was found to be the cystic fibrosis transmembrane conductance regulator (CFTR) itself, the protein that is missing or dysfunctional in CF. The implications of this observation in pathogenesis of P. aeruginosa infection in CF are a major part of the laboratory’s current interests. Currently we are using gene-chip technology and studies in transgenic mice to identify genes regulated by CFTR in response to P. aeruginosa with the goal of defining how these host factors work to clear P. aeruginosa from the airways.

Another major project in the CF field has been the immunochemical characterization of the surface alginate polysaccharide (also called mucoid exopolysaccharide) over-produced by the strains of P. aeruginosa that colonize the lungs of patients with CF. These studies include purification of this antigen, assessment of the immunologic response of the CF patients to the antigen and definition of the pathogenic role alginate plays in preventing CF patients from eliminating this microorganisms from their lungs.

An additional strong focus of the lab involves investigations of mechanisms of pathogenesis and immunity to both S. aureus and coagulase-negative staphylococci. Adherence to biomedical devices and resistance of staphylococci to host immune effectors is due to production a poly N-acetyl glucosamine (PNAG) surface polymer (also referred to as PS/A and PIA in the literature), and a PNAG vaccine prevents S. epidermidis bacteremia and endocarditis. PNAG is also a major surface polysaccharide of S. aureus, produced principally in infected tissues of animals and humans but only at low levels or not at all under most normal in vitro conditions. S. aureus clinical isolates all have the genes needed to produce PNAG and studies in animal models show that PNAG is a broadly-protective vaccine against S. aureus infections. PNAG is also produced by other pathogens, including E. coli, Y. pestis and other Yersinia spp. and we are investigating the vaccine potential of this antigen for multiple bacterial species. Overall the lab is investigating the role of PNAG in bacterial pathogenesis and immunity and extending our vaccine to work to evaluate conjugate vaccines, monoclonal antibody therapy, etc. in a variety of animal models of staphylococcal infection.

In April, 2004 Dr. Pier was also the senior editor of a major new immunology textbook entitled Immunology, Infection and Immunity (G.B Pier, J.B. Lyczak, L.M. Wetzler, eds) published by the American Society for Microbiology Press. Click HERE for details.

Pier GB, Grout M, Zaidi TS, Olsen JC, Johnson LG, Yankaskas JR, Goldberg JB. Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections. Science 1996;271:64-67. [Abstract]

Pier GB, Grout M, Zaidi TS. Cystic fibrosis transmembrane conductance regulator is an epithelial cell receptor for clearance of Pseudomonas aeruginosa from the lung. Proc Nat Acad Sci USA 1997;94:12088-12093. [abstract]

Pier GB, Grout M, Zaidi T, Meluleni G, Mueschenborn SS, Banting G, Ratcliff R, Evans MJ, Colledge WH. Salmonella typhi uses CFTR to enter intestinal epithelial cells. Nature 1998;392:79-82. [Abstract]

McKenney D, Pouliot KL, Wang Y, Murthy V, Ulrich M, Döring G, Lee JC, Goldmann DA, Pier GB. Broadly-protective vaccine for Staphylococcus aureus based on an in vivo expressed antigen. Science 1999; 284:1523-7. [Abstract]

Schroeder TH, Lee MM, Yacono PW, Cannon CL, Gerçeker AA, Golan DE, and Pier GB. CFTR is a pattern recognition molecule that extracts Pseudomonas aeruginosa LPS from the outer membrane into epithelial cells and activates NF-?B translocation. Proc. Soc. Natl. Acad. Sci. USA 2002; 99:6907-6912. [Abstract]

Priebe GP, Meluleni G, Coleman FT, Goldberg JB, and Pier GB. Protection against fatal Pseudomonas aeruginosa pneumonia in mice after nasal immunization with a live, attenuated aroA deletion mutant. Infect. Immun 2003; 71: 1453-1461. [Abstract]

Coleman FT, Mueschenborn S, Meluleni G, Ray C, Carey VC, Vargas SO, Cannon CL Ausubel FM and Pier GB. Hypersusceptibility of cystic fibrosis mice to chronic Pseudomonas aeruginosa oropharyngeal colonization and lung infection. Proc. Soc. Natl. Acad. Sci. USA 2003: 100:1949-1954. [Abstract]

Jefferson KK, Cramton SE, Götz, F and Pier GB. Identification of a 5-nucleotide sequence that controls expression of the ica locus in Staphylococcus aureus and characterization of the DNA-binding properties of IcaR. Molec. Microbiol. 2003; 48: 889-899. [Abstract]

Theilacker C, Coleman FT, Mueschenborn S, Llosa N, Grout M, Pier GB. Construction and characterization of a Pseudomonas aeruginosa mucoid exopolysaccharide-alginate conjugate vaccine. Infect Immun. 2003;71:3875-84. [Abstract]

Kowalski MP and Pier GB. Localization of cystic fibrosis transmembrane conductance regulator to lipid rafts of epithelial cells is required for Pseudomonas aeruginosa induced cellular activation. J. Immunol 2004; 172: 418-425. [Abstract]

Jefferson KK, Pier DB, Goldmann DA, Pier GB. The teicoplanin-associated locus regulator (TcaR) and the intercellular adhesin locus regulator (IcaR) are transcriptional inhibitors of the ica locus in Staphylococcus aureus. J. Bacteriol 2004; 18:2449-2456. [Abstract]

Anisimov AP, Lindler LE, Pier GB. Intraspecific diversity of Yersinia pestis. Clin. Microbiol. Rev. 2004; 17:434-464. [Abstract]

Knirel YA, Lindner B, Vinogradov EV, Kocharova NA, Senchenkova SN, Shaikhutdinova RZ, Dentovskaya SV, Fursova NK, Bakhteeva IV, Titareva GM, Balakhonov SV, Holst O, Gremyakova TA, Pier GB, Anisimov AP. Temperature-dependent variations and intraspecies diversity of the structure of the lipopolysaccharide of Yersinia pestis. Biochem. 2005; 44:1731-1743. [Abstract]

Koh AY, Priebe GP, Pier GB. Virulence of Pseudomonas aeruginosa in a murine model of gastrointestinal colonization and dissemination in neutropenia. Infect Immun. 2005 Apr;73(4):2262-72. [Abstract]

Jefferson KK, Goldmann DA, Pier GB. Use of confocal microscopy to analyze the rate of vancomycin penetration through Staphylococcus aureus biofilms. Antimicrob. Agents Chemother. 2005;49:2528-2532. [Abstract]

Maira-Litran T, Kropec A, Goldmann DA, Pier GB. Comparative opsonic and protective activities against Staphylococcus aureus of conjugate vaccines containing native or deacetylated staphylococcal poly-N-acetyl-?-(1-6)-glucosamine. Infect. Immun. 2005; 73:6752-6762. [Abstract]

Kropec A, Maira-Litran T, Jefferson KK, Grout M, Cramton SE, Gotz F, Goldmann DA, Pier GB. Poly-N-acetyl glucosamine production in Staphlococcus aureus is essential for virulence in murine models of systemic infection. Infect Immun. 2005 Oct;73(10):6868-76. [Abstract]

Reiniger N, Ichikawa J, Pier GB. Influence of CFTR on gene expression in response to Pseudomonas aeruginosa infection of human bronchial epithelial cells. Infect. Immun. 2005; 73: 6822-6830. [Abstract]

Kelly-Quintos K., Kropec A., Briggs S., Ordonez C. Goldmann DA, Pier GB. The role of epitope specificity in the human opsonic antibody response to the staphylococcal surface polysaccharide PNAG. J. Infect. Dis. 2005; 192: 2012-2019. [Abstract]

Bystrova OV, Krirel YA, Lindner B, Kocharova NA, Kondakova AN, Zahringer U, Pier GB. Structures of the core oligosaccharide and O-units in the R- and SR-type lipopolysaccharides of reference strains of Pseudomonas aeruginosa O-serogroups. FEMS Immunol Med Microbiol. 2006 Feb;46(1):85-99. [Abstract]

Zaidi TS, Priebe GP, Pier GB. A live-attenuated Pseudomonas aeruginosa vaccine elicits outer membrane protein-specific active and passive protection against corneal infection. Infect Immun. 2006 Feb;74(2):975-83. [Abstract]

Kelly-Quintos C, Cavacini LA, Posner MR, Goldmann DA, Pier GB. Characterization of the opsonic and protective activity against Staphylococcus aureus of fully human monoclonal antibodies specific for the bacterial surface polysaccharide poly-N-acetyl glucosamine. Infect Immun. 2006 May;74(5):2742-50. [Abstract]