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Gerald B. Pier, PhD


Professor of Medicine
Microbiology and Molecular Genetics
Harvard Medical School

Microbiologist, Department of Medicine
Brigham and Women's Hospital

 

gpier@channing.harvard.edu


Research Interests

Our research encompasses identification of the molecular basis for the interactions of major human and animal bacterial pathogens with mammalian hosts, with the primary goal being identification of surface antigens eliciting protective innate and adaptive immunity that also contribute to the organism’s virulence. As a result of our interest in a conserved surface polysaccharide, poly-N-acetyl glucosamine (PNAG), which we and others have found is synthesized by a diverse range of bacterial species, we now are investigating how this molecule plays a role in virulence and immunity to numerous pathogens, including Staphylococcus aureus, S. epidermidis, E. coli, Y. pestis, K. pneumoniae, and others. In addition, the research effort has also focused on Pseudomonas aeruginosa, a major nosocomial pathogen and cause of serious infections in the setting of cystic fibrosis.

Our basic research approaches involve understanding the molecular biologic process these bacteria use to produce and regulate virulence factor expression, which encompasses 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. Vaccines targeting the PNAG antigen, as well as fully human monoclonal antibodies, have entered or are about to enter human trials, which will advance our opportunities to understand how and why some many diverse bacterial pathogens produce a conserved surface antigen without facing high-level resistance to infection from humans that are commonly exposed to PNAG. We also study basic aspects of human immunity to infection to identify both infection-resisting and infection-enhancing responses that contribute to the progression of an infection to a serious disease.

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 high-throughput DNA sequencing to identify genes regulated by CFTR in response to P. aeruginosa as well as genes whose products are needed for virulence in a variety of tissues, with the goal of defining how host factors work to clear P. aeruginosa while bacterial factors counteract the host responses.


Selected Publications

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-κB translocation. Proc. Soc. Natl. Acad. Sci. USA 2002; 99:6907-6912. [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]

Koh AY, Priebe GP, Pier GB. A murine model of gastrointestinal colonization and dissemination during neutropenia for studying virulence of Pseudomonas aeruginosa. Infect Immun. 2005 Apr;73(4):2262-72. PMID: 15784570. [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 Jun;49(6):2467-73. PMID: 15917548. [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]

DiGiandomenico A, Rao J, Harcher K, Zaidi TS, Gardner J, Neely AN, Pier GB, Goldberg JB. Intranasal immunization with heterologously expressed polysaccharide protects against multiple Pseudomonas aeruginosa infections. Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4624-9. Epub 2007 Mar 5. [Abstract]

Cerca N, Maira-Litrán T, Jefferson KK, Grout M, Goldmann DA, Pier GB. Protection against Escherichia coli infection by antibody to the Staphylococcus aureus poly-N-acetylglucosamine surface polysaccharide. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7528-33. Epub 2007 Apr 19. [Abstract]

Priebe GP, Walsh RL, Cederroth TA, Kamei A, Coutinho-Sledge YS, Goldberg JB, Pier GB. IL-17 is a critical component of vaccine-induced protection against lung infection by lipopolysaccharide-heterologous strains of Pseudomonas aeruginosa. J Immunol. 2008 Oct 1;181(7):4965-75. [Abstract]

Gadjeva M, Paradis-Bleau C, Priebe G, Fichorova R, Pier GB. Caveolin-1 modifies the immunity to P. aeruginosa. J Immunol. 2010 Jan 1;184(1):296-302. Epub 2009 Nov 30. PMID: 19949109. [Abstract]

Yoong P, Pier GB. Antibody-mediated enhancement of community-acquired methicillin-resistant Staphylococcus aureus infection. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2241-6. Epub 2010 Jan 19. [abstract]

Gening M, Maira-Litran T, Kropec A, Skurnik D, Grout M, Tsvetkov YE, Nifantiev NE, Pier GB. Synthetic {beta}-(1->6)-linked N-acetylated and nonacetylated oligoglucosamines used to produce conjugate vaccines for bacterial pathogens. Infect Immun. 2010 Feb;78(2):764-72. Epub 2009 Nov 30. PMID: 19948836. [Abstract]

Gadjeva M, Nagashim J, Zaidi T, Mitchell RA, Pier GB. Inhibition of macrophage migration inhibitory factor ameliorates ocular Pseudomonas aeruginosa-induced keratitis. PLoS Pathog. 2010 March; 6(3): e1000826. Published online 2010 March 26. doi: 10.1371/journal.ppat.1000826. [Abstract]

Skurnik D, Merighi M, Grout M, Gadjeva M, Maira-Litran T, Ericsson M, Goldmann DA, Huang SS, Datta R, Lee JC, Pier GB. Animal and human antibodies to Staphylococcus aureus capsular polysaccharides poly-N-acetyl glucosamine mutually neutralize opsonic killing and protection. J Clin Invest. 2010 Sep 1;120(9):3220-33. doi: 10.1172/JCI42748. Epub 2010 Aug 25. PMID: 20739753. PMCID: PMC2929724. [Abstract]

Hermos CR, Yoong P, Pier GB. High levels of antibody to Panton-Valentine leukocidin are not associated with resistance to Staphlococcus aureus-associated skin and soft-tissue infection. Clin Infect Dis. 2010 Nov 15;51(10): 1138-46. Epub 2010 Oct 14. PubMed PMCID: 20946065; PubMed Central PMCID: PMC2962716. [Abstract]