.

Department of Pathology, Microbiology, and Immunology

 

 

D. Borden Lacy, Ph.D

 

 

Associate Professor

Dept of Pathology, Microbiology and Immunology

Dept of  Biochemistry

 

 

Contact Information

 

 

Office Location:
MCN A-4116A

Phone: 615-343-9080

E-mail:  borden.lacy@vanderbilt.edu

 

Lab URL: 

http://structbio.vanderbilt.edu/lacy

 

Campus Mail address:

Pathology, Microbiology and Immunology-5th Fl

MCN A-5301 (2363)

 

Mailing address:
Vanderbilt University School of Medicine
Dept of Pathology, Microbiology and Immunology-5th Fl
MCN A-5301
1161 21st Ave. S.

Nashville, TN 37232

 

 

 

Education

 

 

Postdoctoral, Harvard Medical School, Boston, MA
Ph.D., University of California, Berkeley, CA
B.S., University of North Carolina, Chapel Hill, NC

 

 

Research Keywords

 

 

bacterial protein toxins, host responses to bacterial pathogens, Clostridium difficile, structural biology

 

 

Research Description

 

 

Pathogenic bacteria have evolved a diverse array of mechanisms for delivering toxins and other virulence factors into the interior of host cells. Studying the molecular structures of these virulence factors alone and in complex with host receptors, membranes, and inhibitors can lend insight into how these delivery processes occur and how these processes can be exploited or prevented. Current research in the Lacy laboratory is primarily focused on the structure and function of large clostridial cytotoxins, including the two toxins responsible for symptoms in C. difficile infection. Structural biology is combined with cellular and animal models of intoxication and infection to understand the toxin-host interaction at the molecular level. In addition, we aim to identify new toxin inhibitors using both rational design and high-throughput screening approaches.

 

 

Publications

 

 

Varela Chavez, C, Hoos, S, Haustant, GM, Chenal, A, England, P, Blondel, A, Pauillac, S, Lacy, DB, Popoff, MR. The catalytic domains of Clostridium sordellii lethal toxin and related large clostridial glucosylating toxins specifically recognize the negatively charged phospholipids phosphatidylserine and phosphatidic acid. Cell Microbiol, 2015

Wang, X, Yamamoto, Y, Wilson, LH, Zhang, T, Howitt, BE, Farrow, MA, Kern, F, Ning, G, Hong, Y, Khor, CC, Chevalier, B, Bertrand, D, Wu, L, Nagarajan, N, Sylvester, FA, Hyams, JS, Devers, T, Bronson, R, Lacy, DB, Ho, KY, Crum, CP, McKeon, F, Xian, W. Cloning and variation of ground state intestinal stem cells. Nature, 522(7555), 173-8, 2015

LaFrance, ME, Farrow, MA, Chandrasekaran, R, Sheng, J, Rubin, DH, Lacy, DB. Identification of an epithelial cell receptor responsible for Clostridium difficile TcdB-induced cytotoxicity. Proc Natl Acad Sci U S A, 112(22), 7073-8, 2015

Dumont, AL, Yoong, P, Liu, X, Day, CJ, Chumbler, NM, James, DB, Alonzo, F, Bode, NJ, Lacy, DB, Jennings, MP, Torres, VJ. Identification of a Crucial Residue Required for Staphylococcus aureus LukAB Cytotoxicity and Receptor Recognition. Infect Immun, 82(3), 1268-76, 2014

Zhang, Z, Park, M, Tam, J, Auger, A, Beilhartz, GL, Lacy, DB, Melnyk, RA. Translocation domain mutations affecting cellular toxicity identify the Clostridium difficile toxin B pore. Proc Natl Acad Sci U S A, 2014

Benefield, DA, Dessain, SK, Shine, N, Ohi, MD, Lacy, DB. Molecular assembly of botulinum neurotoxin progenitor complexes. Proc Natl Acad Sci U S A, 110(14), 5630-5, 2013

Farrow, MA, Chumbler, NM, Lapierre, LA, Franklin, JL, Rutherford, SA, Goldenring, JR, Lacy, DB. Clostridium difficile toxin B-induced necrosis is mediated by the host epithelial cell NADPH oxidase complex. Proc Natl Acad Sci U S A, 2013

Reyes-Robles, T, Alonzo, F, Kozhaya, L, Lacy, DB, Unutmaz, D, Torres, VJ. Staphylococcus aureus Leukotoxin ED Targets the Chemokine Receptors CXCR1 and CXCR2 to Kill Leukocytes and Promote Infection. Cell Host Microbe, 14(4), 453-9, 2013

Slater, LH, Hett, EC, Mark, K, Chumbler, NM, Patel, D, Lacy, DB, Collier, RJ, Hung, DT. Identification of novel host-targeted compounds that protect from anthrax lethal toxin-induced cell death. ACS Chem Biol, 8(4), 812-22, 2013

Chambers, MG, Pyburn, TM, Gonzalez-Rivera, C, Collier, SE, Eli, I, Yip, CK, Takizawa, Y, Lacy, DB, Cover, TL, Ohi, MD. Structural Analysis of the Oligomeric States of Helicobacter pylori VacA Toxin. J Mol Biol, 2012

Pruitt, RN, Chumbler, NM, Rutherford, SA, Farrow, MA, Friedman, DB, Spiller, B, Lacy, DB. Structural determinants of Clostridium difficile toxin A glucosyltransferase activity. J Biol Chem, 287(11), 8013-20, 2012

Chumbler, NM, Farrow, MA, Lapierre, LA, Franklin, JL, Haslam, D, Goldenring, JR, Lacy, DB. Clostridium difficile Toxin B Causes Epithelial Cell Necrosis through an Autoprocessing-Independent Mechanism. PLoS Pathog, 8(12), e1003072, 2012

Pruitt, RN, Lacy, DB. Toward a structural understanding of Clostridium difficile toxins A and B. Front Cell Infect Microbiol, 2, 28, 2012

Johnson, PM, Chen, SS, Santomango, TS, Williams, PE, Lacy, DB, McGuinness, OP. Continuous low-dose fructose infusion does not reverse glucagon-mediated decrease in hepatic glucose utilization. Metabolism, 60(6), 867-73, 2011

Mushrush, DJ, Koteiche, HA, Sammons, MA, Link, AJ, McHaourab, HS, Lacy, DB. Studies of the Mechanistic Details of the pH-dependent Association of Botulinum Neurotoxin with Membranes. J Biol Chem, 286(30), 27011-8, 2011

Pruitt, RN, Chambers, MG, Ng, KK, Ohi, MD, Lacy, DB. Structural organization of the functional domains of Clostridium difficile toxins A and B. Proc Natl Acad Sci U S A, 107(30), 13467-72, 2010

Gonz?!lez-Rivera, C, Gangwer, KA, McClain, MS, Eli, IM, Chambers, MG, Ohi, MD, Lacy, DB, Cover, TL. Reconstitution of Helicobacter pylori VacA toxin from purified components. Biochemistry, 49(27), 5743-52, 2010

Ivie, SE, McClain, MS, Algood, HM, Lacy, DB, Cover, TL. Analysis of a beta-helical region in the p55 domain of Helicobacter pylori vacuolating toxin. BMC Microbiol, 10, 60, 2010

Gangwer, KA, Shaffer, CL, Suerbaum, S, Lacy, DB, Cover, TL, Bordenstein, SR. Molecular evolution of the Helicobacter pylori vacuolating toxin gene (vacA). J Bacteriol, 2010

Schmitt, J, Karalewitz, A, Benefield, DA, Mushrush, DJ, Pruitt, RN, Spiller, BW, Barbieri, JT, Lacy, DB. Structural analysis of botulinum neurotoxin type G receptor binding . Biochemistry, 49(25), 5200-5, 2010

Chen, SS, Santomango, TS, Williams, PE, Lacy, DB, McGuinness, OP. Glucagon-mediated impairments in hepatic and peripheral tissue nutrient disposal are not aggravated by increased lipid availability. Am J Physiol Endocrinol Metab, 296(5), E1172-8, 2009

Pruitt, RN, Chagot, B, Cover, M, Chazin, WJ, Spiller, B, Lacy, DB. Structure-function analysis of inositol hexakisphosphate-induced autoprocessing in Clostridium difficile toxin A. J Biol Chem, 284(33), 21934-40, 2009

Ivie, SE, McClain, MS, Torres, VJ, Algood, HM, Lacy, DB, Yang, R, Blanke, SR, Cover, TL. Helicobacter pylori VacA subdomain required for intracellular toxin activity and assembly of functional oligomeric complexes. Infect Immun, 76(7), 2843-51, 2008

Fischer, A, Mushrush, DJ, Lacy, DB, Montal, M. Botulinum neurotoxin devoid of receptor binding domain translocates active protease. PLoS Pathog, 4(12), e1000245, 2008

Gangwer, KA, Mushrush, DJ, Stauff, DL, Spiller, B, McClain, MS, Cover, TL, Lacy, DB. Crystal structure of the Helicobacter pylori vacuolating toxin p55 domain. Proc Natl Acad Sci U S A, 104(41), 16293-8, 2007

Scobie, HM, Marlett, JM, Rainey, GJ, Lacy, DB, Collier, RJ, Young, JA. Anthrax toxin receptor 2 determinants that dictate the pH threshold of toxin pore formation. PLoS ONE, 2, e329, 2007

Scobie, HM, Wigelsworth, DJ, Marlett, JM, Thomas, D, Rainey, GJ, Lacy, DB, Manchester, M, Collier, RJ, Young, JA. Anthrax Toxin Receptor 2-Dependent Lethal Toxin Killing In Vivo. PLoS Pathog, 2(10), 2006

Melnyk, RA, Hewitt, KM, Lacy, DB, Lin, HC, Gessner, CR, Li, S, Woods, VL, Collier, RJ. Structural determinants for the binding of anthrax lethal factor to oligomeric protective antigen. J Biol Chem, 281(3), 1630-5, 2006

Lacy, DB, Lin, HC, Melnyk, RA, Schueler-Furman, O, Reither, L, Cunningham, K, Baker, D, Collier, RJ. A model of anthrax toxin lethal factor bound to protective antigen. Proc Natl Acad Sci U S A, 102(45), 16409-14, 2005

Krantz, BA, Melnyk, RA, Zhang, S, Juris, SJ, Lacy, DB, Wu, Z, Finkelstein, A, Collier, RJ. A phenylalanine clamp catalyzes protein translocation through the anthrax toxin pore. Science, 309(5735), 777-81, 2005

Lacy, DB, Wigelsworth, DJ, Scobie, HM, Young, JA, Collier, RJ. Crystal structure of the von Willebrand factor A domain of human capillary morphogenesis protein 2: an anthrax toxin receptor. Proc Natl Acad Sci U S A, 101(17), 6367-72, 2004

Lacy, DB, Wigelsworth, DJ, Melnyk, RA, Harrison, SC, Collier, RJ. Structure of heptameric protective antigen bound to an anthrax toxin receptor: a role for receptor in pH-dependent pore formation. Proc Natl Acad Sci U S A, 101(36), 13147-51, 2004

Wigelsworth, DJ, Krantz, BA, Christensen, KA, Lacy, DB, Juris, SJ, Collier, RJ. Binding stoichiometry and kinetics of the interaction of a human anthrax toxin receptor, CMG2, with protective antigen. J Biol Chem, 279(22), 23349-56, 2004

Mourez, M, Yan, M, Lacy, DB, Dillon, L, Bentsen, L, Marpoe, A, Maurin, C, Hotze, E, Wigelsworth, D, Pimental, RA, Ballard, JD, Collier, RJ, Tweten, RK. Mapping dominant-negative mutations of anthrax protective antigen by scanning mutagenesis. Proc Natl Acad Sci U S A, 100(24), 13803-8, 2003

Lacy, DB, Collier, RJ. Structure and function of anthrax toxin. Curr Top Microbiol Immunol, 271, 61-85, 2002

Lacy, DB, Mourez, M, Fouassier, A, Collier, RJ. Mapping the anthrax protective antigen binding site on the lethal and edema factors. J Biol Chem, 277(4), 3006-10, 2002

Mogridge, J, Cunningham, K, Lacy, DB, Mourez, M, Collier, RJ. The lethal and edema factors of anthrax toxin bind only to oligomeric forms of the protective antigen. Proc Natl Acad Sci U S A, 99(10), 7045-8, 2002

Cunningham, K, Lacy, DB, Mogridge, J, Collier, RJ. Mapping the lethal factor and edema factor binding sites on oligomeric anthrax protective antigen. Proc Natl Acad Sci U S A, 99(10), 7049-53, 2002

Mourez, M, Lacy, DB, Cunningham, K, Legmann, R, Sellman, BR, Mogridge, J, Collier, RJ. 2001: a year of major advances in anthrax toxin research. Trends Microbiol, 10(6), 287-93, 2002

Pannifer, AD, Wong, TY, Schwarzenbacher, R, Renatus, M, Petosa, C, Bienkowska, J, Lacy, DB, Collier, RJ, Park, S, Leppla, SH, Hanna, P, Liddington, RC. Crystal structure of the anthrax lethal factor. Nature, 414(6860), 229-33, 2001

Lacy, DB, Stevens, RC. Sequence homology and structural analysis of the clostridial neurotoxins. J Mol Biol, 291(5), 1091-104, 1999

Lacy, DB, Tepp, W, Cohen, AC, DasGupta, BR, Stevens, RC. Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat Struct Biol, 5(10), 898-902, 1998

Lacy, DB, Stevens, RC. Unraveling the structures and modes of action of bacterial toxins. Curr Opin Struct Biol, 8(6), 778-84, 1998

Lacy, DB, Stevens, RC. Recombinant expression and purification of the botulinum neurotoxin type A translocation domain. Protein Expr Purif, 11(2), 195-200, 1997

McGuinness, OP, Lacy, DB, Ejiofor, J, Bagby, GG. Hepatic release of tumor necrosis factor in the endotoxin-treated conscious dog. Shock, 5(5), 344-8, 1996

Crimmins, MT, Huang, S, Guise, LE, Lacy DB. Addition of functionalized zinc copper reagents to acetylenic esters: synthesis of 2-carboalkoxy cyclohexenones. Tetrahedron Letters, 36, 7061-64, 1995