Lacy Lab Contact

Vanderbilt University School of Medicine
Department of Pathology, Microbiology and Immunology
A-5301 Medical Center North
1161 21st Avenue South
Nashville, TN 37232-2363
tel: (615) 343-9080; email: borden.lacy -at-

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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 Clostridium 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.

Elucidating the molecular structures and functions of these virulence factors alone and in complex with host receptors and membranes will reveal vital information about fundamental mechanisms in bacterial pathogenesis.

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N.M. Chumbler, M.A. Farrow, L. A. Lapierre, J. L. Franklin, D. B. Lacy. (2016) Clostridium difficile toxins TcdA and TcdB cause colonic tissue damage by distinct mechanisms. Infection and Immunity. doi:10.1128/IAI.00583-16. Epub ahead of print.

González-Rivera C, Campbell AM, Rutherford SA, Pyburn TM, Foegeding NJ, Barke TL, Spiller BW, McClain MS, Ohi MD, Lacy DB1, Cover TL1. (2016) A non-oligomerizing mutant form of Helicobacter pylori VacA allows structural analysis of the p33 domain. Infection and Immunity 2016 Jul 5. pii: IAI.00254-16. Epub ahead of print. 1Co-corresponding authors.

T. Reyes-Robles, A. Lubkin, F. Alonzo III, D. B. Lacy, V. Torres. (2016) Exploiting dominant-negative toxins to combat Staphylococcus aureus pathogenesis. EMBO Reports. 2016 Feb 8. pii: e201540994.

C. Quesada-Gómez, D. López-Ureña, N. Chumbler, H. Kroh, C. Castro-Peña, C. Rodríguez, J. Orozco-Aguilar, S. González-Camacho, A. Rucavado, C. Guzmán-Verri, T. Lawley, D.B. Lacy, E. Chaves-Olarte. (2016) Analysis of TcdBs within the hypervirulent clade 2 reveals an impact of RhoA glucosylation in Clostridium difficile pro inflammatory activities. Infection and Immunity. doi:10.1128/IAI.01291-15

N.M. Chumbler, S.A. Rutherford, Z. Zhang, M.A. Farrow, J.P. Lisher, E. Farquhar, D.P. Giedroc, B.W. Spiller, R.A. Melnyk, D.B. Lacy. Crystal structure of Clostridium difficile Toxin A. (2016) Nature Microbiology. 1:15002. doi : 10.1038/nmicrobiol.2015.2

R.E. Craven and D.B. Lacy. Clostridium sordellii Lethal Toxin Autoprocessing and Membrane Localization Activities Drive GTPase Glucosylation Profiles in Endothelial Cells. mSphere. 1(1):1-9. doi: 10.1128/mSphere.00012-15.

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 [print-electronic]. 2015 Oct; 17(10): 1477-93. PMID: 25882477

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 [print-electronic]. 2015 Jun 6/11/2015; 522(7555): 173-8. PMID: 26040716

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 [print-electronic]. 2015 Jun 6/2/2015; 112(22): 7073-8. PMID: 26038560

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 [print-electronic]. 2014 Mar 3/11/2014; 111(10): 3721-6. PMID: 24567384

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 [print-electronic]. 2014 Mar; 82(3): 1268-76. PMID: 24379286

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 [print-electronic]. 2013 Nov 11/12/2013; 110(46): 18674-9. PMID: 24167244

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. 2013 Oct 10/16/2013; 14(4): 453-9. PMID: 24139401

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 [print-electronic]. 2013 Apr 4/19/2013; 8(4): 812-22. PMID: 23343607

Benefield DA, Dessain SK, Shine N, Ohi MD, Lacy DB. Molecular assembly of botulinum neurotoxin progenitor complexes. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2013 Apr 4/2/2013; 110(14): 5630-5. PMID: 23509303

Chambers MG, Pyburn TM, González-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 [print-electronic]. 2013 Feb 2/8/2013; 425(3): 524-35. PMID: 23178866

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 [print-electronic]. 2012 Mar 3/9/2012; 287(11): 8013-20. PMID: 22267739

Chumbler NM, Farrow MA, Lapierre LA, Franklin JL, Haslam DB, Goldenring JR, Lacy DB. Clostridium difficile Toxin B causes epithelial cell necrosis through an autoprocessing-independent mechanism. PLoS Pathog [print-electronic]. 2012; 8(12): e1003072. PMID: 23236283 br />
Pruitt RN, Lacy DB. Toward a structural understanding of Clostridium difficile toxins A and B. Front Cell Infect Microbiol. 2012; 2: 28. PMID: 22919620

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 [print-electronic]. 2011 Jul 7/29/2011; 286(30): 27011-8. PMID: 21652698.

Gangwer KA, Shaffer CL, Suerbaum S, Lacy DB, Cover TL, Bordenstein SR. Molecular evolution of the Helicobacter pylori vacuolating toxin gene vacA. J. Bacteriol [print-electronic]. 2010 Dec; 192(23): 6126-35. PMID: 20870762

C. Gonzalez-Rivera1, K. A. Gangwer1, M. S. McClain, I. M. Eli, M. G. Chambers, M. D. Ohi, D. B. Lacy2, T. L. Cover2. (2010) Reconstitution of Helicobacter pylori VacA toxin from purified components. Biochemistry, 49, 5743-52.

R. N. Pruitt, M. G. Chambers, K. Ng, M. D. Ohi, and D. B. Lacy. (2010) Structural organization of the functional domains of Clostridium difficile toxins A and B. Proc Natl Acad Sci U S A. 107, 13467-72.

J. Schmitt, A. Karalewitz, D. A. Benefield, D. J. Mushrush, R. N. Pruitt, B. W. Spiller, J. T. Barbieri, D. B. Lacy (2010) A structural analysis of botulinum neurotoxin type G receptor binding. Biochemistry, 49, 5200-5.

S. E. Ivie, M. S. McClain, H. M. S. Algood, D. B. Lacy, T. L. Cover (2010) Analysis of a beta-helical region in the p55 domain of Helicobacter pylori vacuolating toxin. BMC Microbiol. 10:60.

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

A. Fischer, D. J. Mushrush, D. B. Lacy, and M. Montal (2008) Botulinum neurotoxin devoid of receptor binding domain translocates active protease. PLoS Pathog, 4, 12.

S. E. Ivie, M. S. McClain, V. J. Torres, H. M. S. Algood, D. B. Lacy, R. Yang, S. R. Blanke, T. L. Cover (2008) A Helicobacter pylori VacA subdomain required for intracellular toxin activity and assembly of functional oligomeric complexes. Infection and Immunity, 76, 2843-51.

K. A. Gangwer, D. J. Mushrush, D. L. Stauff, B.Spiller, M. S. McClain, T. L. Cover, D. B. Lacy (2007) Crystal Structure of the Helicobacter pylori Vacuolating Toxin p55 Domain. Proc Natl Acad Sci U S A, 104, 16293-8.

H. M. Scobie, J. M. Marlett, G. J. Rainey, D. B. Lacy, R. J. Collier, J. A. Young (2007) Anthrax Toxin Receptor 2 Determinants that Dictate the pH Threshold of Toxin Pore Formation. PLoS ONE, 2, e329.

H. M. Scobie, D. J. Wigelsworth, J. M. Marlett, D. Thomas, G. J. Rainey, D. B. Lacy, M. Manchester, R. J. Collier, J. A. Young (2006) Anthrax toxin receptor 2-dependent lethal toxin killing in vivo. PLoS Pathog, 2, 949-55.

R. A. Melnyk, K. M. Hewitt, D. B. Lacy, H. C. Lin, C. R. Gessner, S. Li, V. L. Woods Jr, R. J. Collier (2006) Structural determinants for the binding of anthrax lethal factor to oligomeric protective antigen. J Biol Chem. 281, 1630-5.

D. B. Lacy, H. C. Lin, R. A. Melnyk, O. Schueler-Furman, L. Reither, K. Cunningham, D. Baker, R. J. Collier (2005) A model of anthrax toxin lethal factor bound to protective antigen. Proc Natl Acad Sci U S A. 102, 16409-14.

B. A. Krantz, R. A. Melnyk, S. Zhang, S. J. Juris, D. B. Lacy, Z. Wu, A. Finkelstein, R. J. Collier (2005) A phenylalanine clamp catalyzes protein translocation through the anthrax toxin pore. Science 309, 777-81.

D. B. Lacy, D. J. Wigelsworth, R. A. Melnyk, S. C. Harrison, and R. J. Collier (2004) 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, 13147-51.

D. J. Wigelsworth , B. A. Krantz, K. A. Christensen, D. B. Lacy, S. J. Juris, and R. J. Collier (2004) Binding stoichiometry and kinetics of the interaction of a human anthrax toxin receptor, CMG2, with protective antigen. J. Biol. Chem. 279, 23349-56.

D. B. Lacy, D. J. Wigelsworth, H. M. Scobie, J. A. T. Young, and R. J. Collier (2004) 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, 6367-72.

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

D. B. Lacy and R. J. Collier (2002) Structure and function of anthrax toxin. Curr Top Microbiol Immunol. 271, 61-85.

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

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

J. Mogridge, K. Cunningham, D. B. Lacy, M. Mourez, and R. J. Collier (2002) 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, 7045-8.

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

A. D. Pannifer, T. Y. Wong, R. Schwarzenbacher, M. Renatus, C. Petosa, J. Bienkowska, D. B. Lacy, R. J. Collier, S. Park, S. H. Leppla, P. Hanna, and R. C. Liddington (2001) Crystal structure of the anthrax lethal factor. Nature 414, 229-33.

D. B. Lacy and R. C. Stevens (1999) Sequence homology and structural analysis of the clostridial neurotoxins. Journal of Molecular Biology 291, 1091-104.

D. B. Lacy and R. C. Stevens (1998) Unraveling structures and modes of action of bacterial toxins. Current Opinion in Structural Biology 8, 778-84.

D. B. Lacy, W. Tepp, A. C. Cohen, B. R. DasGupta, and R. C. Stevens (1998) The crystal structure of botulinum neurotoxin type A and implications for toxicity. Nature Structural Biology 5, 898-902.

D. B. Lacy and R. C. Stevens (1997) Recombinant expression and purification of the botulinum neurotoxin type A translocation domain. Protein Expression and Purification 11, 195-200.

M. T. Crimmins, S. Huang, L. E. Guise, and D. B. Lacy (1995) Addition of functionalized zinc copper reagents to acetylenic esters: synthesis of 2-carboalkoxy cyclohexenones. Tetrahedron Letters 36, 7061-64.

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Lab Members

D. Borden Lacy, Ph.D., Associate Professor of PMI and Biochemistry
Melissa Farrow, Ph.D. Research Instructor in PMI
Stacey Rutherford Seeback, Research Assistant III in PMI
McKenzie King, Research Assistant I in PMI

Postdoctoral Fellows

Heather Kroh, Ph.D. 2012-present
David Anderson, Ph.D. 2015-present
Mitch Lafrance, Ph.D. 2016-present
Michael Sheedlo, Ph.D. 2016-present

Graduate Students

Ramya Chandrasekaran, 2012-present, M.S. from University of Minnesota
Joe Alvin, 2012-present, B.S. from St. Lawrence University
Kevin Childress, 2016-present, B.S. from Emory University

High School Students

Sophia Chen, 2016-present

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Graduate Students

Major John Schmitt, 2007-2009, MS. U.S. Army

Kelly Gangwer Basi, 2006-2010, Ph.D. Microbiologist, United States Army Medical Research Institute for Chemical Defense (USAMRICD).

Darren Mushrush, 2007-2011, Ph.D. Scientist at Bristol Myers Squibb, MA

Rory Pruitt, 2007-2011, Ph.D. Postdoctoral fellowship with Thorsten Nurnberger, Tubingen University.

Desiree Benefield, 2010-2014, Ph.D. Postdoctoral fellowship with Paul Ahlquist, Morgridge Institute at the University of Wisconsin-Madison .

Nicole Chumbler, 2009-2015, Ph.D. Postdoctoral fellowship with Deborah Hung, Harvard Medical School and the Broad Institute.

Ryan Craven, 2011-2015, Ph.D. Clinical Microbiology Training Program, Tennessee Department of Health.

Michelle LaFrance, 2009-2016, post-doc in Lacy lab

Clinical fellows

Chadi Eltaha, M.D. 2014-2016, Neonatologist

Undergraduate Students

Vu Hong Ai, 2015 Present position: Undergraduate Student at Hanoi University of Science
Jonathan Davies, 2015 Present position: Undergraduate Student at Brown University
Taylor Jones, 2012 Present position: Undergraduate Student at University of Tennessee
Reed Jones, 2010
Laura Hood, 2009
Michael Cover, 2008
Erica Bozeman, 2006-2007

High School Students

Sherafghani Khan, 2016

Research Assistant

Adarsh Godbole, Present position: Pfizer

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