Dana Borden Lacy, Ph.D.

Associate Professor

borden.lacy@vanderbilt.edu
Faculty Appointments
Associate Professor of Pathology, Microbiology and Immunology Associate Professor of BiochemistryAssociate Professor of Biochemistry
Education
Ph.D., Chemistry, University of California, Berkeley, CaliforniaB.S., Chemistry, University of North Carolina, Chapel Hill, North Carolina
Office Address
A4116A MCN
Nashville, TN 37232
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 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.
Research Keywords
Understanding the structures and mechanisms of bacterial protein toxins and their host interactions. Clostridium difficile, bacteriology, X-ray crystallography, pathogenesis
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 [print-electronic]. 2015 Oct; 17(10): 1477-93. PMID: 25882477, DOI: 10.1111/cmi.12449, ISSN: 1462-5822.

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, PII: nature14484, DOI: 10.1038/nature14484, ISSN: 1476-4687.

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, PMCID: PMC4460460, PII: 1500791112, DOI: 10.1073/pnas.1500791112, ISSN: 1091-6490.

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, PMCID: PMC3956163, PII: 1400680111, DOI: 10.1073/pnas.1400680111, ISSN: 1091-6490.

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, PMCID: PMC3958006, PII: IAI.01444-13, DOI: 10.1128/IAI.01444-13, ISSN: 1098-5522.

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, PMCID: PMC3831945, PII: 1313658110, DOI: 10.1073/pnas.1313658110, ISSN: 1091-6490.

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, PMCID: PMC3876884, PII: S1931-3128(13)00325-9, DOI: 10.1016/j.chom.2013.09.005, ISSN: 1934-6069.

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, PMCID: PMC3638717, DOI: 10.1021/cb300555n, ISSN: 1554-8937.

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, PMCID: PMC3619295, PII: 1222139110, DOI: 10.1073/pnas.1222139110, ISSN: 1091-6490.

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, PMCID: PMC3612943, PII: S0022-2836(12)00892-3, DOI: 10.1016/j.jmb.2012.11.020, ISSN: 1089-8638.

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, PMCID: PMC3318759, PII: M111.298414, DOI: 10.1074/jbc.M111.298414, ISSN: 1083-351X.

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, PMCID: PMC3516567, PII: PPATHOGENS-D-12-01408, DOI: 10.1371/journal.ppat.1003072, ISSN: 1553-7374.

Pruitt RN, Lacy DB. Toward a structural understanding of Clostridium difficile toxins A and B. Front Cell Infect Microbiol. 2012; 2: 28. PMID: 22919620, PMCID: PMC3417631, DOI: 10.3389/fcimb.2012.00028, ISSN: 2235-2988.

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, PMCID: PMC3143659, PII: M111.256982, DOI: 10.1074/jbc.M111.256982, ISSN: 1083-351X.

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. Metab. Clin. Exp [print-electronic]. 2011 Jun; 60(6): 867-73. PMID: 20940071, PMCID: PMC3736817, PII: S0026-0495(10)00288-X, DOI: 10.1016/j.metabol.2010.08.006, ISSN: 1532-8600.

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, PMCID: PMC2981223, PII: JB.01081-10, DOI: 10.1128/JB.01081-10, ISSN: 1098-5530.

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 [print-electronic]. 2010 Jul 7/27/2010; 107(30): 13467-72. PMID: 20624955, PMCID: PMC2922184, PII: 1002199107, DOI: 10.1073/pnas.1002199107, ISSN: 1091-6490.

González-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. 2010 Jul 7/13/2010; 49(27): 5743-52. PMID: 20527875, PMCID: PMC2910095, DOI: 10.1021/bi100618g, ISSN: 1520-4995.

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. 2010 Jun 6/29/2010; 49(25): 5200-5. PMID: 20507178, PMCID: PMC2894633, DOI: 10.1021/bi100412v, ISSN: 1520-4995.

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. 2010; 10: 60. PMID: 20178613, PMCID: PMC2836311, PII: 1471-2180-10-60, DOI: 10.1186/1471-2180-10-60, ISSN: 1471-2180.

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 [print-electronic]. 2009 Aug 8/14/2009; 284(33): 21934-40. PMID: 19553670, PMCID: PMC2755918, PII: M109.018929, DOI: 10.1074/jbc.M109.018929, ISSN: 0021-9258.

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 [print-electronic]. 2009 May; 296(5): E1172-8. PMID: 19208853, PMCID: PMC2681308, PII: 90821.2008, DOI: 10.1152/ajpendo.90821.2008, ISSN: 0193-1849.

Fischer A, Mushrush DJ, Lacy DB, Montal M. Botulinum neurotoxin devoid of receptor binding domain translocates active protease. PLoS Pathog [print-electronic]. 2008 Dec; 4(12): e1000245. PMID: 19096517, PMCID: PMC2596314, DOI: 10.1371/journal.ppat.1000245, ISSN: 1553-7374.

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 [print-electronic]. 2008 Jul; 76(7): 2843-51. PMID: 18443094, PMCID: PMC2446698, PII: IAI.01664-07, DOI: 10.1128/IAI.01664-07, ISSN: 1098-5522.

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 [print-electronic]. 2007 Oct 10/9/2007; 104(41): 16293-8. PMID: 17911250, PMCID: PMC2042200, PII: 0707447104, DOI: 10.1073/pnas.0707447104, ISSN: 0027-8424.

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. 2007; 2(3): e329. PMID: 17389920, PMCID: PMC1824706, DOI: 10.1371/journal.pone.0000329, ISSN: 1932-6203.

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. 2006 Oct; 2(10): e111. PMID: 17054395, PMCID: PMC1617126, PII: 06-PLPA-RA-0138R2, DOI: 10.1371/journal.ppat.0020111, ISSN: 1553-7374.

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 [print-electronic]. 2006 Jan 1/20/2006; 281(3): 1630-5. PMID: 16293620, PII: M511164200, DOI: 10.1074/jbc.M511164200, ISSN: 0021-9258.

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 [print-electronic]. 2005 Nov 11/8/2005; 102(45): 16409-14. PMID: 16251269, PMCID: PMC1283467, PII: 0508259102, DOI: 10.1073/pnas.0508259102, ISSN: 0027-8424.

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. 2005 Jul 7/29/2005; 309(5735): 777-81. PMID: 16051798, PMCID: PMC1815389, PII: 309/5735/777, DOI: 10.1126/science.1113380, ISSN: 1095-9203.

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 [print-electronic]. 2004 Sep 9/7/2004; 101(36): 13147-51. PMID: 15326297, PMCID: PMC516539, PII: 0405405101, DOI: 10.1073/pnas.0405405101, ISSN: 0027-8424.

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 [print-electronic]. 2004 May 5/28/2004; 279(22): 23349-56. PMID: 15044490, PII: M401292200, DOI: 10.1074/jbc.M401292200, ISSN: 0021-9258.

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 [print-electronic]. 2004 Apr 4/27/2004; 101(17): 6367-72. PMID: 15079089, PMCID: PMC404051, PII: 0401506101, DOI: 10.1073/pnas.0401506101, ISSN: 0027-8424.

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 [print-electronic]. 2003 Nov 11/25/2003; 100(24): 13803-8. PMID: 14623961, PMCID: PMC283502, PII: 2436299100, DOI: 10.1073/pnas.2436299100, ISSN: 0027-8424.

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. 2002 Jun; 10(6): 287-93. PMID: 12088665, PII: S0966842X02023697, ISSN: 0966-842X.

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 [print-electronic]. 2002 May 5/14/2002; 99(10): 7049-53. PMID: 11997439, PMCID: PMC124526, PII: 062160399, DOI: 10.1073/pnas.062160399, ISSN: 0027-8424.

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 [print-electronic]. 2002 May 5/14/2002; 99(10): 7045-8. PMID: 11997437, PMCID: PMC124525, PII: 052160199, DOI: 10.1073/pnas.052160199, ISSN: 0027-8424.

Lacy DB, Mourez M, Fouassier A, Collier RJ. Mapping the anthrax protective antigen binding site on the lethal and edema factors. J. Biol. Chem [print-electronic]. 2002 Jan 1/25/2002; 277(4): 3006-10. PMID: 11714723, PII: M109997200, DOI: 10.1074/jbc.M109997200, ISSN: 0021-9258.

Lacy DB, Collier RJ. Structure and function of anthrax toxin. Curr. Top. Microbiol. Immunol. 2002; 271: 61-85. PMID: 12224524, ISSN: 0070-217X.

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. 2001 Nov 11/8/2001; 414(6860): 229-33. PMID: 11700563, PII: n35101999, DOI: 10.1038/n35101998, ISSN: 0028-0836.

Lacy DB, Stevens RC. Sequence homology and structural analysis of the clostridial neurotoxins. J. Mol. Biol. 1999 Sep 9/3/1999; 291(5): 1091-104. PMID: 10518945, PII: S0022-2836(99)92945-5, DOI: 10.1006/jmbi.1999.2945, ISSN: 0022-2836.

Lacy DB, Stevens RC. Unraveling the structures and modes of action of bacterial toxins. Curr. Opin. Struct. Biol. 1998 Dec; 8(6): 778-84. PMID: 9914258, ISSN: 0959-440X.

Lacy DB, Tepp W, Cohen AC, DasGupta BR, Stevens RC. Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat. Struct. Biol. 1998 Oct; 5(10): 898-902. PMID: 9783750, DOI: 10.1038/2338, ISSN: 1072-8368.

Lacy DB, Stevens RC. Recombinant expression and purification of the botulinum neurotoxin type A translocation domain. Protein Expr. Purif. 1997 Nov; 11(2): 195-200. PMID: 9367816, PII: S1046-5928(97)90772-5, DOI: 10.1006/prep.1997.0772, ISSN: 1046-5928.

McGuinness OP, Lacy DB, Ejiofor J, Bagby GG. Hepatic release of tumor necrosis factor in the endotoxin-treated conscious dog. Shock. 1996 May; 5(5): 344-8. PMID: 9156790, ISSN: 1073-2322.

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

Available Postdoctoral Position Details
Posted: 8/19/2015
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