Borden Lacy
Last active: 4/2/2019

Profile

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.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. A neutralizing antibody that blocks delivery of the enzymatic cargo of toxin TcdB into host cells. Kroh HK, Chandrasekaran R, Zhang Z, Rosenthal K, Woods R, Jin X, Nyborg AC, Rainey GJ, Warrener P, Melnyk RA, Spiller BW, Lacy DB (2018) J Biol Chem 293(3): 941-952
    › Primary publication · 29180448 (PubMed) · PMC5777265 (PubMed Central)
  2. The role of toxins in Clostridium difficile infection. Chandrasekaran R, Lacy DB (2017) FEMS Microbiol Rev 41(6): 723-750
    › Primary publication · 29048477 (PubMed) · PMC5812492 (PubMed Central)
  3. Functional defects in TcdB toxin uptake identify CSPG4 receptor-binding determinants. Gupta P, Zhang Z, Sugiman-Marangos SN, Tam J, Raman S, Julien JP, Kroh HK, Lacy DB, Murgolo N, Bekkari K, Therien AG, Hernandez LD, Melnyk RA (2017) J Biol Chem 292(42): 17290-17301
    › Primary publication · 28842504 (PubMed) · PMC5655507 (PubMed Central)
  4. Antibacterial photosensitization through activation of coproporphyrinogen oxidase. Surdel MC, Horvath DJ, Lojek LJ, Fullen AR, Simpson J, Dutter BF, Salleng KJ, Ford JB, Jenkins JL, Nagarajan R, Teixeira PL, Albertolle M, Georgiev IS, Jansen ED, Sulikowski GA, Lacy DB, Dailey HA, Skaar EP (2017) Proc Natl Acad Sci U S A 114(32): E6652-E6659
    › Primary publication · 28739897 (PubMed) · PMC5559000 (PubMed Central)
  5. Use of a neutralizing antibody helps identify structural features critical for binding of toxin TcdA to the host cell surface. Kroh HK, Chandrasekaran R, Rosenthal K, Woods R, Jin X, Ohi MD, Nyborg AC, Rainey GJ, Warrener P, Spiller BW, Lacy DB (2017) J Biol Chem 292(35): 14401-14412
    › Primary publication · 28705932 (PubMed) · PMC5582835 (PubMed Central)
  6. Clostridium difficile toxin glucosyltransferase domains in complex with a non-hydrolyzable UDP-glucose analogue. Alvin JW, Lacy DB (2017) J Struct Biol 198(3): 203-209
    › Primary publication · 28433497 (PubMed) · PMC5534367 (PubMed Central)
  7. Epitopes and Mechanism of Action of the Clostridium difficile Toxin A-Neutralizing Antibody Actoxumab. Hernandez LD, Kroh HK, Hsieh E, Yang X, Beaumont M, Sheth PR, DiNunzio E, Rutherford SA, Ohi MD, Ermakov G, Xiao L, Secore S, Karczewski J, Racine F, Mayhood T, Fischer P, Sher X, Gupta P, Lacy DB, Therien AG (2017) J Mol Biol 429(7): 1030-1044
    › Primary publication · 28232034 (PubMed)
  8. Integrated, High-Throughput, Multiomics Platform Enables Data-Driven Construction of Cellular Responses and Reveals Global Drug Mechanisms of Action. Norris JL, Farrow MA, Gutierrez DB, Palmer LD, Muszynski N, Sherrod SD, Pino JC, Allen JL, Spraggins JM, Lubbock AL, Jordan A, Burns W, Poland JC, Romer C, Manier ML, Nei YW, Prentice BM, Rose KL, Hill S, Van de Plas R, Tsui T, Braman NM, Keller MR, Rutherford SA, Lobdell N, Lopez CF, Lacy DB, McLean JA, Wikswo JP, Skaar EP, Caprioli RM (2017) J Proteome Res 16(3): 1364-1375
    › Primary publication · 28088864 (PubMed)
  9. Clostridium difficile Toxin A Undergoes Clathrin-Independent, PACSIN2-Dependent Endocytosis. Chandrasekaran R, Kenworthy AK, Lacy DB (2016) PLoS Pathog 12(12): e1006070
    › Primary publication · 27942025 (PubMed) · PMC5152916 (PubMed Central)
  10. Crystal structure of Clostridium difficile toxin A. Chumbler NM, Rutherford SA, Zhang Z, Farrow MA, Lisher JP, Farquhar E, Giedroc DP, Spiller BW, Melnyk RA, Lacy DB (2016) Nat Microbiol : 15002
    › Primary publication · 27571750 (PubMed) · PMC4976693 (PubMed Central)
  11. Clostridium difficile Toxins TcdA and TcdB Cause Colonic Tissue Damage by Distinct Mechanisms. Chumbler NM, Farrow MA, Lapierre LA, Franklin JL, Lacy DB (2016) Infect Immun 84(10): 2871-7
    › Primary publication · 27456833 (PubMed) · PMC5038081 (PubMed Central)
  12. A Nonoligomerizing Mutant Form of Helicobacter pylori VacA Allows Structural Analysis of the p33 Domain. González-Rivera C, Campbell AM, Rutherford SA, Pyburn TM, Foegeding NJ, Barke TL, Spiller BW, McClain MS, Ohi MD, Lacy DB, Cover TL (2016) Infect Immun 84(9): 2662-70
    › Primary publication · 27382020 (PubMed) · PMC4995914 (PubMed Central)
  13. Clostridium sordellii Lethal-Toxin Autoprocessing and Membrane Localization Activities Drive GTPase Glucosylation Profiles in Endothelial Cells. Craven R, Lacy DB (2016) mSphere 1(1)
    › Primary publication · 27303685 (PubMed) · PMC4863631 (PubMed Central)
  14. Clostridium difficile infection. Smits WK, Lyras D, Lacy DB, Wilcox MH, Kuijper EJ (2016) Nat Rev Dis Primers : 16020
    › Primary publication · 27158839 (PubMed) · PMC5453186 (PubMed Central)
  15. Exploiting dominant-negative toxins to combat Staphylococcus aureus pathogenesis. Reyes-Robles T, Lubkin A, Alonzo F, Lacy DB, Torres VJ (2016) EMBO Rep 17(5): 780
    › Primary publication · 27139260 (PubMed) · PMC5341525 (PubMed Central)
  16. Exploiting dominant-negative toxins to combat Staphylococcus aureus pathogenesis. Reyes-Robles T, Lubkin A, Alonzo F, Lacy DB, Torres VJ (2016) EMBO Rep 17(3): 428-40
    › Primary publication · 26882549 (PubMed) · PMC4772982 (PubMed Central)
  17. Analysis of TcdB Proteins within the Hypervirulent Clade 2 Reveals an Impact of RhoA Glucosylation on Clostridium difficile Proinflammatory Activities. Quesada-Gómez C, López-Ureña D, Chumbler N, Kroh HK, Castro-Peña C, Rodríguez C, Orozco-Aguilar J, González-Camacho S, Rucavado A, Guzmán-Verri C, Lawley TD, Lacy DB, Chaves-Olarte E (2016) Infect Immun 84(3): 856-65
    › Primary publication · 26755157 (PubMed) · PMC4771349 (PubMed Central)
  18. Cloning and variation of ground state intestinal stem cells. 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 (2015) Nature 522(7555): 173-8
    › Primary publication · 26040716 (PubMed) · PMC4853906 (PubMed Central)
  19. Identification of an epithelial cell receptor responsible for Clostridium difficile TcdB-induced cytotoxicity. LaFrance ME, Farrow MA, Chandrasekaran R, Sheng J, Rubin DH, Lacy DB (2015) Proc Natl Acad Sci U S A 112(22): 7073-8
    › Primary publication · 26038560 (PubMed) · PMC4460460 (PubMed Central)
  20. The catalytic domains of Clostridium sordellii lethal toxin and related large clostridial glucosylating toxins specifically recognize the negatively charged phospholipids phosphatidylserine and phosphatidic acid. Varela Chavez C, Hoos S, Haustant GM, Chenal A, England P, Blondel A, Pauillac S, Lacy DB, Popoff MR (2015) Cell Microbiol 17(10): 1477-93
    › Primary publication · 25882477 (PubMed)
  21. Translocation domain mutations affecting cellular toxicity identify the Clostridium difficile toxin B pore. Zhang Z, Park M, Tam J, Auger A, Beilhartz GL, Lacy DB, Melnyk RA (2014) Proc Natl Acad Sci U S A 111(10): 3721-6
    › Primary publication · 24567384 (PubMed) · PMC3956163 (PubMed Central)
  22. Identification of a crucial residue required for Staphylococcus aureus LukAB cytotoxicity and receptor recognition. DuMont AL, Yoong P, Liu X, Day CJ, Chumbler NM, James DB, Alonzo F, Bode NJ, Lacy DB, Jennings MP, Torres VJ (2014) Infect Immun 82(3): 1268-76
    › Primary publication · 24379286 (PubMed) · PMC3958006 (PubMed Central)
  23. Clostridium difficile toxin B-induced necrosis is mediated by the host epithelial cell NADPH oxidase complex. Farrow MA, Chumbler NM, Lapierre LA, Franklin JL, Rutherford SA, Goldenring JR, Lacy DB (2013) Proc Natl Acad Sci U S A 110(46): 18674-9
    › Primary publication · 24167244 (PubMed) · PMC3831945 (PubMed Central)
  24. Staphylococcus aureus leukotoxin ED targets the chemokine receptors CXCR1 and CXCR2 to kill leukocytes and promote infection. Reyes-Robles T, Alonzo F, Kozhaya L, Lacy DB, Unutmaz D, Torres VJ (2013) Cell Host Microbe 14(4): 453-9
    › Primary publication · 24139401 (PubMed) · PMC3876884 (PubMed Central)
  25. Molecular assembly of botulinum neurotoxin progenitor complexes. Benefield DA, Dessain SK, Shine N, Ohi MD, Lacy DB (2013) Proc Natl Acad Sci U S A 110(14): 5630-5
    › Primary publication · 23509303 (PubMed) · PMC3619295 (PubMed Central)
  26. Identification of novel host-targeted compounds that protect from anthrax lethal toxin-induced cell death. Slater LH, Hett EC, Mark K, Chumbler NM, Patel D, Lacy DB, Collier RJ, Hung DT (2013) ACS Chem Biol 8(4): 812-22
    › Primary publication · 23343607 (PubMed) · PMC3638717 (PubMed Central)
  27. Clostridium difficile Toxin B causes epithelial cell necrosis through an autoprocessing-independent mechanism. Chumbler NM, Farrow MA, Lapierre LA, Franklin JL, Haslam DB, Haslam D, Goldenring JR, Lacy DB (2012) PLoS Pathog 8(12): e1003072
    › Primary publication · 23236283 (PubMed) · PMC3516567 (PubMed Central)
  28. Structural analysis of the oligomeric states of Helicobacter pylori VacA toxin. Chambers MG, Pyburn TM, González-Rivera C, Collier SE, Eli I, Yip CK, Takizawa Y, Lacy DB, Cover TL, Ohi MD (2013) J Mol Biol 425(3): 524-35
    › Primary publication · 23178866 (PubMed) · PMC3612943 (PubMed Central)
  29. Toward a structural understanding of Clostridium difficile toxins A and B. Pruitt RN, Lacy DB (2012) Front Cell Infect Microbiol : 28
    › Primary publication · 22919620 (PubMed) · PMC3417631 (PubMed Central)
  30. Structural determinants of Clostridium difficile toxin A glucosyltransferase activity. Pruitt RN, Chumbler NM, Rutherford SA, Farrow MA, Friedman DB, Spiller B, Lacy DB (2012) J Biol Chem 287(11): 8013-20
    › Primary publication · 22267739 (PubMed) · PMC3318759 (PubMed Central)
  31. Studies of the mechanistic details of the pH-dependent association of botulinum neurotoxin with membranes. Mushrush DJ, Koteiche HA, Sammons MA, Link AJ, McHaourab HS, Lacy DB (2011) J Biol Chem 286(30): 27011-8
    › Primary publication · 21652698 (PubMed) · PMC3143659 (PubMed Central)
  32. Molecular evolution of the Helicobacter pylori vacuolating toxin gene vacA. Gangwer KA, Shaffer CL, Suerbaum S, Lacy DB, Cover TL, Bordenstein SR (2010) J Bacteriol 192(23): 6126-35
    › Primary publication · 20870762 (PubMed) · PMC2981223 (PubMed Central)
  33. Structural organization of the functional domains of Clostridium difficile toxins A and B. Pruitt RN, Chambers MG, Ng KK, Ohi MD, Lacy DB (2010) Proc Natl Acad Sci U S A 107(30): 13467-72
    › Primary publication · 20624955 (PubMed) · PMC2922184 (PubMed Central)
  34. Reconstitution of Helicobacter pylori VacA toxin from purified components. González-Rivera C, Gangwer KA, McClain MS, Eli IM, Chambers MG, Ohi MD, Lacy DB, Cover TL (2010) Biochemistry 49(27): 5743-52
    › Primary publication · 20527875 (PubMed) · PMC2910095 (PubMed Central)
  35. Structural analysis of botulinum neurotoxin type G receptor binding . Schmitt J, Karalewitz A, Benefield DA, Mushrush DJ, Pruitt RN, Spiller BW, Barbieri JT, Lacy DB (2010) Biochemistry 49(25): 5200-5
    › Primary publication · 20507178 (PubMed) · PMC2894633 (PubMed Central)
  36. Analysis of a beta-helical region in the p55 domain of Helicobacter pylori vacuolating toxin. Ivie SE, McClain MS, Algood HM, Lacy DB, Cover TL (2010) BMC Microbiol : 60
    › Primary publication · 20178613 (PubMed) · PMC2836311 (PubMed Central)
  37. Structure-function analysis of inositol hexakisphosphate-induced autoprocessing in Clostridium difficile toxin A. Pruitt RN, Chagot B, Cover M, Chazin WJ, Spiller B, Lacy DB (2009) J Biol Chem 284(33): 21934-40
    › Primary publication · 19553670 (PubMed) · PMC2755918 (PubMed Central)
  38. Botulinum neurotoxin devoid of receptor binding domain translocates active protease. Fischer A, Mushrush DJ, Lacy DB, Montal M (2008) PLoS Pathog 4(12): e1000245
    › Primary publication · 19096517 (PubMed) · PMC2596314 (PubMed Central)
  39. Helicobacter pylori VacA subdomain required for intracellular toxin activity and assembly of functional oligomeric complexes. Ivie SE, McClain MS, Torres VJ, Algood HM, Lacy DB, Yang R, Blanke SR, Cover TL (2008) Infect Immun 76(7): 2843-51
    › Primary publication · 18443094 (PubMed) · PMC2446698 (PubMed Central)
  40. Crystal structure of the Helicobacter pylori vacuolating toxin p55 domain. Gangwer KA, Mushrush DJ, Stauff DL, Spiller B, McClain MS, Cover TL, Lacy DB (2007) Proc Natl Acad Sci U S A 104(41): 16293-8
    › Primary publication · 17911250 (PubMed) · PMC2042200 (PubMed Central)
  41. Anthrax toxin receptor 2 determinants that dictate the pH threshold of toxin pore formation. Scobie HM, Marlett JM, Rainey GJ, Lacy DB, Collier RJ, Young JA (2007) PLoS One 2(3): e329
    › Primary publication · 17389920 (PubMed) · PMC1824706 (PubMed Central)
  42. Anthrax toxin receptor 2-dependent lethal toxin killing in vivo. Scobie HM, Wigelsworth DJ, Marlett JM, Thomas D, Rainey GJ, Lacy DB, Manchester M, Collier RJ, Young JA (2006) PLoS Pathog 2(10): e111
    › Primary publication · 17054395 (PubMed) · PMC1617126 (PubMed Central)
  43. Structural determinants for the binding of anthrax lethal factor to oligomeric protective antigen. Melnyk RA, Hewitt KM, Lacy DB, Lin HC, Gessner CR, Li S, Woods VL, Collier RJ (2006) J Biol Chem 281(3): 1630-5
    › Primary publication · 16293620 (PubMed)
  44. A model of anthrax toxin lethal factor bound to protective antigen. Lacy DB, Lin HC, Melnyk RA, Schueler-Furman O, Reither L, Cunningham K, Baker D, Collier RJ (2005) Proc Natl Acad Sci U S A 102(45): 16409-14
    › Primary publication · 16251269 (PubMed) · PMC1283467 (PubMed Central)
  45. A phenylalanine clamp catalyzes protein translocation through the anthrax toxin pore. Krantz BA, Melnyk RA, Zhang S, Juris SJ, Lacy DB, Wu Z, Finkelstein A, Collier RJ (2005) Science 309(5735): 777-81
    › Primary publication · 16051798 (PubMed) · PMC1815389 (PubMed Central)
  46. Structure of heptameric protective antigen bound to an anthrax toxin receptor: a role for receptor in pH-dependent pore formation. Lacy DB, Wigelsworth DJ, Melnyk RA, Harrison SC, Collier RJ (2004) Proc Natl Acad Sci U S A 101(36): 13147-51
    › Primary publication · 15326297 (PubMed) · PMC516539 (PubMed Central)
  47. Crystal structure of the von Willebrand factor A domain of human capillary morphogenesis protein 2: an anthrax toxin receptor. Lacy DB, Wigelsworth DJ, Scobie HM, Young JA, Collier RJ (2004) Proc Natl Acad Sci U S A 101(17): 6367-72
    › Primary publication · 15079089 (PubMed) · PMC404051 (PubMed Central)
  48. Binding stoichiometry and kinetics of the interaction of a human anthrax toxin receptor, CMG2, with protective antigen. Wigelsworth DJ, Krantz BA, Christensen KA, Lacy DB, Juris SJ, Collier RJ (2004) J Biol Chem 279(22): 23349-56
    › Primary publication · 15044490 (PubMed)
  49. Mapping dominant-negative mutations of anthrax protective antigen by scanning mutagenesis. 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 (2003) Proc Natl Acad Sci U S A 100(24): 13803-8
    › Primary publication · 14623961 (PubMed) · PMC283502 (PubMed Central)
  50. Structure and function of anthrax toxin. Lacy DB, Collier RJ (2002) Curr Top Microbiol Immunol : 61-85
    › Primary publication · 12224524 (PubMed)
  51. 2001: a year of major advances in anthrax toxin research. Mourez M, Lacy DB, Cunningham K, Legmann R, Sellman BR, Mogridge J, Collier RJ (2002) Trends Microbiol 10(6): 287-93
    › Primary publication · 12088665 (PubMed)
  52. Mapping the lethal factor and edema factor binding sites on oligomeric anthrax protective antigen. Cunningham K, Lacy DB, Mogridge J, Collier RJ (2002) Proc Natl Acad Sci U S A 99(10): 7049-53
    › Primary publication · 11997439 (PubMed) · PMC124526 (PubMed Central)
  53. The lethal and edema factors of anthrax toxin bind only to oligomeric forms of the protective antigen. Mogridge J, Cunningham K, Lacy DB, Mourez M, Collier RJ (2002) Proc Natl Acad Sci U S A 99(10): 7045-8
    › Primary publication · 11997437 (PubMed) · PMC124525 (PubMed Central)
  54. Mapping the anthrax protective antigen binding site on the lethal and edema factors. Lacy DB, Mourez M, Fouassier A, Collier RJ (2002) J Biol Chem 277(4): 3006-10
    › Primary publication · 11714723 (PubMed)
  55. Sequence homology and structural analysis of the clostridial neurotoxins. Lacy DB, Stevens RC (1999) J Mol Biol 291(5): 1091-104
    › Primary publication · 10518945 (PubMed)
  56. Unraveling the structures and modes of action of bacterial toxins. Lacy DB, Stevens RC (1998) Curr Opin Struct Biol 8(6): 778-84
    › Primary publication · 9914258 (PubMed)
  57. Crystal structure of botulinum neurotoxin type A and implications for toxicity. Lacy DB, Tepp W, Cohen AC, DasGupta BR, Stevens RC (1998) Nat Struct Biol 5(10): 898-902
    › Primary publication · 9783750 (PubMed)
  58. Recombinant expression and purification of the botulinum neurotoxin type A translocation domain. Lacy DB, Stevens RC (1997) Protein Expr Purif 11(2): 195-200
    › Primary publication · 9367816 (PubMed)