Mark S. McClain, Ph.D.

Research Professor
Faculty Appointments
Research Professor of Medicine
Ph.D., Microbiology and Immunology, University of Michigan, Ann Arbor, MichiganB.S., Genetics, Ohio State University, Columbus, Ohio
Office Address
Division of Infectious Disease
A2200 Medical Center North
1161 21st Ave. North
Nashville, TN 37232-2605
Research Description
We are interested in bacterial pathogenesis, with an emphasis in bacterial protein toxins. These proteins play critical roles in infectious diseases. Current studies focus on toxins produced by the human pathogens Helicobacter pylori and Clostridium perfringens. Through studying such toxins, we expect to better understand the molecular events that contribute to disease and to develop therapeutic inhibitors that will be used to treat disease.

One focus of our studies is the Clostridium perfringens epsilon toxin. C. perfringens is a gram positive, anaerobic bacterium that causes a wide variety of illnesses, ranging from diarrhea to lethal toxemias, in humans and other animals. The epsilon toxin is an extremely potent pore-forming toxin responsible for an often fatal enterotoxemia in animals (particularly livestock, but also possibly in humans). A recent study suggests the toxin contributes to Multiple Sclerosis. Using a high-throughput screen and molecular biological, biochemical, and cell biological techniques, we seek to develop safe and effective inhibitors of the toxin. As we continue to develop inhibitors of the toxin, we also are working to understand the interaction between the toxin and mammalian cells and the cellular responses to the toxin.

A second focus of our studies is the gram negative bacterium Helicobacter pylori, an organism associated with peptic ulcers and gastric cancer in humans. Two proteins secreted by H. pylori are VacA and CagA. VacA is a secreted pore-forming toxin with a variety of effects on epithelial cells. CagA is a protein that is translocated directly from the bacterial cytoplasm into the cytoplasm of host epithelial cells through a specialized secretion apparatus. Using molecular biological, biochemical, and cell biological techniques, our current studies focus on structure-function relationships of the VacA toxin, the type IV secretion apparatus required for CagA secretion, and efforts to identify proteins other than CagA that are translocated by the H. pylori CagA secretion apparatus. As a result of these studies, we hope to better understand the contribution of H. pylori to peptic ulcers and gastric cancer.
Research Keywords
bacterial pathogenesis and bacterial protein toxins
González-Rivera C, Campbell AM, Rutherford SA, Pyburn TM, Foegeding NJ, Barke TL, Spiller BW, McClain MS, Ohi MD, Lacy DB, Cover TL. A Nonoligomerizing Mutant Form of Helicobacter pylori VacA Allows Structural Analysis of the p33 Domain. Infect. Immun [electronic-print]. 2016 Sep; 84(9): 2662-70. PMID: 27382020, PMCID: PMC4995914, PII: IAI.00254-16, DOI: 10.1128/IAI.00254-16, ISSN: 1098-5522.

Foegeding NJ, Caston RR, McClain MS, Ohi MD, Cover TL. An Overview of Helicobacter pylori VacA Toxin Biology. Toxins (Basel). 2016; 8(6): PMID: 27271669, PII: toxins8060173, DOI: 10.3390/toxins8060173, ISSN: 2072-6651.

Miller SE, Bell CS, McClain MS, Cover TL, Giorgio TD. Dynamic Computational Model of Symptomatic Bacteremia to Inform Bacterial Separation Treatment Requirements. PLoS ONE. 2016; 11(9): e0163167. PMID: 27657881, PII: PONE-D-16-28144, DOI: 10.1371/journal.pone.0163167, ISSN: 1932-6203.

Rumah KR, Ma Y, Linden JR, Oo ML, Anrather J, Schaeren-Wiemers N, Alonso MA, Fischetti VA, McClain MS, Vartanian T. The Myelin and Lymphocyte Protein MAL Is Required for Binding and Activity of Clostridium perfringens e-Toxin. PLoS Pathog. 2015 May; 11(5): e1004896. PMID: 25993478, PMCID: PMC4439126, PII: PPATHOGENS-D-13-03285, DOI: 10.1371/journal.ppat.1004896, ISSN: 1553-7374.

Radin JN, González-Rivera C, Frick-Cheng AE, Sheng J, Gaddy JA, Rubin DH, Algood HM, McClain MS, Cover TL. Role of connexin 43 in Helicobacter pylori VacA-induced cell death. Infect. Immun [print-electronic]. 2014 Jan; 82(1): 423-32. PMID: 24191302, PMCID: PMC3911829, PII: IAI.00827-13, DOI: 10.1128/IAI.00827-13, ISSN: 1098-5522.

McClain MS, Duncan SS, Gaddy JA, Cover TL. Control of gene expression in Helicobacter pylori using the Tet repressor. J. Microbiol. Methods [print-electronic]. 2013 Dec; 95(3): 336-41. PMID: 24113399, PMCID: PMC3856897, PII: S0167-7012(13)00302-3, DOI: 10.1016/j.mimet.2013.09.019, ISSN: 1872-8359.

Duncan SS, Bertoli MT, Kersulyte D, Valk PL, Tamma S, Segal I, McClain MS, Cover TL, Berg DE. Genome Sequences of Three hpAfrica2 Strains of Helicobacter pylori. Genome Announc. 2013; 1(5): PMID: 24072860, PMCID: PMC3784780, PII: 1/5/e00729-13, DOI: 10.1128/genomeA.00729-13, ISSN: 2169-8287.

Duncan SS, Valk PL, McClain MS, Shaffer CL, Metcalf JA, Bordenstein SR, Cover TL. Comparative genomic analysis of East Asian and non-Asian Helicobacter pylori strains identifies rapidly evolving genes. PLoS ONE [print-electronic]. 2013; 8(1): e55120. PMID: 23383074, PMCID: PMC3561388, PII: PONE-D-12-28737, DOI: 10.1371/journal.pone.0055120, ISSN: 1932-6203.

Ivie SE, McClain MS. Identification of amino acids important for binding of Clostridium perfringens epsilon toxin to host cells and to HAVCR1. Biochemistry [print-electronic]. 2012 Sep 9/25/2012; 51(38): 7588-95. PMID: 22938730, PMCID: PMC3534817, DOI: 10.1021/bi300690a, ISSN: 1520-4995.

González-Rivera C, Algood HM, Radin JN, McClain MS, Cover TL. The intermediate region of Helicobacter pylori VacA is a determinant of toxin potency in a Jurkat T cell assay. Infect. Immun [print-electronic]. 2012 Aug; 80(8): 2578-88. PMID: 22585965, PMCID: PMC3434591, PII: IAI.00052-12, DOI: 10.1128/IAI.00052-12, ISSN: 1098-5522.

Fennessey CM, Ivie SE, McClain MS. Coenzyme depletion by members of the aerolysin family of pore-forming toxins leads to diminished ATP levels and cell death. Mol Biosyst [print-electronic]. 2012 Aug; 8(8): 2097-105. PMID: 22688384, PMCID: PMC3759351, DOI: 10.1039/c2mb25142f, ISSN: 1742-2051.

Fennessey CM, Sheng J, Rubin DH, McClain MS. Oligomerization of Clostridium perfringens epsilon toxin is dependent upon caveolins 1 and 2. PLoS ONE [print-electronic]. 2012; 7(10): e46866. PMID: 23056496, PMCID: PMC3462777, PII: PONE-D-12-17436, DOI: 10.1371/journal.pone.0046866, ISSN: 1932-6203.

Loh JT, Shaffer CL, Piazuelo MB, Bravo LE, McClain MS, Correa P, Cover TL. Analysis of cagA in Helicobacter pylori strains from Colombian populations with contrasting gastric cancer risk reveals a biomarker for disease severity. Cancer Epidemiol. Biomarkers Prev [print-electronic]. 2011 Oct; 20(10): 2237-49. PMID: 21859954, PMCID: PMC3189306, PII: 1055-9965.EPI-11-0548, DOI: 10.1158/1055-9965.EPI-11-0548, ISSN: 1538-7755.

Shaffer CL, Gaddy JA, Loh JT, Johnson EM, Hill S, Hennig EE, McClain MS, McDonald WH, Cover TL. Helicobacter pylori exploits a unique repertoire of type IV secretion system components for pilus assembly at the bacteria-host cell interface. PLoS Pathog [print-electronic]. 2011 Sep; 7(9): e1002237. PMID: 21909278, PMCID: PMC3164655, PII: PPATHOGENS-D-11-00533, DOI: 10.1371/journal.ppat.1002237, ISSN: 1553-7374.

Radin JN, González-Rivera C, Ivie SE, McClain MS, Cover TL. Helicobacter pylori VacA induces programmed necrosis in gastric epithelial cells. Infect. Immun [print-electronic]. 2011 Jul; 79(7): 2535-43. PMID: 21482684, PMCID: PMC3191986, PII: IAI.01370-10, DOI: 10.1128/IAI.01370-10, ISSN: 1098-5522.

Ivie SE, Fennessey CM, Sheng J, Rubin DH, McClain MS. Gene-trap mutagenesis identifies mammalian genes contributing to intoxication by Clostridium perfringens e-toxin. PLoS ONE. 2011; 6(3): e17787. PMID: 21412435, PMCID: PMC3055893, DOI: 10.1371/journal.pone.0017787, ISSN: 1932-6203.

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.

Lewis M, Weaver CD, McClain MS. Identification of Small Molecule Inhibitors of Clostridium perfringens e-Toxin Cytotoxicity Using a Cell-Based High-Throughput Screen. Toxins (Basel). 2010 Jul 7/1/2010; 2(7): 1825-47. PMID: 20721308, PMCID: PMC2922765, DOI: 10.3390/toxins2071825, ISSN: 2072-6651.

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.

Pelish TM, McClain MS. Dominant-negative inhibitors of the Clostridium perfringens epsilon-toxin. J. Biol. Chem [print-electronic]. 2009 Oct 10/23/2009; 284(43): 29446-53. PMID: 19720828, PMCID: PMC2785577, PII: M109.021782, DOI: 10.1074/jbc.M109.021782, ISSN: 1083-351X.

McClain MS, Shaffer CL, Israel DA, Peek RM, Cover TL. Genome sequence analysis of Helicobacter pylori strains associated with gastric ulceration and gastric cancer. BMC Genomics. 2009; 10: 3. PMID: 19123947, PMCID: PMC2627912, PII: 1471-2164-10-3, DOI: 10.1186/1471-2164-10-3, ISSN: 1471-2164.

Loh JT, Torres VJ, Algood HM, McClain MS, Cover TL. Helicobacter pylori HopQ outer membrane protein attenuates bacterial adherence to gastric epithelial cells. FEMS Microbiol. Lett. 2008 Dec; 289(1): 53-8. PMID: 19065710, PMCID: PMC2651568, ISSN: 0378-1097.

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.

McClain MS, Cover TL. Functional analysis of neutralizing antibodies against Clostridium perfringens epsilon-toxin. Infect. Immun [print-electronic]. 2007 Apr; 75(4): 1785-93. PMID: 17261609, PMCID: PMC1865726, PII: IAI.01643-06, DOI: 10.1128/IAI.01643-06, ISSN: 0019-9567.

McClain MS, Czajkowsky DM, Torres VJ, Szabo G, Shao Z, Cover TL. Random mutagenesis of Helicobacter pylori vacA to identify amino acids essential for vacuolating cytotoxic activity. Infect. Immun [print-electronic]. 2006 Nov; 74(11): 6188-95. PMID: 16954403, PMCID: PMC1695532, PII: IAI.00915-06, DOI: 10.1128/IAI.00915-06, ISSN: 0019-9567.

Busler VJ, Torres VJ, McClain MS, Tirado O, Friedman DB, Cover TL. Protein-protein interactions among Helicobacter pylori cag proteins. J. Bacteriol. 2006 Jul; 188(13): 4787-800. PMID: 16788188, PMCID: PMC1482994, PII: 188/13/4787, DOI: 10.1128/JB.00066-06, ISSN: 0021-9193.

Torres VJ, McClain MS, Cover TL. Mapping of a domain required for protein-protein interactions and inhibitory activity of a Helicobacter pylori dominant-negative VacA mutant protein. Infect. Immun. 2006 Apr; 74(4): 2093-101. PMID: 16552038, PMCID: PMC1418911, PII: 74/4/2093, DOI: 10.1128/IAI.74.4.2093-2101.2006, ISSN: 0019-9567.

Torres VJ, Ivie SE, McClain MS, Cover TL. Functional properties of the p33 and p55 domains of the Helicobacter pylori vacuolating cytotoxin. J. Biol. Chem [print-electronic]. 2005 Jun 6/3/2005; 280(22): 21107-14. PMID: 15817461, PII: M501042200, DOI: 10.1074/jbc.M501042200, ISSN: 0021-9258.

Torres VJ, McClain MS, Cover TL. Interactions between p-33 and p-55 domains of the Helicobacter pylori vacuolating cytotoxin (VacA). J. Biol. Chem [print-electronic]. 2004 Jan 1/16/2004; 279(3): 2324-31. PMID: 14593124, PII: M310159200, DOI: 10.1074/jbc.M310159200, ISSN: 0021-9258.

McClain MS, Iwamoto H, Cao P, Vinion-Dubiel AD, Li Y, Szabo G, Shao Z, Cover TL. Essential role of a GXXXG motif for membrane channel formation by Helicobacter pylori vacuolating toxin. J. Biol. Chem [print-electronic]. 2003 Apr 4/4/2003; 278(14): 12101-8. PMID: 12562777, PII: M212595200, DOI: 10.1074/jbc.M212595200, ISSN: 0021-9258.

McClain MS, Cover TL. Expression of Helicobacter pylori vacuolating toxin in Escherichia coli. Infect. Immun. 2003 Apr; 71(4): 2266-71. PMID: 12654854, PMCID: PMC152094, ISSN: 0019-9567.

Schraw W, Li Y, McClain MS, van der Goot FG, Cover TL. Association of Helicobacter pylori vacuolating toxin (VacA) with lipid rafts. J. Biol. Chem [print-electronic]. 2002 Sep 9/13/2002; 277(37): 34642-50. PMID: 12121984, PII: M203466200, DOI: 10.1074/jbc.M203466200, ISSN: 0021-9258.

McClain MS, Cao P, Iwamoto H, Vinion-Dubiel AD, Szabo G, Shao Z, Cover TL. A 12-amino-acid segment, present in type s2 but not type s1 Helicobacter pylori VacA proteins, abolishes cytotoxin activity and alters membrane channel formation. J. Bacteriol. 2001 Nov; 183(22): 6499-508. PMID: 11673417, PMCID: PMC95478, DOI: 10.1128/JB.183.22.6499-6508.2001, ISSN: 0021-9193.

Vinion-Dubiel AD, McClain MS, Cao P, Mernaugh RL, Cover TL. Antigenic diversity among Helicobacter pylori vacuolating toxins. Infect. Immun. 2001 Jul; 69(7): 4329-36. PMID: 11401970, PMCID: PMC98503, DOI: 10.1128/IAI.69.7.4329-4336.2001, ISSN: 0019-9567.

McClain MS, Cao P, Cover TL. Amino-terminal hydrophobic region of Helicobacter pylori vacuolating cytotoxin (VacA) mediates transmembrane protein dimerization. Infect. Immun. 2001 Feb; 69(2): 1181-4. PMID: 11160018, PMCID: PMC98002, DOI: 10.1128/IAI.69.2.1181-1184.2001, ISSN: 0019-9567.

McClain MS, Schraw W, Ricci V, Boquet P, Cover TL. Acid activation of Helicobacter pylori vacuolating cytotoxin (VacA) results in toxin internalization by eukaryotic cells. Mol. Microbiol. 2000 Jul; 37(2): 433-42. PMID: 10931337, PII: mmi2013, ISSN: 0950-382X.

Vinion-Dubiel AD, McClain MS, Czajkowsky DM, Iwamoto H, Ye D, Cao P, Schraw W, Szabo G, Blanke SR, Shao Z, Cover TL. A dominant negative mutant of Helicobacter pylori vacuolating toxin (VacA) inhibits VacA-induced cell vacuolation. J. Biol. Chem. 1999 Dec 12/31/1999; 274(53): 37736-42. PMID: 10608833, ISSN: 0021-9258.

Schraw W, McClain MS, Cover TL. Kinetics and mechanisms of extracellular protein release by Helicobacter pylori. Infect. Immun. 1999 Oct; 67(10): 5247-52. PMID: 10496902, PMCID: PMC96877, ISSN: 0019-9567.

Cao P, McClain MS, Forsyth MH, Cover TL. Extracellular release of antigenic proteins by Helicobacter pylori. Infect. Immun. 1998 Jun; 66(6): 2984-6. PMID: 9596777, PMCID: PMC108299, ISSN: 0019-9567.

Brieland JK, Fantone JC, Remick DG, LeGendre M, McClain M, Engleberg NC. The role of Legionella pneumophila-infected Hartmannella vermiformis as an infectious particle in a murine model of Legionnaire's disease. Infect. Immun. 1997 Dec; 65(12): 5330-3. PMID: 9393834, PMCID: PMC175767, ISSN: 0019-9567.

Brieland J, McClain M, LeGendre M, Engleberg C. Intrapulmonary Hartmannella vermiformis: a potential niche for Legionella pneumophila replication in a murine model of legionellosis. Infect. Immun. 1997 Nov; 65(11): 4892-6. PMID: 9353084, PMCID: PMC175705, ISSN: 0019-9567.

Brieland JK, Heath LA, Huffnagle GB, Remick DG, McClain MS, Hurley MC, Kunkel RK, Fantone JC, Engleberg C. Humoral immunity and regulation of intrapulmonary growth of Legionella pneumophila in the immunocompetent host. J. Immunol. 1996 Dec 12/1/1996; 157(11): 5002-8. PMID: 8943407, ISSN: 0022-1767.

Brieland J, McClain M, Heath L, Chrisp C, Huffnagle G, LeGendre M, Hurley M, Fantone J, Engleberg C. Coinoculation with Hartmannella vermiformis enhances replicative Legionella pneumophila lung infection in a murine model of Legionnaires' disease. Infect. Immun. 1996 Jul; 64(7): 2449-56. PMID: 8698466, PMCID: PMC174097, ISSN: 0019-9567.

McClain MS, Hurley MC, Brieland JK, Engleberg NC. The Legionella pneumophila hel locus encodes intracellularly induced homologs of heavy-metal ion transporters of Alcaligenes spp. Infect. Immun. 1996 May; 64(5): 1532-40. PMID: 8613357, PMCID: PMC173958, ISSN: 0019-9567.

McClain MS, Engleberg NC. Construction of an alkaline phosphatase fusion-generating transposon, mTn10phoA. Gene. 1996 Apr 4/17/1996; 170(1): 147-8. PMID: 8621078, PII: 037811199500856X, ISSN: 0378-1119.

Arroyo J, Hurley MC, Wolf M, McClain MS, Eisenstein BI, Engleberg NC. Shuttle mutagenesis of Legionella pneumophila: identification of a gene associated with host cell cytopathicity. Infect. Immun. 1994 Sep; 62(9): 4075-80. PMID: 8063428, PMCID: PMC303072, ISSN: 0019-9567.

McClain MS, Blomfield IC, Eberhardt KJ, Eisenstein BI. Inversion-independent phase variation of type 1 fimbriae in Escherichia coli. J. Bacteriol. 1993 Jul; 175(14): 4335-44. PMID: 8101185, PMCID: PMC204873, ISSN: 0021-9193.

Blomfield IC, Calie PJ, Eberhardt KJ, McClain MS, Eisenstein BI. Lrp stimulates phase variation of type 1 fimbriation in Escherichia coli K-12. J. Bacteriol. 1993 Jan; 175(1): 27-36. PMID: 8093239, PMCID: PMC196094, ISSN: 0021-9193.

McClain MS, Blomfield IC, Eisenstein BI. Roles of fimB and fimE in site-specific DNA inversion associated with phase variation of type 1 fimbriae in Escherichia coli. J. Bacteriol. 1991 Sep; 173(17): 5308-14. PMID: 1679430, PMCID: PMC208240, ISSN: 0021-9193.

Blomfield IC, McClain MS, Princ JA, Calie PJ, Eisenstein BI. Type 1 fimbriation and fimE mutants of Escherichia coli K-12. J. Bacteriol. 1991 Sep; 173(17): 5298-307. PMID: 1679429, PMCID: PMC208239, ISSN: 0021-9193.

Blomfield IC, McClain MS, Eisenstein BI. Type 1 fimbriae mutants of Escherichia coli K12: characterization of recognized afimbriate strains and construction of new fim deletion mutants. Mol. Microbiol. 1991 Jun; 5(6): 1439-45. PMID: 1686292, ISSN: 0950-382X.

McClain, M. S. and T. L Cover. "Helicobacter pylori vacuolating toxin" in The Comprehensive Sourcebook of Bacterial Protein Toxins, 3rd Edition. J. E. Alouf and M. R. Popoff, eds. Academic Press, 2006. [place, publisher, date unknown].

Aragon, V., Kurtz, S., McClain, M., Engleberg, N.C., and N.P Cianciotto. "Analysis of acid phosphatase and esterase/lipase mutants of Legionella pneumophila" in in Legionella, R. Marre, Y. Abu Kwaik, C. Bartlett, N.P. Cianciotto, B.S. Fields, M. Frosch, J. Hacker, P.C. Luck, eds. ASM Press, Washington, D.C. 2002. pp. 18-21. [place, publisher, date unknown].