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People of the MIBRC

Principal Investigators:

Bobby Cherayil, MD

Alessio Fasano, MD

Verena Göbel, MD

Bryan Hurley, PhD

Hai Ning Shi, DVM, PhD

W. Allan Walker, MD

Collaborators:

Beth McCormick, PhD

Hans-Christian Reinecker, MD

Curriculum Vitae

Beth McCormick, PhD

Professor, Harvard Medical School

Office Address:

Department of Pediatrics
Mucosal Immunology Laboratory
Massachusetts General Hospital and Harvard Medical School
114 16th Street 114-3503
Charlestown, MA. 02129

Phone: (617) 726-4168
FAX: (617) 726-4172
Email: mccormic@helix.mgh.harvard.edu

Education:

Postdoctoral Training:

Research Fellowships:

Academic Appointments:

Hospital or Affiliated Institution Appointments:

Major Administrative Responsibilities:

Sponsored Research Programs - Past:

Sponsored Research Programs - Current:

Committee Assignments:

Harvard Medical School

Affiliated Institutions

Regional

National

Memberships in Professional Societies:

Editorial Boards:

Honors and Awards:

RESEARCH, TEACHING AND CLINICAL CONTRIBUTIONS

Narrative Report:

My research is focused on the molecular mechanisms by which the enteric pathogens Salmonella typhimurium and Shigella flexneri induce mucosal inflammatory responses. Such inflammatory responses lead to active states of intestinal inflammation and are a hallmark feature of the disease pathophysiology of inflammatory bowel diseases such as bacterial enterocolitis, Crohn’s Disease, and ulcerative colitis. My original interest in this field of research lead to the development of a novel model system to examine the immunopathology of intestinal inflammation in vitro. My findings from these studies were the first to demonstrate that a pro-inflammatory program, which could recruit inflammatory cells (neutrophils), was orchestrated by epithelial cells in response to enteric pathogens. This work led to the identification of distinct chemokines released from intestinal epithelial cells, which work in concert to direct neutrophil movement into the intestinal lumen in response to enteric pathogens. Research projects in my laboratory are now directed at unraveling the molecular nature of these signals.

In 2001, I was appointed Director of Microbiology of the Mucosal Immunology Laboratories at Massachusetts General Hospital, under the direction of Dr. W. Allan Walker. In this capacity I oversee the day-to-day general operations of the research laboratories in mucosal immunology and developmental gastroenterology. My major responsibilities involve administering the research and development of the Microbiology program within the Mucosal Immunology Laboratories as well as directing the general operations of the Mucosal Immunology Laboratory. I am also a member of the Operations Committee at Massachusetts General Hospital. In this capacity I serve as a liaison between the Mucosal Immunology Laboratories and Research Space Management. For my role in serving on this committee and the work that I accomplished in this regard, I was awarded the Partners in Excellence Award. Most recently, I was elected to serve on the Massachusetts General Hospital emergency response team.

Funding Information - Current:

Report of Current Research Activities:

Current research activities are, at the moment, exclusively focused on bench research. This research is funded by an NIH RO1 and a PO1 award and is focused on dissecting the molecular mechanisms by which enteric pathogens induce mucosal inflammatory responses. Ultimately, results obtained from both of these research projects will provide valuable insight into novel mechanisms of bacterial pathogenesis as well as establish clues for developing novel treatment strategies for active inflammation found in patients with infectious, allergic, and idiopathic colitis.

The RO1 funded project entitled "Intestinal Inflammation Orchestrated by Pathogens" is an extension of my previous work, which demonstrated that intestinal epithelial cells respond to lumenal pathogens, such as S. typhimurium, by releasing distinctive proinflammatory chemoattractants, which sequentially orchestrate PMN movement across the intestinal epithelium. I have found that S. typhimurium-intestinal epithelial cell interactions induce the epithelial synthesis and polarized basolateral release of the potent PMN chemokine, interleukin-8 (IL-8). Such basolateral release of IL-8 imprints subepithelial matrices with long-lived haptotactic gradients that function to guide PMN through the lamina propria to a subepithelial position. However, basolateral release of this chemokine is insufficient to induce migration of PMN across the intestinal epithelium, suggesting that the production of other inflammatory mediator(s), whose release would be polarized apically, are important for the execution of this step in the inflammatory pathway. Recently, I have identified the first such proinflammatory mediator called pathogen elicited epithelial chemoattractant (PEEC), which we have recently identified as the eicosanoid hepoxilin A3. Thus, the general goal of the RO1 funded project is to sort out the molecular and cellular mechanisms by which S. typhimurium induces the epithelial secretion of hepoxilin A3.

I am also the Principal Investigator of Project 3 on a NIH PO1 grant. Project 3 is entitled "Shigellosis. Role of the intestinal epithelium" and is focused on how Shigella flexneri are able to coordinate the mucosal immune response, which leads to an intense inflammatory reaction in humans characterized by bacillary dysentery. The research goals proposed are directed at (i) understanding the nature of the species dependency of Shigella with the human intestine, and (ii) elucidating the molecular basis by which Shigella foster acute infectious colitis. Our studies employ a patho-evolutionary approach and have lead to novel observations with regard to S. flexneri induced-inflammation. These observations support the concept that Shigella evolved from non-pathogenic ancestors by the loss of genes that are incompatible with virulence. Research in my laboratory sponsored by the PO1 award is now directed at exploiting these genes as a molecular tool to unlock the molecular mechanism by which Shigella induces an intense inflammatory response.

The newest project in my lab, sponsored by the Cystic Fibrosis Foundation, focuses on bacterial infections of the lung, another mucosal surface. Lung disease as a consequence of bacterial infection in many situations is marked by severe inflammation, particularly the accumulation of large numbers of neutrophils in the lumenal space along the respiratory tract. It is currently unclear what bacterial factors can trigger this response and exactly how the neutrophils are directed to the site of infection. Understanding this process is the broad long-term objective of our work.

Report of Teaching:

Local contributions:

Teaching responsibilities:

Advisory and supervisory responsibilities in the laboratory setting:

Mentored Responsibilities - Past:

Ph.D. Thesis Advisory Committees:

Regional, national, or international contributions

Invited presentations

Regional:

BIBLIOGRAPHY

Original Articles:

  1. McCormick BA, Stocker BAD, Laux DC, Cohen PS. Roles of motility, chemotaxis, penetration through and growth in intestinal mucus in the ability of an avirulent strain of S. typhimurium to colonize the streptomycin-treated mouse large intestine. Infect. Immun. 1988; 50:2209-2217.
  2. McCormick BA, Franklin DP, Laux DC, Cohen, PS. Type 1 pili are not necessary for the colonization of the streptomycin-treated mouse large intestine by type 1 piliated E. coli F-18 and E. coli K-12. Infect. Immun. 1989;57:3022-3029.
  3. McCormick BA, Laux DC, Cohen PS. Neither motility nor chemotaxis play a role in the ability of E. coli F-18 to colonize the streptomycin-treated mouse large intestine. Infect. Immun. 1990; 59:2957-2961.
  4. Krogfelt KA, McCormick BA, Laux DC, Cohen PS. Expression of E. coli F-18 type 1 fimbriae in the streptomycin-treated mouse large intestine. Infect. Immun. 1991; 59:1567-1568.
  5. Kantor JD, McCormick BA, Steeg PS, and Zetter BR. Inhibition of cell motility after nm 23 transfection of human and murine tumor cells. Cancer Res. 1993;53: 1917-1973.
  6. McCormick BA, Klemm P, Krogfelt KA, Burghoff RL, Pallesen L, Laux DC, Cohen PS. Escherichia coli F-18 phase-locked "on" for expression of type-1 fimbriae is a poor colonizer of the streptomycin-treated mouse large intestine. Microb. Pathogenesis. 1993; 14: 33-43.
  7. McCormick BA, Colgan SP, Delp-Archer C, Miller SI, and Madara, JL. Salmonella typhimurium attachment to human intestinal epithelial monolayers: transcellular signaling to subepithelial neutrophils. J. Cell Biol. 1993; 123: 895- 907.
  8. McCormick, BA, Miller, SI, Carnes, D, Madara, JL. Transepithelial signaling to neutrophils by Salmonellae: A novel virulence mechanism for gastroenteritis. Infect. Immun. 1995; 63: 2302-2309.
  9. McCormick, BA, Hofman PM, Kim J, Carnes, DK, Miller, SI, Madara, JL. Surface attachment of Salmonella typhimurium to intestinal epithelia imprints the subepithelial matrix with gradients chemotactic for neutrophils. J. Cell Biol. 1995; 131: 1599-1608.
  10. Sweeney, NJ, Klemm, P, McCormick, BA, Moller-Nielsen, E, Utley, MJ, Schembri, MA, Laux, DC, and Cohen, PS. The Escherichia coli K-12 gntP gene allows E. coli F-18 to occupy a distinct nutritional niche in the streptomycin- treated mouse large intestine. Infect. Immun. 1996; 64: 3497-3503.
  11. McCormick, BA, Nusrat, A, D'Andrea, L, Parkos, CA, Hofman, PM, Carnes, DK, and Madara, JL. Unmasking of intestinal epithelial lateral membrane b1 integrin consequent to transepithelial neutrophil migration in vitro facilitates inv- mediated invasion by Yersinia. Infect. Immun. 1997; 65: 1414-1421.
  12. McCormick, BA, Parkos, CA, Colgan, SP, Carnes, DK, and Madara, JL. Apical secretion of a pathogen-elicited epithelial chemoattractant (PEEC) activity in response to surface colonization of intestinal epithelia by Salmonella typhimurium. J. Immunol. 1998; 160: 455-466.
  13. Gewirtz, A, McCormick, BA, Petasis, NA, Gronert, K, Serhan, CN, and Madara, JL. Pathogen-induced chemokine secretion from model intestinal epithelium is inhibited by lipoxin A4 analogs. J. Clin. Invest. 1998; 101:1860-1869.
  14. Shaw, SK, Hermanowski-Vosatka, A, Takeshi, S, McCormick, BA, Parkos, CA, Carlson, SL, Ebert, EC, Brenner, MB and Madara, JL. Migration of intestinal intra-epithelial lymphocytes into a polarized epithelial monolayer. Am. J. Physiol. 1998. 275:G584-591.
  15. McCormick, BA, Siber, AM, and Maurelli, AT. Requirement of the Shigella flexneri virulence plasmid in the ability to induce trafficking of neutrophils across polarized monolayers of intestinal epithelia. Infect. Immun. 1998; 66:4237-4243.
  16. Gewirtz, AT, Siber, AM, Madara, JL, and McCormick, BA. Orchestration of neutrophil movement by intestinal epithelial cells in response to Salmonella typhimurium can be uncoupled from bacterial internalization. Infect. Immun. 1999; 67: 608-617.
  17. McCormick, BA, Fernandez, MI, Siber, AM, and Maurelli, AT. Inhibition of Shigella flexneri-induced transepithelial migration of polymorphonuclear leukocytes by cadaverine. Cell. Microbiol. 1999; 1:143-156.
  18. Allen, JH, Utley, M, Bosch, V, Nuijten, P, Witvliet, M, McCormick, BA, Mauel, M, Krogfelt, K, Licht, TR, Brown, D, Leatham, MP, and Cohen, PS. A functional cra gene is required for Salmonella typhimurium pathogenesis in BALB/c mice. Infect. Immun. 2000; 68:3772-3775.
  19. Wood, MW, Jones, MA, Watson, PR, Siber, AM, McCormick, BA, Rosqvist, R, Wallis, TS, and Galyov, EE. The secreted effector protein of Salmonella, SopA, is translocated into eucaryotic cells and influences the induction of enteritis. Cellular Microbiol. 2000; 2:293-304.
  20. Cherayil, BJ, McCormick, BA, and Bosley, J. Salmonella-dependent regulation of inducible nitric oxide synthase expression in macrophages by the invasins SipB, SipC, and SipD, and the effector SopE2. Infect. Immun. 2000; 68:5567- 5574.
  21. Lee, CA, Silva, M, Siber, AM, Kelly, AJ, Galyov, EE, and McCormick, BA. A secreted Salmonella protein induces a proinflammatory response in epithelial cells which promotes neutrophil migration. Proc. Natl. Acad. Sci. USA 2000; 97:12283-12288.
  22. Criss, AK, Ahlgren, DM, Jou, T-S, McCormick, BA., and Casanova, JE. The GTPase Rac1 selectively regulates Salmonella invasion at the apical plasma membrane of polarized epithelial cells. J. Cell Sci. 2001; 114: 1331-1341.
  23. Fernandez, I, Maurelli, AT, Silva, M, Siber, AM, Schuch, R, W. Allan Walker, and McCormick, BA. Cadaverine prevents the escape of Shigella flexneri from out of the phagolysosme: A connection between bacterial dissemination and neutrophil transepithelial signaling. J. Infect. Dis. 2001; 184: 743-753.
  24. Criss, A, Silva, M, Casanova, J, and McCormick, BA. Regulation of Salmonella- induced neutrophil transmigration by epithelial ADP-ribosylation factor 6. J. Biol. Chem. 2001; 276: 48431-48439.
  25. Kohler, H, Rodriques, SP, and McCormick, BA. Shigella flexneri interactions with the basolateral membrane domain of polarized model intestinal epithelium: Role of lipopolysaccharide in cell invasion and in activation of the mitogen- activated protein kinase ERK. Infect. Immun. 2002;70: 1150-1158.
  26. Takanori S, Köhler, H, Gu, X, McCormick, BA and Reinecker H-C. Shigella flexneri regulates tight junction associated proteins in human intestinal epithelial cells. Cell. Microbiol. 2002; 4: 367-381.
  27. Kohler H, Rodrigues, SP, Maurelli AT, and McCormick, BA. Inhibition of Salmonella typhimurium enteropathogenicity by piperidine, a metabolite of the polyamine cadaverine. J. Infect. Dis. 2002; 186:1122-1130.
  28. Nadeau WJ, Pistole, TG, and McCormick, BA. Polymorphonuclear leukocyte migration across model intestinal epithelial enhances Salmonella typhimurium killing via the epithelial derived cytokine, IL-6. Microbes Infect. 2002; 4:1379-1387.
  29. Hisamatsu, T., Suzuki, M., Reinecker, H-C., Nadeau, W.J., McCormick, B. A., Podolsky, D.K. Card15/Nod2 functions as an anti-bacterial factor in human intestinal epithelial cells. Gastroenterology 2003; 124:993-1000.
  30. Silva, M., Song, C., Nadeau, W.J., Matthews, J.B., McCormick, B.A. Salmonella typhimurium SipA-induced neutrophil transepithelial migration: involvement of a PKC-a dependent signal transduction pathway. Am. J. Physiol. Gastrointest. Liver Physiol. 2004; 286:G1024-G1031.
  31. Mrsny, R.J., Gewirtz, A.T. , Siccardi,,D., Savidge, T.C., Hurley, B.P., Madara, JL, and McCormick, B.A. Identification of hepoxilin A3 in inflammatory events: A required role in neutrophil migration across the intestinal epithelia. Proc. Natl. Acad. Sci. USA 2004; 101: 7421-7426.
  32. Tenor, J.L., McCormick, B.A., Ausubel, F.M., Aballay, A. Caenorhabditis elegans-Based screen identifies Salmonella virulence factors required for conserved host-pathogen interactions. Curr. Biol. 2004; 14:1018-1024.
  33. Hurley, B.P., Siccardi, D., Mrsny, R.J., McComick, B.A. PMN transepithelial migration induced by Pseudomonas aeruginosa requires the eicosinoid hepoxilin A3. J. Immunol. 2004; 173:5712-5720.
  34. Niess, J.H., Brand, S., Gu, X., Landsman, L., McCormick, B.A., Vyas, J.M., Boes, Ploegh, H.L., Fox, J.G., Littman, D.R., Reinecker, H-C. Control of dendritic cell access to the intestinal lumen and of bacterial clearance by CX3CR1. Science 2005; 307; 254-258.
  35. Chen, C.C., Louie, S., McCormick, B.A., Walker, W.A., Shi, H.N. Concurrent infection of an intestinal helminth parasite impairs host resistance to enteric Citrobacter rodentium and enhances Citrobacter-induced colitis in mice. Infect. Immun. 2005; 73: 5468-81.
  36. Chen, C.C., Louie, S., McCormick, B.A., Walker, W.A., Shi, H.N. Helminth primed dendritic cells alter the host response to enteric bacterial infection. 2005 In Press: J.Immunol.
  37. Hurley, B.P., Williams, N., McCormick, B.A. Involvement of phospholipase A2 in Pseudomonas aeruginosa mediated PMN transepithelial migration. 2005 In Press AJP-Lung Cellular and Molecular Physiology
  38. Savidge, T.C., Newman, P.G., Pan, W-H, Weng, M.Q., Shi, H.N., McCormick, B.A., Quaroni, A., Walker, W.A. Lipopolysaccharide-induced human enterocyte tolerance to cytokine-mediated interleukin-8 production may occur independently of TLR-4/MD-2 signaling. In Press J. Pediatric Res.
  39. Salazar-Gonzalez, R.M., Niess, J.H., Zammit, D.J., Ravindran, R., Srinivasan, A., Maxwell, J.R., Stoklasek, T., Yadav, R., Williams, I.R., Gu, X., McCormick, B.A., Pazos, M.A., Vella, A.T., Lefrancois, L., Reinecker, H-C., McSorley, S.J. CCR6-mediated dendritic cell activation of pathogen specific T cells in Peyer’s patches. In Press Immunity

Reviews:

  1. McCormick BA and Zetter BR. (1992) Adhesive interactions in angiogenesis and metastasis. J. Pharmacol. Theur. 53:239-260.
  2. McCormick, BA, Miller, SI, and Madara, JL. (1996) New insights on molecular pathways utilized by Salmonella species in cell binding. Frontiers in Bioscience 1: d131-145.
  3. McCormick, BA, Gewirtz, AT, and Madara JL. (1998) Epithelial cross-talk with bacteria and immune cells. Current Opinion in Gastroenterology; 14; 492-497.
  4. McCormick, BA. (2001) Molecular basis of Salmonella-induced enteritis. Recent Research Developments in Immunology. 4: 65-77.
  5. McCormick, BA. (2003) Use of transepithelial models to examine host-pathogen interactions. Curr Opin Microbiol. 6;77-81.
  6. Kohler H, McCormick BA, Walker WA. (2003) Bacterial-enterocyte crosstalk: cellular mechanisms in health and disease. J Pediatr Gastroenterol Nutr. 36;175-85.
  7. Hurley, B.P. and McCormick, B.A. (2003) Translating tissue culture results into animal models: the case of Salmonella typhimurium. Trends in Microbiol. 11; 562-69.
  8. Hurley, B.P. and McCormick, B.A. (2004) Intestinal epithelial defense systems protect against bacterial threats. Curr. Gastroenterol. Rep. 6; 355-361.
  9. Mumy, K.L. and McCormick, B.A. (2005) Events at the host-microbial interface of the gastrointestinal tract II. Role of the intestinal epithelium in pathogen-induced inflammation. Am J Physiol Gastrointest Liver Physiol. 288; G854-G859.

Book chapters:

  1. Cohen PS, McCormick BA, Franklin DP, Burghoff RL, Laux DC. The role of large intestine mucus in the colonization of the mouse large intestine by E. coli F- 18 and S. typhimurium. In, Wadstrom T, Maksela PH, Svennerholm AM, Wolf- Watz H, eds. Molecular Pathogenesis of Gastrointestinal Infections. New York and London: Plenum Press, 1991: 29-31.
  2. Krogfelt KA, McCormick BA, Burghoff RL, Laux DC, Cohen PS. Expression of type 1 fimbriae in the streptomycin-treated large intestine. In, Wadstrom T, Maksela PH, Svennerholm AM, Wolf-Watz H, eds. Molecular Pathogenesis of Gastrointestinal Infections. New York and London: Plenum Press, 1991: 317- 319.
  3. McCormick, BA. Salmonella: Masters of Inflammation. In, Hecht G.A., ed. Microbial Pathogens and the Intestinal Epithelial Cell. Washington, DC: ASM Press, 2003:439-454.
  4. McCormick, BA. Salmonella Invasion Mechanisms. In, Lamont, R.J., ed. Bacterial Invasion of Host Cells Cambridge, U.K: Cambridge Press, 2004: 1-24.
  5. McCormick, B.A. Signal Transduction in the Mucosa. In, Nataro, J.P., Cohen, P.S., Mobley, H.L., and Weiser, J.N., eds. Colonization of Mucosal Surfaces, ASM Press, 2005:265-282.
  6. McCormick, B.A. Editor: Bacterial-Epithelial Cell Cross-Talk: Molecular Mechanisms in Pathogenesis (Cambridge University Press; 2006)2006)

Ph. D. Thesis:

McCormick, BA. The role of type-1 fimbriae, motility, and chemotaxis in the colonization of the mouse large intestine by a human fecal E. coli strain and an avirulent Salmonella typhimurium strain [Ph.D. Thesis], Kingston, Rhode Island: University of Rhode Island, 1990 256 pp.

Published Abstracts:

  1. McCormick BA, Colgan SP, Miller SI, Madara JL. Apical binding of Salmonella to intestinal epithelial cells modulates neutrophil-epithelial interactions [Abstract]. Gastroenterology 1993; (Suppl); A740.
  2. McCormick BA, Miller SI, Colgan SP, Madara JL. Transepithelial signaling by Salmonella typhimurium to neutrophils is associated with bacterial mediated endocytosis [Abstract]. Gastroenterology 1994; (Suppl): 104:A731.
  3. McCormick, BA, Parkos, CA, Colgan, SP, Carnes, DA, and Madara, JL. Surface attachment of Salmonella typhimurium to intestinal epithelia elicits the secretion of a novel neutrophil chemoattractant [Abstract]. Keystone Symposia on The Role of Chemokines in Leukocyte Trafficking and Disease 1997; pg. 11.
  4. Shibahara T, Shaw SK, Hermanowski-Vosatka A, McCormick, BA., and Madara J.L. Efficient homing of intraepithelial-derived lymphocytes (IEL) back to the intercellular spaces of model- polarized intestinal epithelia. [Abstract]. Gastroenterology 1998; (Suppl): 114: A1083.
  5. Gewirtz AT, Siber AM, Madara JL, and McCormick, BA. Specific apical intestinal epithelial-S typhimurium interactions disociable from bacterial invasion mediate epithelial orchestration of neutrophil movement [Abstract]. Gastroenterology 1999; (Suppl): 116: A773.
  6. Chaturvedi P, McCormick, BA., Warren, CD., Siber, AM., and Newburg, DS. Human milk sulfated glycolipids inhibit Salmonella typhimurium pathogenesis in vitro. [Abstract] Glycobiology 1998; 8:155.
  7. Lee CA, Silva M, Kelly AJ, and McCormick, B.A. Intestinal epithelial orchestration of neutrophil movement in response to S. typhimurium (S.t.) is mediated by a S.t. secreted protein, SipA [Abstract]. Gastroenterology 2000; (Suppl): 118: A695.
  8. Kohler, H, Rodrigues, S, Maurelli, AT, Cario, E, Podolsky, DK, and McCormick, BA. Invasion of Shigella flexneri into model human intestinal epithelia is dependent on a lipopolysaccharide interaction with the host cell. [Abstract]. Gastroenterology 2001; (Suppl); 120: A371.
  9. Sakaguchi, T, Köhler, H, Xuibin, G, McCormick, BA, and Reinecker, H-C. Mechanistic repertoire of Shigella flexneri to regulate tight junctional complexes in human intestinal epithelial cells. [Abstract] Gastroentrology 2001; (Suppl): 120: A767.
  10. Kohler, H., Sakagushi, T, Kase, BJ, Reinecker, H-C, and McCormick, BA. Salmonella typhimurium regulates epithelial tight junctions: the effects on polymorphonuclear leukocyte movement across model intestinal epithelium Abstract]. Gastroenterology. 2002; (Suppl) 122: A125.
  11. Kohler, H., Rodrigues, SP, and McCormick, BA. Piperidine, a metabolite of the intestinal microflora, adversely influences Salmonella typhimurium enteropathogenicity [Abstract]. Gastroenterology 2002; (Suppl) 122: A141.
  12. Muzumdar, H.V., Wang, M-Y, McCormick, BA, Saban, MR, Saban, R, and Wershil, B.K. Critical role of tumor-necrosis factor-alpha in host defense against Salmonella typhimurium [Abstract]. Gastroenterology 2003; (Suppl) 122: A734.

Patents