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    Beth A McCormick PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentMicrobiology and Physiological Systems
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North, AS8-2049
    Worcester MA 01655
    Phone508-856-6048
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMolecular Genetics and Microbiology

        Overview 
        Narrative

        Beth McCormickB.A. University of New Hampshire
        Ph.D. University of Rhode Island
        Post-doctoral training Harvard Medical School

        Research Summary:

        Work in my laboratory is centered around three major research programs: Mucosal inflammation, host:pathogen interactions, and cancer biology.

        Image 1The objective of the mucosal inflammatory program is to investigate the molecular mechanisms by which bacterial pathogens induce mucosal inflammation at sites of the intestinal and respiratory epithelium. This work is based on longstanding pathologic observations that attachment of an array of bacterial pathogens to epithelial surfaces is accompanied by recruitment of host defense cells, as manifested by neutrophil infiltration of the epithelium. While neutrophils and their responses in the context of an inflammatory response are integral to the control of bacterial infection, when their responses become excessive or unregulated, injury to the host tissues ensues. To understand what goes awry under pathologic conditions, we originally used Salmonella typhimurium as a prototypical enteric pathogen to study the transepithelial migration of neutrophils across intestinal epithelia, a hallmark of gastroenteritis. This research effort has been expanded to include the following intestinal and lung pathogens: Shigella flexneri, E. coli, Pseudomonas aeruginosa, and S. pneumoniae. In response to these pathogens we have discovered a novel inflammatory signaling cascade in which epithelial cells lining mucosal surfaces release the potent neutrophil chemoattractant hepoxilin A3, (HXA3). HXA3 functions as the “gate keeper” of the mucosal epithelium, as it emanates from the site of infection to establish a chemotactic gradient that guides neutrophils across mucosal surfaces. We are now investigating the mechanisms that orchestrate the synthesis/release of HXA3 for the design of more targeted and effective anti-inflammatory therapies for the treatment of infectious, allergic, and idiopathic mucosal inflammatory conditions (i.e., salmonellosis, shigellosis, inflammatory bowel diseases, pneumonia, cystic fibrosis, and chronic obstructive pulmonary disease).

        SopA StructureThe second research program in my laboratory is centered on the study of host-pathogen interactions. Specifically, we investigate strategies used by enteric and respiratory pathogens to induce proinflammatory responses. Using S. typhimurium as an example, we have uncovered a novel mechanism by which this pathogen sabotages host defense mechanisms. Salmonella tricks the host into synthesizing and secreting the apoptotic enzyme caspase-3, diverting this host enzyme to its own use. The Salmonella effector protein SipA has amino acid motifs that are recognized by caspase-3, which cleaves the bacterial protein into active virulence effectors: one stimulates actin polymerization to help cell entry and the other induces inflammation. If the caspase motif contains a single-point mutation, then virulence is lost in mouse models of infection. This straregy isn’t limited to SipA. Other proteins that are injected by Salmonella, such as SopA (see crystal structure) and those from other gut bacteria like E. coli and Shigella flexneri, also carry targets for caspase-3, demonstrating the broad significance of this finding. This discovery unveils a new paradigm in the field of bacterial pathogenesis and opens the door to novel investigation on the tactics used by bacterial pathogens to promote disease.

        Colonic TumorThe third research program in my laboratory is focused on cancer biology. My original interest in this field of study was cultivated by the observation that Salmonella is able to preferentially locate to sites of tumor growth (achieving tumor/normal tissue ratios of approximately 1,000:1). Work in my laboratory has shown that Salmonella causes a profound reduction on the multidrug resistance (MDR) transporter P-glycoprotein (Pgp) in colon cancer cells. Pgp over-expression is one form of the MDR phenotype that is commonly acquired by cancer patients initially responsive to chemotherapy. We are interested in uncovering the mechanism used by Salmonella to downregulate Pgp. The ultimate goal of this work is to exploit Salmonella for the development of a new and robust class of multidrug resistance inhibitors designed as an adjuvant to chemotherapeutics for cancers that are known to express high levels of Pgp, such as colorectal cancers and breast cancer.



        Bibliographic 
        selected publications
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        1. Szabady RL, McCormick BA. Control of neutrophil inflammation at mucosal surfaces by secreted epithelial products. Front Immunol. 2013; 4:220.
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        2. Jandhyala DM, Vanguri V, Boll EJ, Lai Y, McCormick BA, Leong JM. Shiga Toxin-Producing Escherichia coli O104:H4: An Emerging Pathogen with Enhanced Virulence. Infect Dis Clin North Am. 2013 Sep; 27(3):631-49.
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        3. Boll EJ, McCormick BA. A new understanding of enteroaggregative Escherichia coli as an inflammatory pathogen. Cell Adh Migr. 2012 Sep 1; 6(5):413-8.
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        4. Boll EJ, Struve C, Sander A, Demma Z, Nataro JP, McCormick BA, Krogfelt KA. The Fimbriae of Enteroaggregative Escherichia coli Induce Epithelial Inflammation In Vitro and in a Human Intestinal Xenograft Model. J Infect Dis. 2012 Sep; 206(5):714-22.
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        5. Boll EJ, Struve C, Sander A, Demma Z, Krogfelt KA, McCormick BA. Enteroaggregative Escherichia coli promotes transepithelial migration of neutrophils through a conserved 12-lipoxygenase pathway. Cell Microbiol. 2012 Jan; 14(1):120-32.
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        6. Agbor TA, McCormick BA. Salmonella effectors: important players modulating host cell function during infection. Cell Microbiol. 2011 Dec; 13(12):1858-69.
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        7. Srikanth CV, Mercado-Lubo R, Hallstrom K, McCormick BA. Salmonella effector proteins and host-cell responses. Cell Mol Life Sci. 2011 Nov; 68(22):3687-97.
          View in: PubMed
        8. Agbor TA, Demma ZC, Mumy KL, Bien JD, McCormick BA. The ERM protein, Ezrin, regulates neutrophil transmigration by modulating the apical localization of MRP2 in response to the SipA effector protein during Salmonella Typhimurium infection. Cell Microbiol. 2011 Dec; 13(12):2007-21.
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        9. McCormick BA. Shigella gets captured to gain entry. Cell Host Microbe. 2011 Jun 16; 9(6):449-50.
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        10. Hallstrom K, McCormick BA. Salmonella Interaction with and Passage through the Intestinal Mucosa: Through the Lens of the Organism. Front Microbiol. 2011; 2:88.
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        11. Wall DM, Srikanth CV, McCormick BA. Targeting tumors with salmonella typhimurium- potential for therapy. Oncotarget. 2010 Dec; 1(8):721-8.
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        12. Maldonado-Contreras AL, McCormick BA. Intestinal epithelial cells and their role in innate mucosal immunity. Cell Tissue Res. 2011 Jan; 343(1):5-12.
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        13. Hurley BP, Pirzai W, Mumy KL, Gronert K, McCormick BA. Selective eicosanoid-generating capacity of cytoplasmic phospholipase A2 in Pseudomonas aeruginosa-infected epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2011 Feb; 300(2):L286-94.
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        14. Srikanth CV, Wall DM, Maldonado-Contreras A, Shi HN, Zhou D, Demma Z, Mumy KL, McCormick BA. Salmonella pathogenesis and processing of secreted effectors by caspase-3. Science. 2010 Oct 15; 330(6002):390-3.
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        15. Hurley BP, Goodman AL, Mumy KL, Murphy P, Lory S, McCormick BA. The two-component sensor response regulator RoxS/RoxR plays a role in Pseudomonas aeruginosa interactions with airway epithelial cells. Microbes Infect. 2010 Mar; 12(3):190-8.
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        16. Mercado-Lubo R, McCormick BA. A unique subset of Peyer's patches express lysozyme. Gastroenterology. 2010 Jan; 138(1):36-9.
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        17. Mumy KL, McCormick BA. The role of neutrophils in the event of intestinal inflammation. Curr Opin Pharmacol. 2009 Dec; 9(6):697-701.
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        18. Figueiredo JF, Lawhon SD, Gokulan K, Khare S, Raffatellu M, Tsolis RM, Bäumler AJ, McCormick BA, Adams LG. Salmonella enterica Typhimurium SipA induces CXC-chemokine expression through p38MAPK and JUN pathways. Microbes Infect. 2009 Feb; 11(2):302-10.
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        19. Pazos M, Siccardi D, Mumy KL, Bien JD, Louie S, Shi HN, Gronert K, Mrsny RJ, McCormick BA. Multidrug resistance-associated transporter 2 regulates mucosal inflammation by facilitating the synthesis of hepoxilin A3. J Immunol. 2008 Dec 1; 181(11):8044-52.
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        20. Zurawski DV, Mumy KL, Faherty CS, McCormick BA, Maurelli AT. Shigella flexneri type III secretion system effectors OspB and OspF target the nucleus to downregulate the host inflammatory response via interactions with retinoblastoma protein. Mol Microbiol. 2009 Jan; 71(2):350-68.
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        21. Srikanth CV, McCormick BA. Interactions of the intestinal epithelium with the pathogen and the indigenous microbiota: a three-way crosstalk. Interdiscip Perspect Infect Dis. 2008; 2008:626827.
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        22. Mumy KL, Bien JD, Pazos MA, Gronert K, Hurley BP, McCormick BA. Distinct isoforms of phospholipase A2 mediate the ability of Salmonella enterica serotype typhimurium and Shigella flexneri to induce the transepithelial migration of neutrophils. Infect Immun. 2008 Aug; 76(8):3614-27.
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        23. Siccardi D, Mumy KL, Wall DM, Bien JD, McCormick BA. Salmonella enterica serovar Typhimurium modulates P-glycoprotein in the intestinal epithelium. Am J Physiol Gastrointest Liver Physiol. 2008 Jun; 294(6):G1392-400.
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        24. McCormick BA. Using Salmonella enterica serotype typhimurium to model intestinal fibrosis. Gastroenterology. 2008 Mar; 134(3):872-5.
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        25. Mumy KL, Chen X, Kelly CP, McCormick BA. Saccharomyces boulardii interferes with Shigella pathogenesis by postinvasion signaling events. Am J Physiol Gastrointest Liver Physiol. 2008 Mar; 294(3):G599-609.
          View in: PubMed
        26. Zurawski DV, Mumy KL, Badea L, Prentice JA, Hartland EL, McCormick BA, Maurelli AT. The NleE/OspZ family of effector proteins is required for polymorphonuclear transepithelial migration, a characteristic shared by enteropathogenic Escherichia coli and Shigella flexneri infections. Infect Immun. 2008 Jan; 76(1):369-79.
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        27. Prunier AL, Schuch R, Fernández RE, Mumy KL, Kohler H, McCormick BA, Maurelli AT. nadA and nadB of Shigella flexneri 5a are antivirulence loci responsible for the synthesis of quinolinate, a small molecule inhibitor of Shigella pathogenicity. Microbiology. 2007 Jul; 153(Pt 7):2363-72.
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        28. Köhler H, Sakaguchi T, Hurley BP, Kase BA, Kase BJ, Reinecker HC, McCormick BA. Salmonella enterica serovar Typhimurium regulates intercellular junction proteins and facilitates transepithelial neutrophil and bacterial passage. Am J Physiol Gastrointest Liver Physiol. 2007 Jul; 293(1):G178-87.
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        29. Wall DM, Nadeau WJ, Pazos MA, Shi HN, Galyov EE, McCormick BA. Identification of the Salmonella enterica serotype typhimurium SipA domain responsible for inducing neutrophil recruitment across the intestinal epithelium. Cell Microbiol. 2007 Sep; 9(9):2299-313.
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        30. Zhang Y, Higashide WM, McCormick BA, Chen J, Zhou D. The inflammation-associated Salmonella SopA is a HECT-like E3 ubiquitin ligase. Mol Microbiol. 2006 Nov; 62(3):786-93.
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        31. Zurawski DV, Mitsuhata C, Mumy KL, McCormick BA, Maurelli AT. OspF and OspC1 are Shigella flexneri type III secretion system effectors that are required for postinvasion aspects of virulence. Infect Immun. 2006 Oct; 74(10):5964-76.
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        32. Salazar-Gonzalez RM, Niess JH, Zammit DJ, Ravindran R, Srinivasan A, Maxwell JR, Stoklasek T, Yadav R, Williams IR, Gu X, McCormick BA, Pazos MA, Vella AT, Lefrancois L, Reinecker HC, McSorley SJ. CCR6-mediated dendritic cell activation of pathogen-specific T cells in Peyer's patches. Immunity. 2006 May; 24(5):623-32.
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        33. Canny G, Swidsinski A, McCormick BA. Interactions of intestinal epithelial cells with bacteria and immune cells: methods to characterize microflora and functional consequences. Methods Mol Biol. 2006; 341:17-35.
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        34. Hurley BP, Williams NL, McCormick BA. Involvement of phospholipase A2 in Pseudomonas aeruginosa-mediated PMN transepithelial migration. Am J Physiol Lung Cell Mol Physiol. 2006 Apr; 290(4):L703-L709.
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        35. Mumy KL, McCormick BA. 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. 2005 May; 288(5):G854-9.
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        36. Niess JH, Brand S, Gu X, Landsman L, Jung S, McCormick BA, Vyas JM, Boes M, Ploegh HL, Fox JG, Littman DR, Reinecker HC. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science. 2005 Jan 14; 307(5707):254-8.
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        37. Hurley BP, Siccardi D, Mrsny RJ, McCormick BA. Polymorphonuclear cell transmigration induced by Pseudomonas aeruginosa requires the eicosanoid hepoxilin A3. J Immunol. 2004 Nov 1; 173(9):5712-20.
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        38. Tenor JL, McCormick BA, Ausubel FM, Aballay A. Caenorhabditis elegans-based screen identifies Salmonella virulence factors required for conserved host-pathogen interactions. Curr Biol. 2004 Jun 8; 14(11):1018-24.
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        39. Mrsny RJ, Gewirtz AT, Siccardi D, Savidge T, Hurley BP, Madara JL, McCormick BA. Identification of hepoxilin A3 in inflammatory events: a required role in neutrophil migration across intestinal epithelia. Proc Natl Acad Sci U S A. 2004 May 11; 101(19):7421-6.
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        40. Silva M, Song C, Nadeau WJ, Matthews JB, McCormick BA. Salmonella typhimurium SipA-induced neutrophil transepithelial migration: involvement of a PKC-alpha-dependent signal transduction pathway. Am J Physiol Gastrointest Liver Physiol. 2004 Jun; 286(6):G1024-31.
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        41. Hurley BP, McCormick BA. Translating tissue culture results into animal models: the case of Salmonella typhimurium. Trends Microbiol. 2003 Dec; 11(12):562-9.
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        42. Hisamatsu T, Suzuki M, Reinecker HC, Nadeau WJ, McCormick BA, Podolsky DK. CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells. Gastroenterology. 2003 Apr; 124(4):993-1000.
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        43. McCormick BA. The use of transepithelial models to examine host-pathogen interactions. Curr Opin Microbiol. 2003 Feb; 6(1):77-81.
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        44. Nadeau WJ, Pistole TG, McCormick BA. Polymorphonuclear leukocyte migration across model intestinal epithelia enhances Salmonella typhimurium killing via the epithelial derived cytokine, IL-6. Microbes Infect. 2002 Nov; 4(14):1379-87.
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        45. Köhler H, Rodrigues SP, Maurelli AT, McCormick BA. Inhibition of Salmonella typhimurium enteropathogenicity by piperidine, a metabolite of the polyamine cadaverine. J Infect Dis. 2002 Oct 15; 186(8):1122-30.
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        46. Sakaguchi T, Köhler H, Gu X, McCormick BA, Reinecker HC. Shigella flexneri regulates tight junction-associated proteins in human intestinal epithelial cells. Cell Microbiol. 2002 Jun; 4(6):367-81.
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        47. Criss AK, Silva M, Casanova JE, McCormick BA. Regulation of Salmonella-induced neutrophil transmigration by epithelial ADP-ribosylation factor 6. J Biol Chem. 2001 Dec 21; 276(51):48431-9.
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        48. Fernandez IM, Silva M, Schuch R, Walker WA, Siber AM, Maurelli AT, McCormick BA. Cadaverine prevents the escape of Shigella flexneri from the phagolysosome: a connection between bacterial dissemination and neutrophil transepithelial signaling. J Infect Dis. 2001 Sep 15; 184(6):743-53.
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        49. Criss AK, Ahlgren DM, Jou TS, McCormick BA, Casanova JE. The GTPase Rac1 selectively regulates Salmonella invasion at the apical plasma membrane of polarized epithelial cells. J Cell Sci. 2001 Apr; 114(Pt 7):1331-41.
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        50. Lee CA, Silva M, Siber AM, Kelly AJ, Galyov E, McCormick BA. A secreted Salmonella protein induces a proinflammatory response in epithelial cells, which promotes neutrophil migration. Proc Natl Acad Sci U S A. 2000 Oct 24; 97(22):12283-8.
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        51. Cherayil BJ, McCormick BA, Bosley J. Salmonella enterica serovar typhimurium-dependent regulation of inducible nitric oxide synthase expression in macrophages by invasins SipB, SipC, and SipD and effector SopE2. Infect Immun. 2000 Oct; 68(10):5567-74.
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        52. Wood MW, Jones MA, Watson PR, Siber AM, McCormick BA, Hedges S, Rosqvist R, Wallis TS, Galyov EE. The secreted effector protein of Salmonella dublin, SopA, is translocated into eukaryotic cells and influences the induction of enteritis. Cell Microbiol. 2000 Aug; 2(4):293-303.
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        53. Allen JH, Utley M, van Den Bosch H, Nuijten P, Witvliet M, McCormick BA, Krogfelt KA, Licht TR, Brown D, Mauel M, Leatham MP, Laux DC, Cohen PS. A functional cra gene is required for Salmonella enterica serovar typhimurium virulence in BALB/c mice. Infect Immun. 2000 Jun; 68(6):3772-5.
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        54. McCormick BA, Fernandez MI, Siber AM, Maurelli AT. Inhibition of Shigella flexneri-induced transepithelial migration of polymorphonuclear leucocytes by cadaverine. Cell Microbiol. 1999 Sep; 1(2):143-55.
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        55. Gewirtz AT, Siber AM, Madara JL, McCormick BA. Orchestration of neutrophil movement by intestinal epithelial cells in response to Salmonella typhimurium can be uncoupled from bacterial internalization. Infect Immun. 1999 Feb; 67(2):608-17.
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        56. McCormick BA, Siber AM, Maurelli AT. Requirement of the Shigella flexneri virulence plasmid in the ability to induce trafficking of neutrophils across polarized monolayers of the intestinal epithelium. Infect Immun. 1998 Sep; 66(9):4237-43.
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        57. Shaw SK, Hermanowski-Vosatka A, Shibahara T, McCormick BA, Parkos CA, Carlson SL, Ebert EC, Brenner MB, Madara JL. Migration of intestinal intraepithelial lymphocytes into a polarized epithelial monolayer. Am J Physiol. 1998 Sep; 275(3 Pt 1):G584-91.
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        58. Gewirtz AT, McCormick B, Neish AS, Petasis NA, Gronert K, Serhan CN, Madara JL. Pathogen-induced chemokine secretion from model intestinal epithelium is inhibited by lipoxin A4 analogs. J Clin Invest. 1998 May 1; 101(9):1860-9.
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        59. McCormick BA, Parkos CA, Colgan SP, Carnes DK, Madara JL. Apical secretion of a pathogen-elicited epithelial chemoattractant activity in response to surface colonization of intestinal epithelia by Salmonella typhimurium. J Immunol. 1998 Jan 1; 160(1):455-66.
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        60. McCormick BA, Nusrat A, Parkos CA, D'Andrea L, Hofman PM, Carnes D, Liang TW, Madara JL. Unmasking of intestinal epithelial lateral membrane beta1 integrin consequent to transepithelial neutrophil migration in vitro facilitates inv-mediated invasion by Yersinia pseudotuberculosis. Infect Immun. 1997 Apr; 65(4):1414-21.
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        61. Sweeney NJ, Klemm P, McCormick BA, Moller-Nielsen E, Utley M, Schembri MA, Laux DC, 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 Sep; 64(9):3497-503.
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        62. 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 Dec; 131(6 Pt 1):1599-608.
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        63. McCormick BA, Colgan SP, Delp-Archer C, Miller SI, Madara JL. Salmonella typhimurium attachment to human intestinal epithelial monolayers: transcellular signalling to subepithelial neutrophils. J Cell Biol. 1993 Nov; 123(4):895-907.
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        64. McCormick BA, Stocker BA, Laux DC, Cohen PS. Roles of motility, chemotaxis, and penetration through and growth in intestinal mucus in the ability of an avirulent strain of Salmonella typhimurium to colonize the large intestine of streptomycin-treated mice. Infect Immun. 1988 Sep; 56(9):2209-17.
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