Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

The Department of ImmunologyDefensins Pose a First DefenseAgainst PathogensThe recent isolation and characterization ofantimicrobial peptides have unveiled apreviously unrecognized component of animalhost defense. These peptidesexhibit a broad spectrum ofantimicrobial activity in relationto bacteria, fungi and certainviruses. The peptides have beenisolated from diverse speciesthroughout the plant and animalkingdoms.Recent work from ourlaboratory has revealed thatthese peptides are abundantlyexpressed at wet mucosalsurfaces of humans and othermammals. Our long-range goalis to understand how theseepithelial antimicrobial peptidescontribute to mucosal hostdefense and to characterize thepathophysiology that resultsfrom altered expression of thesepeptides.Although the epithelia ofmammalian mucosal tissues were once regarded as aprimarily passive barrier to noxious agents, our recentwork supports a model: Induction of antimicrobialpeptide expression by bacterial and pro-inflammatorystimuli constitutes part of an active, early hostdefense response of challenged epithelial cells.Charles L. Bevins, M.D., Ph.D.A major interest of this laboratory isantimicrobial peptides of the mammalian intestine.Previously, we identified two human defensinsexpressed at high levels in thePaneth cells of the smallintestine. Work in our laboratoryis better defining the role ofthese (and similar) entericpeptides in human host defenseand in disease processes,including inflammatory boweldisease (IBD). These investigationswill serve as a basis forbuilding an interactive bridgingprogram, linking basic sciencestudies in the Lerner ResearchInstitute with the resources ofCCF’s Center for InflammatoryBowel Disease.Our current studiesinclude: (i) characterizing theprimary structure and biologicalactivity of the tissue forms ofenteric defensins, (ii) defining thekey regulatory steps for theexpression of these molecules, and (iii) exploringpotential mechanisms of therapeutic modulationof these systems. The investigations includebiochemical and molecular biological approachesand analysis of transgenic models.THE BEVINSLABORATORYFELLOWSScott Howell, Ph.D.Bo Shen, M.D.Aurelie Tasiemski, Ph.DTECHNICAL ASSOCIATEDennis Wilk, B.S.COLLABORATORSJohn Crabb, Ph.D. 1Gill Diamond, Ph.D. 2Judy Drazba, Ph.D. 3Tomas Ganz, M.D., Ph.D. 4Paul McCray, M.D. 5Edith Martin Porter, M.D. 4Nita Salzman, M.D., Ph.D. 6Satya Yadav, Ph.D. 71Cole Eye Inst., CCF2UMDNJ Med. School, Newark,NJ3Imaging Core, CCF4UCLA Med. School, LosAngeles, CA5Univ. of Iowa Coll. of Med.,Iowa City6Med. Coll. of Wisconsin,Madison7Biotechnology Core, CCFJia, H.-P., Wowk, S.A., Schutte, B.C., Lee, S.K., Vivado, A., Tack, B.F., Bevins, C.L., and P.B. McCray, Jr. (2000) Anovel murine β-defensin expressed in tongue, esophagus and trachea. J. Biol. Chem. 275:33314-33320.Diamond, G., Kaiser, V., Rhodes, J., Russell, J., and C. Bevins (2000) Transcriptional regulation of β-defensin geneexpression in tracheal epithelial cells. Infect. Immun. 68:113-119.Ghosh, D., Porter, E., Shen, B., Lee, S.K., Wilk, D., Drazba, J., Yadav, S.P., Crabb, J.W., Ganz, T., and C.L.Bevins (2002) Paneth cell trypsin is the processing enzyme for human defensin-5. Nature Immunol. 3:583-590.Bevins, C.L., and G. Diamond (2002) Mammalian antimicrobial peptides. In: Dutton, C.J., Haxell, M.A., McArthur,H.A.I., and R.G. Wax, eds. Peptide Antibiotics: Discovery, Modes of Action, and Applications. New York: MarcelDekker, pp. 145-192.Ghosh, D., Porter, E., Shen, B., Lee, S.K., Wilk, D., Drazba, J., Yadav, S.P., Crabb, J.W., Ganz, T., and C.L.Bevins (2002) Paneth cell trypsin is the processing enzyme for human defensin-5. Nat. Immunol. 3:583-590.Bevins, C.L. (2003) Antimicrobial peptides as effector molecules of mammalian host defense. Contrib. Microbiol.10:106-48.Salzman, N.H., Ghosh, D., Huttner, K.M., Paterson, Y., and C.L. Bevins (2003) Protection against entericsalmonellosis in transgenic mice expressing a human intestinal defensin. Nature 422:522-526.89