Charles L. Bevins, M.D., Ph.D.
GBSF Room 5515
- Characterization of Antimicrobial Peptides from Human and Rodent Mucosal Tissues
- Study of the Regulated Expression and Processing of Antimicrobial Peptides
- In vivo models of defensin activity
- Altered Expression of Antimicrobial Peptides in Inflammatory Bowel Disease, Otitis Media, and Necrotizing Enterocolitis
Our laboratory is interested in innate immunity of mucosal tissues and we are focused on a key effector component of host defense: antimicrobial peptides. Antimicrobial peptides are endogenous antibiotics, isolated from diverse species throughout the plant and animal kingdoms. They represent an evolutionary ancient mechanism of host defense. These peptides have a broad-spectrum of antimicrobial activity that includes bacteria, fungi and certain viruses. Additional biological activities of many antimicrobial peptides (for example, chemotaxis) are a result of high affinity interactions with various cell surface receptors. Defensins are the major class of antimicrobial peptides in humans and other mammals. Recent work from our laboratory has discovered that certain defensins are expressed in abundance by epithelial cells at wet mucosal surface. The long-range goal of our research is to understand the specific role that these epithelial antimicrobial peptides play in mucosal host defense and to characterize the pathophysiology that characterizes altered expression of these peptides.
Although the epithelia of mammalian mucosal tissues were once regarded as a primarily a passive barrier to noxious agents, our studies support a model: Antimicrobial peptide constitutes part of an active, early host defense response of challenged epithelial cells. Our current collaborative studies include: (i) characterizing the primary structure and biological activity of the tissue forms defensins, (ii) defining the key regulatory steps for the expression of these molecules, (iii) exploring potential mechanisms of therapeutic modulation of these systems. The investigations include biochemical and molecular biological approaches and analysis of transgenic and other animal models.
Salzman, NH, Hung, K, Haribhai, D, Chu, H, Karlsson-Sjöberg, J, Amir, E, Teggatz, P, Barman, M, Hayward, M, Eastwood, D, Stoel, M, Zhou, Y, Sodergren, E, Weinstock, GM, Bevins, CL, Williams, C and Bos, NA. Enteric defensins are essential regulators of intestinal microbial ecology. Nat Immunol 76-82, 2010.
Hornsby, MJ, Huff, JL, Kays, RJ, Canfield, DR, Bevins, CL and Solnick, JV Helicobacter pylori induces an antimicrobial host response in rhesus macaques in a Cag Pathogenicity Island-Dependent Manner. Gastroenterology 134:1049-1057, 2008.
Wehkamp, J, Wang, G, Kübler, I, Schaeffeler, E, Nuding, S, Gregorieff, A, Schnabel, Kays, RJ, Reinisch, W, Teml, A, Vermeire, S, Rutgeerts, P, Fellermann, K, Burk, O, Clevers, H, Schwab, M, Bevins, CL and Stange, EF. The Paneth Cell α-Defensin Deficiency of Ileal Crohn´s Disease is Linked to Wnt/Tcf-4. J. Immunol. 179:3109-3118, 2007.
Wehkamp J, Salzman NH, Porter E, Weichenthal M, Petras RE, Shen B, Schaeffeler E, Schwab M, Linzmeier R, Feathers RW, Chu H, Lima JH, Fellermann K, Ganz T, Stange EF, Bevins CL. Reduced Paneth cell alpha-defensins in ileal Crohn's disease. Proc Natl Acad Sci U S A 102, 18129-18134, 2005.
Sherman MP, Bennett SH, Hwang FFY, Sherman J, Bevins CL. Paneth Cells and Antibacterial Host Defense in Neonatal Small Intestine. Infect. Immun. 73:6143-6146, 2005.
Salzman N, Ghosh D, Huttner KM, Paterson Y, Bevins CL. Human defensin-5 gene in transgenic mice: Paneth cell specific expression and protection from lethal Salmonella typhimurium infection. Nature 422:522-526, 2003.
Ghosh D, Porter EM, Shen B, Lee SK, Wilk DJ, Crabb JW, Drazba J, Yadav SY, Ganz T, Bevins CL. Paneth cell trypsin is the processing enzyme for human defensin-5. Nat. Immunol. 3:583-590, 2002.
Jia H-P, Wowk SA, Schutte BC, Lee SK, Vivado A, Tack BF, Bevins CL, McCray Jr PB. A novel murine b-defensin expressed in tongue, esophagus and trachea. J. Biol. Chem. 275:33314-33320, 2000.
Diamond G, Kaiser V, Rhodes J, Russell J, Bevins C. Transcriptional regulation of b-defensin gene expression in tracheal epithelial cells. Infect Immun 68: 113-119, 2000.
Yount NY, Yuan J, Tarver AP, Diamond G, Levy JN, McGuire PA, McCullogh C, Cullor JS, Bevins CL, Selsted ME. Molecular cloning and expression of bovine neutrophil b-defensin 4. Characterization of cDNA and genomic sequences, pattern of tissue expression, and localization of the fully-processed peptide to neutrophil dense granules. J. Biol. Chem. 274: 26249-26258, 1999.
Tarver AP, Clark DP, Diamond G, Russell JP, Erdjument-Bromage H, Tempst P, Cohen K, Jones DE, Sweeney RW, Wines M, Huang S, Bevins CL. Enteric beta-Defensin: Molecular Cloning and Characterization of a Gene with Inducible Intestinal Epithelial Cell Expression Associated with Cryptosporidium parvum Infection. Infection and Immunity 66: 1045-56, 1998.
Diamond G, Russell JP, Bevins CL. Inducible expression of an endogenous antibiotic in lipopolysaccharide-challenged tracheal epithelial cells. PNAS 93: 5156-5160, 1996.
Mallow EM, Harris A, Salzman N, Russell JP, DeBerardinis JP, Ruchelli E, Bevins CL. Human enteric defensins: Gene structure and developmental expression. J. Biol. Chem. 271: 4038-4045, 1996.
Jones, D.E. and Bevins, CL: Paneth cells of the human small intestine express an antimicrobial peptide gene. J. Biol. Chem. 267: 23216-23225, 1992.
Diamond, G., Zasloff, M., Eck, H., Brasseur, M., Maloy, W.L. and Bevins, CL: Tracheal antimicrobial peptide, a novel cysteine-rich peptide from mammalian tracheal mucosa: Peptide isolation and cloning of a cDNA. Proc. Natl. Acad. Sci. USA 88:3952-56, 1991.