Mammalian defensins in the antimicrobial immune response

Hoffmann, J.A., Kafatos, F.C., Janeway, C.A. & Ezekowitz, R.A. Phylogenetic perspectives in innate immunity. Science 284, 1313–1318 (1999).

Janeway, C.A., Jr & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).

Zasloff, M. Antimicrobial peptides of multicellular organisms. Nature 415, 389–395 (2002).

Levy, O. Antimicrobial proteins and peptides: anti-infective molecules of mammalian leukocytes. J. Leukoc. Biol. 76, 909–925 (2004).

Yang, D., Biragyn, A., Hoover, D.M., Lubkowski, J. & Oppenheim, J.J. Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense. Annu. Rev. Immunol. 22, 181–215 (2004).

Zanetti, M. Cathelicidins, multifunctional peptides of the innate immunity. J. Leukoc. Biol. 75, 39–48 (2004).

Ganz, T. Defensins: antimicrobial peptides of innate immunity. Nat. Rev. Immunol. 3, 710–720 (2003).

Lehrer, R.I. Primate defensins. Nat. Rev. Microbiol. 2, 727–738 (2004).

Schutte, B.C. & McCray, P.B., Jr. β-defensins in lung host defense. Annu. Rev. Physiol. 64, 709–748 (2002).

Patil, A., Hughes, A.L. & Zhang, G. Rapid evolution and diversification of mammalian alpha-defensins as revealed by comparative analysis of rodent and primate genes. Physiol. Genomics 20, 1–11 (2004).

Semple, C.A., Rolfe, M. & Dorin, J.R. Duplication and selection in the evolution of primate beta-defensin genes. Genome Biol. 4, R31 (2003).

Taudien, S. et al. Polymorphic segmental duplications at 8p23.1 challenge the determination of individual defensin gene repertoires and the assembly of a contiguous human reference sequence. BMC Genomics 5, 92 (2004).

Lynn, D.J., Lloyd, A.T., Fares, M.A. & O'Farrelly, C. Evidence of positively selected sites in mammalian α-defensins. Mol. Biol. Evol. 21, 819–827 (2004).

Leonova, L. et al. Circular minidefensins and posttranslational generation of molecular diversity. J. Leukoc. Biol. 70, 461–464 (2001).

Tang, Y.Q. et al. A cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated α-defensins. Science 286, 498–502 (1999).

Tran, D. et al. Homodimeric θ-defensins from rhesus macaque leukocytes: isolation, synthesis, antimicrobial activities, and bacterial binding properties of the cyclic peptides. J. Biol. Chem. 277, 3079–3084 (2002).

Nguyen, T.X., Cole, A.M. & Lehrer, R.I. Evolution of primate θ-defensins: a serpentine path to a sweet tooth. Peptides 24, 1647–1654 (2003).

Cole, A.M. et al. Retrocyclin: a primate peptide that protects cells from infection by T- and M-tropic strains of HIV-1. Proc. Natl. Acad. Sci. USA 99, 1813–1818 (2002).

Zeya, H.I. & Spitznagel, J.K. Antimicrobial specificity of leukocyte lysosomal cationic proteins. Science 154, 1049–1051 (1966).

Eisenhauer, P.B. & Lehrer, R.I. Mouse neutrophils lack defensins. Infect. Immun. 60, 3446–3447 (1992).

Mackewicz, C.E. et al. alpha-Defensins can have anti-HIV activity but are not CD8 cell anti-HIV factors. AIDS 17, F23–F32 (2003).

Chalifour, A. et al. Direct bacterial protein PAMP recognition by human NK cells involves TLRs and triggers α-defensin production. Blood 104, 1778–1783 (2004).

Wilson, C.L. et al. Regulation of intestinal α-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286, 113–117 (1999).

Ghosh, D. et al. Paneth cell trypsin is the processing enzyme for human defensin-5. Nat. Immunol. 3, 583–590 (2002).

Wu, E.R., Daniel, R. & Bateman, A. RK-2: a novel rabbit kidney defensin and its implications for renal host defense. Peptides 19, 793–799 (1998).

Satchell, D.P. et al. Interactions of mouse Paneth cell α-defensins and α-defensin precursors with membranes. Prosegment inhibition of peptide association with biomimetic membranes. J. Biol. Chem. 278, 13838–13846 (2003).

Valore, E.V. & Ganz, T. Posttranslational processing of defensins in immature human myeloid cells. Blood 79, 1538–1544 (1992).

Wu, Z. et al. From pro defensins to defensins: synthesis and characterization of human neutrophil pro α-defensin-1 and its mature domain. J. Pept. Res. 62, 53–62 (2003).

Daher, K.A., Selsted, M.E. & Lehrer, R.I. Direct inactivation of viruses by human granulocyte defensins. J. Virol. 60, 1068–1074 (1986).

Mandal, M. & Nagaraj, R. Antibacterial activities and conformations of synthetic α-defensin HNP-1 and analogs with one, two and three disulfide bridges. J. Pept. Res. 59, 95–104 (2002).

Maemoto, A. et al. Functional analysis of the α-defensin disulfide array in mouse cryptdin-4. J. Biol. Chem. 279, 44188–44196 (2004).

Wu, Z. et al. Engineering disulfide bridges to dissect antimicrobial and chemotactic activities of human β-defensin 3. Proc. Natl. Acad. Sci. USA 100, 8880–8885 (2003).

Diamond, G. et al. Tracheal antimicrobial peptide, a cysteine-rich peptide from mammalian tracheal mucosa: Peptide isolation and cloning of a cDNA. Proc. Natl. Acad. Sci. USA 88, 3952–3956 (1991).

Diamond, G. & Bevins, C.L. Endotoxin upregulates expression of an antimicrobial peptide gene in mammalian airway epithelial cells. Chest 105, 51S–52S (1994).

Selsted, M.E. et al. Purification, primary structures, and antibacterial activities of β-defensins, a new family of antimicrobial peptides from bovine neutrophils. J. Biol. Chem. 268, 6641–6648 (1993).

Schutte, B.C. et al. Discovery of five conserved β-defensin gene clusters using a computational search strategy. Proc. Natl. Acad. Sci. USA 99, 2129–2133 (2002).

Rodriguez-Jimenez, F.J. et al. Distribution of new human β-defensin genes clustered on chromosome 20 in functionally different segments of epididymis. Genomics 81, 175–183 (2003).

Zhou, C.X. et al. An epididymis-specific β-defensin is important for the initiation of sperm maturation. Nat. Cell Biol. 6, 458–464 (2004).

Yudin, A.I. et al. ESP13.2, a member of the β-defensin family, is a macaque sperm surface-coating protein involved in the capacitation process. Biol. Reprod. 69, 1118–1128 (2003).

Bensch, K.W., Raida, M., Magert, H.J., Schulz-Knappe, P. & Forssmann, W.G. hBD-1: a novel β-defensin from human plasma. FEBS Lett. 368, 331–335 (1995).

Valore, E.V. et al. Human β-defensin-1: an antimicrobial peptide of urogenital tissues. J. Clin. Invest. 101, 1633–1642 (1998).

Harder, J., Bartels, J., Christophers, E. & Schroder, J.M. A peptide antibiotic from human skin. Nature 387, 861 (1997).

Harder, J., Bartels, J., Christophers, E. & Schroder, J.M. Isolation and characterization of human β-defensin-3, a novel human inducible peptide antibiotic. J. Biol. Chem. 276, 5707–5713 (2001).

Harder, J. & Schroder, J.M. Psoriatic scales: a promising source for the isolation of human skin-derived antimicrobial proteins. J. Leukoc. Biol. 77, 476–486 (2005).

Garcia, J.R. et al. Human β-defensin 4: a novel inducible peptide with a specific salt-sensitive spectrum of antimicrobial activity. FASEB J. 15, 1819–1821 (2001).

Hiratsuka, T. et al. Increased concentrations of human β-defensins in plasma and bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis. Thorax 58, 425–430 (2003).

Ross, D.J. et al. Increased bronchoalveolar lavage human β-defensin type 2 in bronchiolitis obliterans syndrome after lung transplantation. Transplantation 78, 1222–1224 (2004).

Ong, P.Y. et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N. Engl. J. Med. 347, 1151–1160 (2002).

Nomura, I. et al. Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J. Immunol. 171, 3262–3269 (2003).

Ganz, T. Extracellular release of antimicrobial defensins by human polymorphonulear leukocytes. Infect. Immun. 55, 568–571 (1987).

Ayabe, T. et al. Modulation of mouse Paneth cell α-defensin secretion by mIKCa1, a Ca2+-activated, intermediate conductance potassium channel. J. Biol. Chem. 277, 3793–3800 (2002).

Rumio, C. et al. Degranulation of paneth cells via Toll-like receptor 9. Am. J. Pathol. 165, 373–381 (2004).

Duits, L.A., Ravensbergen, B., Rademaker, M., Hiemstra, P.S. & Nibbering, P.H. Expression of β-defensin 1 and 2 mRNA by human monocytes, macrophages and dendritic cells. Immunology 106, 517–525 (2002).

Fang, X.M. et al. Differential expression of α- and β-defensins in human peripheral blood. Eur. J. Clin. Invest. 33, 82–87 (2003).

Harder, J., Meyer-Hoffert, U., Wehkamp, K., Schwichtenberg, L. & Schroder, J.M. Differential gene induction of human β-defensins (hBD-1, -2, -3, and -4) in keratinocytes is inhibited by retinoic acid. J. Invest. Dermatol. 123, 522–529 (2004).

Singh, P.K. et al. Production of β-defensins by human airway epithelia. Proc. Natl. Acad. Sci. USA 95, 14961–14966 (1998).

Tsutsumi-Ishii, Y. & Nagaoka, I. Modulation of human β-defensin-2 transcription in pulmonary epithelial cells by lipopolysaccharide-stimulated mononuclear phagocytes via proinflammatory cytokine production. J. Immunol. 170, 4226–4236 (2003).

Liu, L., Roberts, A.A. & Ganz, T. By IL-1 signaling, monocyte-derived cells dramatically enhance the epidermal antimicrobial response to lipopolysaccharide. J. Immunol. 170, 575–580 (2003).

Wang, T.T. et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J. Immunol. 173, 2909–2912 (2004).

Wolk, K. et al. IL-22 increases the innate immunity of tissues. Immunity 21, 241–254 (2004).

Hertz, C.J. et al. Activation of Toll-like receptor 2 on human tracheobronchial epithelial cells induces the antimicrobial peptide human β defensin-2. J. Immunol. 171, 6820–6826 (2003).

Wang, X. et al. Airway epithelia regulate expression of human β-defensin 2 through Toll-like receptor 2. FASEB J. 17, 1727–1729 (2003).

Vora, P. et al. Beta-defensin-2 expression is regulated by TLR signaling in intestinal epithelial cells. J. Immunol. 173, 5398–5405 (2004).

Schaefer, T.M., Fahey, J.V., Wright, J.A. & Wira, C.R. Innate immunity in the human female reproductive tract: antiviral response of uterine epithelial cells to the TLR3 agonist poly(I:C). J. Immunol. 174, 992–1002 (2005).

Proud, D., Sanders, S.P. & Wiehler, S. Human rhinovirus infection induces airway epithelial cell production of human β-defensin 2 both in vitro and in vivo. J. Immunol. 172, 4637–4645 (2004).

Platz, J. et al. Microbial DNA induces a host defense reaction of human respiratory epithelial cells. J. Immunol. 173, 1219–1223 (2004).

Chung, W.O., Hansen, S.R., Rao, D. & Dale, B.A. Protease-activated receptor signaling increases epithelial antimicrobial peptide expression. J. Immunol. 173, 5165–5170 (2004).

Ganz, T., Selsted, M.E. & Lehrer, R.I. Antimicrobial activity of phagocyte granule proteins. Sem. Resp. Infect. 1, 107–117 (1986).

Ayabe, T. et al. Secretion of microbicidal α-defensins by intestinal Paneth cells in response to bacteria. Nat. Immunol. 1, 113–118 (2000).

Salzman, N.H., Ghosh, D., Huttner, K.M., Paterson, Y. & Bevins, C.L. Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 422, 522–526 (2003).

Moser, C. et al. β-Defensin 1 contributes to pulmonary innate immunity in mice. Infect. Immun. 70, 3068–3072 (2002).

Morrison, G., Kilanowski, F., Davidson, D. & Dorin, J. Characterization of the mouse β defensin 1, Defb1, mutant mouse model. Infect. Immun. 70, 3053–3060 (2002).

Bader, M.W. et al. Regulation of Salmonella typhimurium virulence gene expression by cationic antimicrobial peptides. Mol. Microbiol. 50, 219–230 (2003).

Lehrer, R.I., Szklarek, D., Ganz, T. & Selsted, M.E. Correlation of binding of rabbit granulocyte peptides to Candida albicans with candidacidal activity. Infect. Immun. 49, 207–211 (1985).

Lehrer, R.I., Ganz, T., Szklarek, D. & Selsted, M.E. Modulation of the in vitro candidacidal activity of human neutrophil defensins by target cell metabolism and divalent cations. J. Clin. Invest. 81, 1829–1835 (1988).

Lehrer, R.I. et al. Interaction of human defensins with Escherichia coli. Mechanism of bactericidal activity. J. Clin. Invest. 84, 553–561 (1989).

Boniotto, M. et al. A study of host defence peptide β-defensin 3 in primates. Biochem. J. 374, 707–714 (2003).

Edgerton, M. et al. Salivary histatin 5 and human neutrophil defensin 1 kill Candida albicans via shared pathways. Antimicrob. Agents Chemother. 44, 3310–3316 (2000).

Helmerhorst, E.J. et al. The cellular target of histatin 5 on Candida albicans is the energized mitochondrion. J. Biol. Chem. 274, 7286–7291 (1999).

Sahl, H.G. et al. Mammalian defensins: structures and mechanism of antibiotic activity. J. Leukoc. Biol. 77, 466–475 (2005).

Panyutich, A.V., Voitenok, N.N., Lehrer, R.I. & Ganz, T. An enzyme immunoassay for human defensins. J. Immunol. Methods 141, 149–155 (1991).

Kagan, B.L., Selsted, M.E., Ganz, T. & Lehrer, R.I. antimicrobial defensin peptides form voltage-dependent ion-permeable channels in planar lipid bilayer membranes. Proc. Natl. Acad. Sci. USA 87, 210–214 (1990).

Lohner, K., Latal, A., Lehrer, R.I. & Ganz, T. Differential scanning microcalorimetry indicates that human defensin, HNP-2, interacts specifically with biomembrane mimetic systems. Biochemistry 36, 1525–1531 (1997).

Wimley, W.C., Selsted, M.E. & White, S.H. Interactions between human defensins and lipid bilayers: evidence for formation of multimeric pores. Protein Sci. 3, 1362–1373 (1994).

Hristova, K., Selsted, M.E. & White, S.H. Critical role of lipid composition in membrane permeabilization by rabbit neutrophil defensins. J. Biol. Chem. 272, 24224–24233 (1997).

Trabi, M., Schirra, H.J. & Craik, D.J. Three-dimensional structure of RTD-1, a cyclic antimicrobial defensin from Rhesus macaque leukocytes. Biochemistry 40, 4211–4221 (2001).

Abuja, P.M., Zenz, A., Trabi, M., Craik, D.J. & Lohner, K. The cyclic antimicrobial peptide RTD-1 induces stabilized lipid-peptide domains more efficiently than its open-chain analogue. FEBS Lett. 566, 301–306 (2004).

Weiss, T.M. et al. Two states of cyclic antimicrobial peptide RTD-1 in lipid bilayers. Biochemistry 41, 10070–10076 (2002).

Buffy, J.J. et al. Solid-state NMR investigation of the selective perturbation of lipid bilayers by the cyclic antimicrobial peptide RTD-1. Biochemistry 43, 9800–9812 (2004).

Munk, C. et al. The θ-defensin, retrocyclin, inhibits HIV-1 entry. AIDS Res. Hum. Retroviruses 19, 875–881 (2003).

Wang, W., Cole, A.M., Hong, T., Waring, A.J. & Lehrer, R.I. Retrocyclin, an antiretroviral θ-defensin, is a lectin. J. Immunol. 170, 4708–4716 (2003).

Territo, M.C., Ganz, T., Selsted, M.E. & Lehrer, R.I. Monocyte-chemotactic activity of defensins from human neutrophils. J. Clin. Invest. 84, 2017–2020 (1989).

Chertov, O. et al. Identification of defensin-1, defensin-2, and CAP37/azurocidin as T-cell chemoattractant proteins released from interleukin-8-stimulated neutrophils. J. Biol. Chem. 271, 2935–2940 (1996).

Yang, D., Chen, Q., Chertov, O. & Oppenheim, J.J. Human neutrophil defensins selectively chemoattract naive T and immature dendritic cells. J. Leukoc. Biol. 68, 9–14 (2000).

Yang, D. et al. Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286, 525–528 (1999).

Garcia, J.R. et al. Identification of a novel, multifunctional β-defensin (human β-defensin 3) with specific antimicrobial activity. Its interaction with plasma membranes of Xenopus oocytes and the induction of macrophage chemoattraction. Cell Tissue Res. 306, 257–264 (2001).

Yang, D., Biragyn, A., Kwak, L.W. & Oppenheim, J.J. Mammalian defensins in immunity: more than just microbicidal. Trends Immunol. 23, 291–296 (2002).

Befus, A.D. et al. Neutrophil defensins induce histamine secretion from mast cells: mechanisms of action. J. Immunol. 163, 947–953 (1999).

Niyonsaba, F., Iwabuchi, K., Matsuda, H., Ogawa, H. & Nagaoka, I. Epithelial cell-derived human β-defensin-2 acts as a chemotaxin for mast cells through a pertussis toxin-sensitive and phospholipase C-dependent pathway. Int. Immunol. 14, 421–426 (2002).

Murphy, C.J., Foster, B.A., Mannis, M.J., Selsted, M.E. & Reid, T.W. Defensins are mitogenic for epithelial cells and fibroblasts. J. Cell. Physiol. 155, 408–413 (1993).

Aarbiou, J. et al. Human neutrophil defensins induce lung epithelial cell proliferation in vitro. J. Leukoc. Biol. 72, 167–174 (2002).

Chavakis, T. et al. Regulation of neovascularization by human neutrophil peptides (α-defensins): a link between inflammation and angiogenesis. FASEB J. 18, 1306–1308 (2004).

Aarbiou, J. et al. Neutrophil defensins enhance lung epithelial wound closure and mucin gene expression in vitro. Am. J. Respir. Cell Mol. Biol. 30, 193–201 (2004).