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Human Beta-Defensin 2 Is a Salt-Sensitive Peptide Antibiotic Expressed in Human Lung

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Human Beta-Defensin 2 Is a Salt-Sensitive Peptide Antibiotic Expressed in Human Lung Human beta-defensin 2 is a salt-sensitive peptide antibiotic expressed in human lung. R Bals, … , M Zasloff, J M Wilson J Clin Invest. 1998;102(5):874-880. https://doi.org/10.1172/JCI2410. Research Article Previous studies have implicated the novel peptide antibiotic human beta-defensin 1 (hBD-1) in the pathogenesis of cystic fibrosis. We describe in this report the isolation and characterization of the second member of this defensin family, human beta-defensin 2 (hBD-2). A cDNA for hBD-2 was identified by homology to hBD-1. hBD-2 is expressed diffusely throughout epithelia of many organs, including the lung, where it is found in the surface epithelia and serous cells of the submucosal glands. A specific antibody made of recombinant peptide detected hBD-2 in airway surface fluid of human lung. The fully processed peptide has broad antibacterial activity against many organisms, which is salt sensitive and synergistic with lysozyme and lactoferrin. These data suggest the existence of a family of beta-defensin molecules on mucosal surfaces that in the aggregate contributes to normal host defense. Find the latest version: https://jci.me/2410/pdf Human b-Defensin 2 Is a Salt-sensitive Peptide Antibiotic Expressed in Human Lung Robert Bals,* Xiaorong Wang,* Zhongren Wu,* Theresa Freeman,* Vineet Bafna,‡ Michael Zasloff,§ and James M. Wilson* *Institute for Human Gene Therapy, Department of Medicine and Molecular and Cellular Engineering, The Wistar Institute, Philadelphia, Pennsylvania 19104; ‡Bioinformatics Division, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406; and §Magainin Pharmaceutical, Plymouth Meeting, Pennsylvania 19662 Abstract Recent studies suggest that the pulmonary consequences of cystic fibrosis (CF) may initiate through an early breach in in- Previous studies have implicated the novel peptide antibi- nate immunity. Children with this disease are born with nor- otic human b-defensin 1 (hBD-1) in the pathogenesis of cys- mal pulmonary function. Soon after birth their respiratory tic fibrosis. We describe in this report the isolation and char- tract becomes colonized with bacterial pathogens such as acterization of the second member of this defensin family, Pseudomonas aeruginosa leading to chronic respiratory in- human b-defensin 2 (hBD-2). A cDNA for hBD-2 was iden- flammation (6, 7). A direct link between the genetic defect in tified by homology to hBD-1. hBD-2 is expressed diffusely CF and host defense was provided by Smith et al., who demon- throughout epithelia of many organs, including the lung, strated strong antibacterial activity in airway surface fluid from where it is found in the surface epithelia and serous cells of normal lung epithelia that was substantially reduced in the the submucosal glands. A specific antibody made of recom- high salt environment of the CF airway surface fluid (8). They binant peptide detected hBD-2 in airway surface fluid of speculated that the primary genetic defect in CF increases the human lung. The fully processed peptide has broad antibac- salt content of fluid lining the airway (9, 10), which reversibly terial activity against many organisms, which is salt sensi- inactivates antimicrobial molecules (8). tive and synergistic with lysozyme and lactoferrin. These We proposed a model for CF pathogenesis, in which hu- data suggest the existence of a family of b-defensin mole- man b-defensins secreted by airway epithelia onto the airway cules on mucosal surfaces that in the aggregate contributes surface are inactivated in the milieu of CF (11). The first char- to normal host defense. (J. Clin. Invest. 1998. 102:874–880.) acterized human b-defensin (hBD-1), was originally isolated Key words: peptide antibiotics • cystic fibrosis • lung infec- from large volumes of hemodialysate (12). We showed that tion • mucosal immunity hBD-1 is also expressed in the surface epithelia and submu- cosal glands of both normal and CF lungs (11). A synthetic Introduction hBD-1 peptide showed broad activity against a number of bac- terial organisms that was diminished by high salt (11). Inhibi- Antimicrobial peptides play an important role in host defense tion of hBD-1 expression in normal bronchial xenografts by at mucosal surfaces. The b-defensins are small, cysteine-rich, antisense oligonucleotides partially compromised the ability of cationic peptides expressed by a number of epithelia (1). The epithelia to secrete antimicrobial activity, thereby providing a first such peptide, called tracheal antimicrobial peptide (TAP),1 direct link between the expression of an antibiotic peptide and was isolated from cow trachea (2); it is expressed throughout host defense in the lung (11). the surface epithelia of the cow lung where it is believed to Defensins often exist as families of homologous genes with contribute to host defense (3). A homologous peptide called complementary and/or redundant activity (1). An example is lingual antimicrobial peptide was subsequently purified from the large family of enteric defensin genes expressed in Paneth cow tongue and shown to express in multiple epithelia, includ- cells of the mouse intestine (13). The goal of this study was to ing those of the lung (4). Expression of these defensin genes is identify other members of the b-defensin family in humans regulated in response to infection and inflammation (5). and evaluate their role in lung host defense. Methods Isolation and characterization of a cDNA clone for human b-defensin Address correspondence to James M. Wilson, 3601 Spruce Street, 204 2 (hBD-2). The b-defensin specific cysteine pattern was used to per- Wistar Institute, Philadelphia, PA 19104-4268. Phone: 215-898-3000; form a “basic local alignment search tool” search at an expressed se- FAX: 215-898-6588; E-mail: [email protected] quence tag database (SmithKline Beecham, Inc., King of Prussia, Received for publication 5 December 1997 and accepted in revised PA) and three overlapping sequences were found. Primers for the 39 form 7 July 1998. region were designed from the database sequences as follows: CCT TTC TGA ATC CGC ATC AGC CAC AG (H2 rapid amplification 1. Abbreviations used in this paper: CF, cystic fibrosis; hBD-1, human of cDNA ends [RACE] 1) and GTC GCA CGT CTC TGA TGA b-defensin 1; hBD-2, human b-defensin 2; RACE, rapid amplification GGG AG (H2 RACE 2), and used in RACE with cDNA from hu- of cDNA ends; TAP, tracheal antimicrobial peptide; TFA, trifluoro- man lung as template (Marathon-Ready cDNA; Clontech, Palo Alto, acetic acid. CA). PCR products between 200 and 550 bp were cloned into pGEM-T (pGEM-T Cloning Systems; Promega, Madison, WI) and sequenced J. Clin. Invest. using an Applied Biosystems Model 373 fluorescent DNA sequencer © The American Society for Clinical Investigation, Inc. (Applied Biosystems, Foster City, CA). Primers for the 59 region of 0021-9738/98/09/0874/07 $2.00 the cDNA were designed from the sequence determined (CCA GGT Volume 102, Number 5, September 1998, 874–880 GTT TTT GGT GGT ATA GG [H2 P1], GGT GAA GCT CCC http://www.jci.org AGC CAT CAG C [H2 P2]) and together with the RACE primers 874 Bals et al. applied in amplifications using cDNA from human lung as template ear gradient of acetonitrile with 0.1% TFA. Fractions were dried, re- (Quick-clone cDNA; Clontech). A PCR product of z 440 bp was iso- suspended in 50 ml distilled water, and tested for antimicrobial activ- lated, cloned into pGEM-T, and sequenced. ity in agarose diffusion assays (see below). Purified peptides were Dot blot analysis. [32P]dCTP random primer–labeled probes of characterized by mass spectrometry (Voyager BioSpectrometry hBD-2 and ubiquitin cDNA were hybridized separately to a nylon fil- Workstation; PerSeptive Biosystems, Framingham, MA), capillary ter with dotted mRNAs from 50 different human organs (Human zone electrophoresis (270A-HT Capillary Electrophoresis System; RNA Master Blot; Clontech). After washes at high stringency condi- Applied Biosystems), and NH2-terminal amino acid analysis by Ed- tions, the signals were quantified using a Phosphoimager 445 SI (Mo- man degradation (D. Speicher, Wistar Institute, Philadelphia, PA). lecular Dynamics, Sunnyvale, CA). The expression data of hBD-2 Using synthetic hBD-1 as standard, the concentrations of the purified were normalized using hybridization to the housekeeping gene ubiq- peptides were determined by capillary zone electrophoresis. The 44– uitin. amino acid isoform of hBD-1 was purified from human urine by cat- Genomic localization. A genomic sequence containing the in- ion-exchange chromatography and subsequent RP-HPLC, and ana- tron-exon 2 border was amplified (Human GenomeWalker Kit; Clon- lyzed by CZB, NH2-terminal sequencing, and mass spectrometry, as tech), cloned, and sequenced. Two gene specific primers were then described for the isolation of hBD-2 from the baculovirus system. A used to screen a genomic bacterial artificial chromosome library (Ge- similar procedure for purification of hBD-1 from urine was reported nome Systems, Inc., St. Louis, MO). The digoxigenin-labeled DNA of recently (16). a positive clone was used as probe for fluorescent in situ hybridiza- Preparation of antibodies against hBD-2. Antiserum against tion of normal human metaphase chromosomes. The chromosome of hBD-2 purified from the recombinant baculovirus system was ob- interest was identified by analysis of the 49, 6-diamidine-29-phenylin- tained by a standard immunization scheme (Research Genetics, dole dihydrochloride (DAPI)–banding patterns and by cohybridiza- Huntsville, AL). 100 mg of peptide was coupled to keyhole limpet tion of the hBD-2 specific probe with a probe specific for the cen- hemocyanin and injected into two rabbits. Injections were repeated tromere of chromosome 8 (GenomeSystems, Inc.). after two and seven wk using the same dose. The titer against hBD-2 In situ hybridization. Various human tissues were embedded in as assayed by ELISA increased from , 50 (preimmune) to . 100,000 OCT (Tissue–Tek; Miles Laboratories, Inc., Naperville, IL), cryosec- (10 wk) for both animals.
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