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PubMed1994

Defensins.

Defensins are widely distributed and abundant 3-4 kDa antimicrobial peptides that are variable cationic and contain six disulfide-paired cysteines. Three structurally distinct peptide families have been identified: 'classical' defensins, beta-defensins and insect defensins. In many animal species, defensin genes are found in clusters with substantial sequence variability outside the core disulfide-linked cysteines. Defensin peptides have been found in the granules of phagocytes and intestinal Paneth cells, on epithelial surfaces of the intestine and the trachea, and in the hemolymph of insects. They are produced from larger precursors by stepwise, tissue-specific, proteolytic processing, a production resembling that of peptide hormones. Microbes in the phagocytic vacuoles of granulocytes and certain macrophages encounter high concentrations of defensins. Increased transcription of defensin genes and stimulus-dependent release of pre-synthesized defensin-containing cytoplasmic granules contribute to the local antimicrobial response.

Amino Acid Sequence↗
PubMed1996

Production of active bovine tracheal antimicrobial peptide in milk of transgenic mice.

Tracheal antimicrobial peptide (TAP) is a member of the beta-defensin family of antibiotic peptides found in the tracheal mucosa of the cow. TAP gene expression in the bovine airway is inducible by lipopolysaccharide and inflammatory mediators, suggesting that it functions to protect the upper airway from infection. Limited availability of bovine TAP (bTAP) has precluded investigation of its potential utility in agriculture and medicine. To overcome this problem, transgenic mice expressing bTAP using an expression vector driven by control sequences from the murine whey acidic protein (WAP) gene have been generated. The WAP/bTAP transcript was detected in RNA isolated from mammary tissue of transgenic females. bTAP was purified to homogeneity from milk via acid precipitation, reverse-phase HPLC, and ion-exchange chromatography. This milk-derived bTAP had antimicrobial activity against Escherichia coli. Amino-terminal peptide sequencing confirmed the identity of this material as a bTAP isoform. bTAP available from a mammary gland bioreactor will allow evaluation of bTAP for use as an antibiotic in agriculture and medicine.

Amino Acid Sequence↗
PubMed1997

Epithelial antibiotic induced in states of disease.

Epithelial defensins provide an active defense against the external microbial environment. We investigated the distribution and expression of this class of antimicrobial peptides in normal cattle and in animals in varying states of disease. beta-defensin mRNA was found to be widely expressed in numerous exposed epithelia but was found at higher levels in tissues that are constantly exposed to and colonized by microorganisms. We observed induction in ileal mucosa during chronic infection with Mycobacterium paratuberculosis and in bronchial epithelium after acute infection with Pasteurella haemolytica. It has been proposed that expression of antimicrobial peptides is an integral component of the inflammatory response. The results reported here support this hypothesis and suggest that epithelial defensins provide a rapidly mobilized local defense against infectious organisms.

Animals↗
PubMed1998

Avian heterophils in inflammation and disease resistance.

Heterophils are the predominate granulated leukocyte in the acute inflammatory response in gallinaceous birds. Heterophils are highly phagocytic and are capable of a broad spectrum of antimicrobial activity. They accumulate in inflamed tissue, causing tissue damage and forming heterophil granulomas that are morphologically similar to inflammatory lesions in reptiles. The avian heterophil lacks myeloperoxidase and depends primarily on nonoxidative mechanisms for antimicrobial activity. The beta-defensins found in heterophil granules can kill a wide variety of bacterial pathogens and are a major component of the heterophil antimicrobial arsenal. Heterophils form the first line of cellular defense against invading microbial pathogens in the lungs and air sacs where resident macrophages are lacking.

Animals↗
PubMed1999

Detection of cryptdin in mouse skin.

Defensins are widely distributed and broad-spectrum antimicrobial peptides with activities against bacteria, fungi, and enveloped viruses. Defensins have been isolated from granules of neutrophils from humans, rabbits, rats, and guinea pigs. They have also been found in lung macrophages as well as in Paneth cells of the human, rabbit, and mouse small intestine. The human beta-defensin-2 was recently isolated from human skin. In this study, we detected the expression of mRNA for the defensin cryptdin in BALB/c mouse skin by means of reverse transcriptase PCR amplification. Expression was also detected in dispase-separated epidermis and cultured keratinocytes, but expression was not detected in fibroblasts. The expression of cryptdin mRNA was found to begin on embryonic day 17.5. As determined with specific primers, the cDNA sequence cloned from the skin was found to be identical to that previously reported for cryptdin-5. cDNA derived from cultured keratinocytes demonstrated the sequences of the cryptdin-6 and cryptdin-1 isoforms. In situ hybridization analysis showed that the mRNA of cryptdin was expressed in the suprabasal keratinocytes of the skin in embryonic and neonatal days and then shifted to the hair bulbs in the skin of adult mice.

Animals↗
PubMed1996

Six antimicrobial peptide genes of the cathelicidin family map to bovine chromosome 22q24 by fluorescence in situ hybridization.

Six phage clones containing gene members of the family of antimicrobial peptides named cathelicidins, were mapped to bovine chromosome 22q24, by means of fluorescence in situ hybridization. The mapping data suggest the clustering of cathelicidins into a CATHL@ locus, in a similar manner as for beta-defensins, another family of antimicrobial peptides, defining the locus DEFB@ mapped to 27q13-->q14.

Animals↗
PubMed1999

Antibacterial components in bronchoalveolar lavage fluid from healthy individuals and sarcoidosis patients.

Antibacterial peptides and proteins are an integral part of the epithelial defense barrier that provides immediate protection against bacterial invasion. In humans, alpha-defensins are mainly bactericidal effectors in circulating granulocytes, beta-defensin-1 is synthesized in epithelial cells, and LL-37 is produced in granulocytes but is also induced in skin epithelia during inflammation. To investigate the importance of these defense effectors in disease, we analyzed bronchoalveolar lavage fluid (BALF) for bactericidal activity. Antibacterial activity was found in BALF material from healthy individuals and sarcoidosis patients, with enhanced activity in BALF from the patients. The activity was present as several antibacterial components, of which we have so far characterized LL-37, lysozyme, alpha-defensins, and antileukoprotease. In addition, the antibacterial peptide LL-37 was located in alveolar macrophages, bronchial epithelial cells, and bronchial glands, suggesting that it has a defensive role in airway mucosa. In conclusion, the airway epithelium is protected by a complex antibacterial defense system. This is activated in sarcoidosis, and may explain why these patients seldom develop severe respiratory tract infections.

Adult↗
PubMed1998

The effect of chloride concentration on human neutrophil functions: potential relevance to cystic fibrosis.

Recently, some investigators have observed elevated concentrations of chloride in the airway surface fluid (ASF) overlying respiratory epithelia from cystic fibrosis (CF) patients compared with ASF overlying non-CF epithelia. Others have shown that this elevated ASF salt concentration can inactivate human beta-defensin-1, an antimicrobial peptide secreted by respiratory epithelia. This could impair the primary epithelial defense against bacteria in the CF airway, thereby forcing a greater reliance on polymorphonuclear leukocyte (PMN)-mediated defenses. Pseudomonas aeruginosa (Psa) flourishes in the CF airway despite the presence of abundant PMN. We therefore investigated whether elevated ASF chloride concentration in CF might also compromise PMN function. We employed a cell-culture model in which halide concentrations and osmolarity were varied independently. We examined the effects of chloride concentration on three aspects of PMN function: recruitment of PMN to the airway (production of interleukin-8 [IL-8]), PMN antimicrobial activity (killing of Psa), and PMN clearance from the airways (apoptosis and lysis). We found that exposure to elevated chloride concentration increased PMN synthesis of IL-8, decreased PMN killing of Psa, and accelerated PMN apoptosis and lysis. In CF airways, elevated chloride therefore could contribute to the increased number of PMN recruited into the airways, the increased survival of Psa, and the increased quantity of toxic mediators released by PMN into the airways. These effects of elevated chloride on PMN function may provide another causal link between loss of cystic fibrosis transmembrane conductance regulator function and CF lung disease.

Adult↗
PubMed1996

Systematic isolation of circulating human peptides: the concept of peptide trapping.

The structural determination of circulating human peptides is essential to determine their correct posttranslationally processed form. Human hemofiltrate from patients with end stage renal disease is accessible in large quantities and is used as a source for the preparation of circulating peptides. After complete peptide extraction from hemofiltrate, a systematic separation with different chromatographic techniques is achieved. Single peptides are selected according to their mass and chromatographic elution position. Following chromatographic purification, amino acid sequence analysis is performed in combination with data base search. The identification of circulating peptides leads to numerous fragments resulting from cleavage of larger plasma proteins as well as to the discovery of new peptide hormones. The results obtained so far give insight into the degradation of plasma proteins such as fibrinogen, which results in the generation of fragments with biological activity themselves and in the identification of a novel cytokine HCC-1, the first member of beta-defensins in humans, hBD-1, and different peptides not present in any data base.

Amino Acid Sequence↗
PubMed1998

Localization of expression of human beta defensin-1 in the pancreas and kidney.

Defensins are antimicrobial peptides which play a key role in innate immunity. High levels of human beta defensin-1 (hBD-1) have previously been detected in the kidney and pancreas, but the cell-specific location of hBD-1 mRNA has not been determined. The expression of hBD-1 mRNA has been examined in fetal and adult pancreas and kidney by mRNA in situ hybridization. In fetal pancreas, hBD-1 expression was detected in the developing acini and in adult pancreas in the acini, but not in the pancreatic ducts. In both fetal and adult kidney, hBD-1 expression was detected in the collecting ducts and in the loops of Henle in adult kidney. Expression of hBD-1 mRNA in the pancreas and kidney from early development and in the acini of the adult pancreas, rather than in the pancreatic ducts, may indicate that in these tissues, hBD-1 fulfils physiological functions in addition to host defence.

Adult↗
PubMed1991

Bactericidal potency and mechanistic specificity of neutrophil defensins against bovine mastitis pathogens.

Two neutrophil defensins, rabbit peptides NP-1 and NP-5, were examined for their in vitro antibacterial activity against a panel of Gram-positive and Gram-negative organisms isolated from mastitic cows. Incubation for 60 minutes with 5 micrograms/ml of NP-1 in 10 mM sodium phosphate buffer resulted in substantial killing (greater than 95%) of all organisms tested. Although NP-5 was virtually inactive under these same conditions, supplementation of the incubation mixture with dilute nutrient media sensitized otherwise resistant organisms to this defensin. For both NP-1 and NP-5, bactericidal activity was dependent on time and concentration. Our findings demonstrate that the spectrum of defensin bactericidal activities include clinically important bovine pathogens. Further, the data demonstrate that NP-1 and NP-5, peptides which are homologous in 18 of their 33 residue positions, possess distinct mechanisms of action.

Amino Acid Sequence↗
PubMed1999

A novel mouse beta defensin, Defb2, which is upregulated in the airways by lipopolysaccharide.

Studies have shown that beta defensins are present in the human airways and may be relevant to the pathogenesis of cystic fibrosis lung disease. Here we report the identification of a novel mouse gene, Defb2, which shows sequence similarity to previously described mouse and human airway beta defensins. Defb2 does not appear to be expressed in the airways of untreated mice but it is upregulated in response to lipopolysaccharide. The induced expression of this gene by an inflammatory stimulus strongly suggests that this defensin contributes to host defence at the mucosal surface of the airways.

Amino Acid Sequence↗
PubMed1999

Epithelial defensins impair adenoviral infection: implication for adenovirus-mediated gene therapy.

Epithelial cells have been to participate actively in host defense by producing small cationic peptides called defensins. To investigate the biological activity of epithelial defensins in more detail, we expressed two defensins, hBD-1 and HD-5, in eukaryotic cell lines. Defensins were localized in the cytoplasm and in cell culture medium and exhibited strong microbicidal activity toward Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. Moreover, our data indicate that the presence of defensins protected the cells from adenoviral infection. The presence of HD-5 or hBD-1 reduced the infectivity of Av1CF2 three- to fivefold. These results imply that defensins must be considered a serious obstacle whenever adenovirus is used to deliver genes to epithelial cells.

Adenoviridae↗
PubMed1991

A major human epididymis-specific cDNA encodes a protein with sequence homology to extracellular proteinase inhibitors.

The amino acid sequence of a major human epididymis-specific protein was deduced from the nucleotide sequence of its cloned cDNA. The encoded product showed characteristics of a secretory protein, with a signal peptide followed by a small (approximately 10-kDa), acidic (pI 4.3), and cysteine-rich polypeptide. The positions of half-cysteines suggested that it was a two-domain member of the family of 'four-disulfide core' proteins to which a number of proteinase inhibitors belong. Southern blot analyses of human genomic DNA showed that the transcripts originated from a single copy gene. Northern blot and in situ transcript hybridization specifically localized the HE4 (human epididymis gene product) mRNA to the epithelial cells of the epididymal duct, predominantly within the distal sections. A possible function in sperm maturation as indicated by amino acid similarities to extracellular proteinase inhibitors of genital tract mucous secretions is discussed in the context of its tissue-specific transcription.

Aged↗
PubMed1993

Tissue-specific gene expression as an indicator of epididymis-specific functional status in the boar, bull and stallion.

cDNA probes derived from genes expressed specifically in the human epididymis were used to examine gene expression in the epididymides of boar, bull and stallion by Northern hybridization. Two probes for the HE1 and HE4 gene products were found to recognize tissue-specific transcripts in all three species, with a regionally differential distribution within the epididymis. Additionally, antibodies recognizing the HE4 protein were shown to react specifically in the epididymis of the boar and bull. An extensive study of the boar showed that, whereas mRNA for the HE1-homologue was up-regulated markedly only at puberty, the HE4-homologue was already present at moderate levels prepubertally. The distribution of the HE1-homologue changed at sexual maturity from a maximum in the cauda epididymis in the 3-4-week-old pig, to a maximum in the corpus/caput region in the adult, while the shift was in the opposite direction for the HE4-homologue. Evidently, gene expression is not fixed regionally through epididymal development in this species. The abdominal epididymis of a hemicryptorchid pig also showed a differential change in expression for the two gene products by comparison with the scrotal testis from the same animal. The results suggest that the HE1 and HE4 gene homologues may be sensitive markers for physiological changes within the mammalian epididymis, and that the boar could prove a useful model to examine the regulation of these human epididymal transcripts.

Animals↗
PubMedDate not supplied

Function of human epididymal proteins in sperm maturation.

Human post-testicular proteins were cloned by subtractive screening of epididymal cDNA libraries, employing testis as the primary negative control. This method identified six human epididymal cDNAs, named HE1-HE6, which are derived from abundant epididymal mRNAs. With the exception of HE5, which turned out to be identical to the lymphocyte surface antigen CD52, they represented completely novel human gene products. To date, there is little information on their function and the mechanism of their deposition on the sperm surface. Unlike the sperm coating antigens, CD52 binds firmly to the sperm membrane via its GPI anchor during epididymal passage. Its synthesis is carefully regulated by the epididymal epithelium. From the results of both in vivo and in vitro studies it was concluded that androgen and temperature are principal factors synergistically modulating epididymal CD52 expression. The human counterparts of two well-known major rodent epididymal proteins, secretory epididymal glutathione peroxidase (sGPX) and acidic epididymal glycoprotein (AEG = Protein DE), were not cloned by the subtractive screening approach, but by RT-PCR amplification.

Antigens, CD↗
PubMed1994

Killing of Giardia lamblia by cryptdins and cationic neutrophil peptides.

Antimicrobial polypeptides such as the defensins kill a wide range of organisms, including bacteria, fungi, viruses, and tumor cells. Because of the recent finding that intestinal defensins, also known as cryptdins, are synthesized by the Paneth cells of the small intestinal crypts and released into the lumen, we asked whether defensins and other small cationic antimicrobial peptides could kill the trophozoites of Giardia lamblia, which colonize the small intestine. Four mouse cryptdins, two neutrophil defensins (HNP-1 [human] and NP-2 [rabbit]), and the unique tryptophan-rich bovine neutrophil polypeptide indolicidin each had some antigiardial activity against trophozoites in vitro. Cryptdins 2 and 3, indolicidin, and NP-2 each reduced viability by more than 3 log units in 2 h, and killing by all peptides was dose and time dependent. Exposure of trophozoites to peptides frequently resulted in cell aggregation and dramatic changes in morphology. The mechanism of binding and lysis appeared to involve charge interactions, since 150 mM NaCl as well as millimolar levels of Ca2+ and Mg2+ inhibited killing by most of the peptides. Our studies show that G. lamblia is sensitive to defensins and indolicidin and suggest that these small polypeptides could play a role in nonimmune host defenses.

Amino Acid Sequence↗