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Last updated: 13th August 2010

Human beta-defensin 3 inhibits cell wall biosynthesis in Staphylococci.
Sass V, Schneider T, Wilmes M, Körner C, Tossi A, Novikova N, Shamova O, Sahl HG
Institute of Medical Microbiology, Immunology and ParasitologyPharmaceutical Microbiology Section, University of Bonn,53105 Bonn, Germany.
Infect. Immun. 2010 Jun;78 (6):2793-800
Human beta-defensin 3 (hBD3) is a highly charged (+11) cationic host defense peptide, produced by epithelial cells and neutrophils. hBD3 retains antimicrobial activity against a broad range of pathogens, including multiresistant Staphylococcus aureus, even under high-salt conditions. Whereas antimicrobial host defense peptides are assumed to act by permeabilizing cell membranes, the transcriptional response pattern of hBD3-treated staphylococcal cells resembled that of vancomycin-treated cells (V. Sass, U. Pag, A. Tossi, G. Bierbaum, and H. G. Sahl, Int. J. Med. Microbiol. 298:619-633, 2008) and suggested that inhibition of cell wall biosynthesis is a major component of the killing process. hBD3-treated cells, inspected by transmission electron microscopy, showed localized protrusions of cytoplasmic contents, and analysis of the intracellular pool of nucleotide-activated cell wall precursors demonstrated accumulation of the final soluble precursor, UDP-MurNAc-pentapeptide. Accumulation is typically induced by antibiotics that inhibit membrane-bound steps of cell wall biosynthesis and also demonstrates that hBD3 does not impair the biosynthetic capacity of cells and does not cause gross leakage of small cytoplasmic compounds. In in vitro assays of individual membrane-associated cell wall biosynthesis reactions (MraY, MurG, FemX, and penicillin-binding protein 2 [PBP2]), hBD3 inhibited those enzymes which use the bactoprenol-bound cell wall building block lipid II as a substrate; quantitative analysis suggested that hBD3 may stoichiometrically bind to lipid II. We report that binding of hBD3 to defined, lipid II-rich sites of cell wall biosynthesis may lead to perturbation of the biosynthesis machinery, resulting in localized lesions in the cell wall as demonstrated by electron microscopy. The lesions may then allow for osmotic rupture of cells when defensins are tested under low-salt conditions.
Postsplenectomy Sepsis in Splenectomized, Partially Splenectomized and Non-splenectomized Rats after Streptococcus Pneumoniae Challenge.
Volrats O, Pilmane M, Petersons A
University Children´s Hospital, Pediatrics Surgery, Riga, Latvia.
European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift fur Kinderchirurgie 2010 Apr
INTRODUCTION: Purpose of the study was the evaluation of the role of 1/3 of the spleen in host defense after a challenge with Streptococcus pneumoniae. MATERIALS AND METHODS: Forty Wistar rats divided into four groups underwent splenectomy (SPR), partial splenectomy (PSR) or sham operation (SOR). Healthy rats were used as controls (CGR). Operations were performed under general anesthesia. Ten weeks after operation the rats were challenged with 6x107 cfu/ml Streptococcus pneumoniae administered intravenously. All surviving animals were sacrificed 12 days after intravenous injection Interleukin-10, tumor necrosis factor-alpha and human beta-defensin-2 containing cells were detected in the parenchymatous organs (spleen, lungs, liver and kidneys) of all groups. Kaplan-Meier and Mann-Whitney tests were used for statistical analysis. RESULTS: Survival after Streptococcus pneumoniae challenge was longer in animals with a greater amount of splenic tissue, with mortality increased proportionately to the reduction in splenic tissue. In the SOR group survival was 11.6+/-1.3 days (10% mortality). In the PSR group survival was 6.0+/-2.5 days (90% mortality). In the SPR group survival was 1.6+/-0.8 days (100% mortality). In splenic tissue the levels of HbetaD-2, IL-10 and TNF-alpha-containing cells did not differ statistically (z=5.021; p<0.01) and were higher than in other parenchymatous organs (PSR, SOR, CGR). Levels of IL-10-containing cells were higher in parenchymatous organs of the SPR group (z=7.919; p<0.001), similar in the PSR and SOR groups (z=1.020; p=0.308) and lower in the CGR group (z=4.366; p<0.01). There were no statistically significant differences in the levels of IL-10 containing cells in the lungs of all group rats with spleen (z=4.266; p<0.01). Levels of TNF-alpha-containing cells were similar in PSR and SOR groups (z=1.004; p=0.315). Relative levels of HbetaD-2 in kidney differed between all groups (z=2.916; p=0.004). CONCLUSIONS: All of the splenectomized animals (100%) and 90% of the partially splenectomized animals died. Partial splenectomy (with 1/3 of splenic tissues remaining) does not offer full protection against Streptococcus pneumoniae sepsis. In all groups, the amounts of HbetaD-2, IL-10 and TNF-alpha-containing cells in the spleen were higher than in other parenchymatous organs (lungs, liver and kidneys).
Dissection of host cell signal transduction during Acinetobacter baumannii-triggered inflammatory response.
March C, Regueiro V, Llobet E, Moranta D, Morey P, Garmendia J, Bengoechea JA
Program Infection and Immunity, Fundació Caubet-CIMERA Illes Balears, Bunyola, Spain.
PLoS ONE 2010 ;5 (4):e10033
Infected airway epithelial cells up-regulate the expression of chemokines, chiefly IL-8, and antimicrobial molecules including beta-defensins (BD). Acinetobacter baumannii is a cause of hospital-acquired pneumonia. We examined whether A. baumannii induced the expressions of IL-8 and BD2 by airway epithelial cells and the receptors implicated in bacterial detection. A549 and human primary airway cells released IL-8 upon infection. A. baumannii-infected cells also increased the expression of BD2 which killed A. baummannii strains. IL-8 induction was via NF-kappaB and mitogen-activated kinases p38 and p44/42-dependent pathways. A. baumannii engaged Toll-like receptor (TLR) 2 and TLR4 pathways and A549 cells could use soluble CD14 as TLRs co-receptor. A. baumannii lipopolysaccharide stimulated IL-8 release by A549 cells and sCD14 facilitated the recognition of the lipopolysaccharide. Mass spectrometry analysis revealed that A. baumannii lipid A structure matches those with endotoxic potential. These results demonstrate that airway epithelial cells produce mediators important for A. baumannii clearance.
The Decrease of Serum Levels of Human Neutrophil Alpha-Defensins Parallels with the Surgery-Induced Amelioration of NASH in Obesity.
Manco M, Fernandez-Real JM, Vecchio FM, Vellone V, Moreno JM, Tondolo V, Botta´o G, Nanni G, Mingrone G
Scientific Directorate, Bambino Gesxx Hospital and Research Institute, Largo San Onofrio 4, 00165, Rome, Italy,
Obesity surgery 2010 Apr
BACKGROUND: Innate immune system participates actively into inflammatory processes, with immune cells and liver secreting a number of immune peptides. Among them, both soluble CD14 receptor (sCD14) and human neutrophil alpha-defensins (HNDs) may represent serum markers of necro-inflammation in obese patients with non-alcoholic fatty liver disease. METHODS: To verify this hypothesis, we investigated changes in circulating levels of sCD14 and HNDs in 11 severely obese young women following surgery-induced weight loss (bilio-pancreatic diversion). Patients were evaluated before surgery and 2 years later, with NAS score evaluated on liver biopsies and whole body glucose uptake (M value) by euglycemic hyperinsulinemic clamp. RESULTS: NAS score improved in nine patients [median NAS score in the whole sample, 6 (5-6) vs. 3 (3-4), p = 0.016]. Serum concentrations of HNDs decreased significantly in all (p = 0.016), whilst sCD14 increased only in the nine women who showed the amelioration of the NAS score [2.4 (1.7-2.6) vs. 2.6 (2.3-3.3) mug/ml, p = 0.001]. NAS score and HNDs correlated significantly both before (r (o) = 0.671, p = 0.02) and after weight loss (r (o) = 0.683, p = 0.029), NAS score and sCD14 only before surgery (r (o) = 0.605, p = 0.04). The M value increased in all patients [2.67 (1.99-3.01) vs. 6.89 (6.35-7.32) mg kg (FFM) (-1) min(-1); p = 0.01], but independently of NAS score changes. CONCLUSIONS: Changes in levels of HNDs and sCD14 accompany those in hepatic necro-inflammation due to surgical-induced weight loss. Further studies are needed to verify any causative role of these peptides in non-alcoholic steatohepatitis.
Genomic copy number determines functional expression of {beta}-defensin 2 in airway epithelial cells and associates with chronic obstructive pulmonary disease.
Janssens W, Nuytten H, Dupont LJ, Van Eldere J, Vermeire S, Lambrechts D, Nackaerts K, Decramer M, Cassiman JJ, Cuppens H
Department of Human Genetics, Katholieke Universiteit Leuven, Gasthuisberg O&N1 (602), Herestraat 49, B-3000, Leuven, Belgium.
Am J Respir Crit Care Med. 2010 Jul 15;182(2):163-9.
RATIONALE: Copy number variations of the cluster of beta-defensin genes have been associated with psoriasis and inflammatory bowel disease. Controversy still exists on whether the beta-defensins genes determine susceptibility for COPD. Aims: We investigated whether genomic copy number variations of the beta-defensin gene cluster have a functional role in airway epithelial cells and associate with the presence of COPD. METHODS: Baseline and inflammatory induced transcript expression of DEFB4 was studied in nasal epithelial cell cultures and its effect on Pseudomonas aeruginosa inhibition was assessed. Subsequently, relevant functional cut-offs for copy numbers were used to explore associations with COPD in two independent case-control studies. RESULTS: Copy number variation in the beta-defensin encoding genes correlated with baseline mRNA DEFB4 expression levels (R(2)= 0.96, p= 0.02), with a plateau effect from five copies or more. Only when higher copy numbers of beta-defensin genes were present, transcription was significantly up-regulated by tumor necrosis factor alpha (p< 0.0001), which resulted in a better anti-microbial activity in vitro. When comparing healthy smokers with COPD patients, a copy number >/= 5 was associated with increased risk for COPD with an adjusted Odds ratio of 1.8 (CI: 1.1- 2.8; p= 0.02), which was confirmed by a second independent case-control study. CONCLUSION: Genomic copy number variation of beta-defensin encoding genes has a functional role in airway epithelial cells, which may contribute to the pathogenesis of COPD.
Effect of temperature on the shift of Pseudomonas fluorescens from an environmental microorganism to a potential human pathogen.
Donnarumma G, Buommino E, Fusco A, Paoletti I, Auricchio L, Tufano MA
Department of Experimental Medicine, Microbiology and Clinical Microbiology Section, Second University of Naples, Italy.
Int J Immunopathol Pharmacol ;23 (1):227-34
Pseudomonas fluorescens is a Gram-negative bacterium generally considered of scarce clinical significance. However, in the last few years, the isolation of P. fluorescens as the causative agent of nosocomial infections has rapidly increased. P. fluorescens is a psychrophile microorganism which grows at an optimal temperature of 25-30 degrees Celcius. In spite of this constraint, it has recently been reported that the human physiological temperature does not appear to be a barrier for this microorganism. In this study we examined the ability of P. fluorescens, grown at 28 degrees C or at 37 degrees C, to adhere to cultured human A549 pulmonary cells and to form biofilm. The ability of P. fluorescens to induce expression of proinflammatory cytokines, beta-defensin 2 and the intercellular adhesion molecule-1 was also investigated. Our results clearly indicate that inflammatory mediators are induced when the microorganism is grown at a lower temperature, while biofilm is formed only at 37 degrees C. The results presented are consistent with previous reports indicating P. fluorescens as an opportunistic pathogen and underscore the urgent need for further studies to better characterize the virulence of this microorganism.
Precursor processing of human defensin-5 is essential to the multiple functions in vitro and in vivo.
Ishikawa C, Tanabe H, Maemoto A, Ito T, Watari J, Kono T, Fujiya M, Ashida T, Ayabe T, Kohgo Y
Division of Gastroenterology and Hematology/Oncology, Department of Internal Medicine, Asahikawa Medical College, Asahikawa, Japan.
J Innate Immun 2009 Dec;2 (1):66-76
Human defensin-5 (HD-5) is one of the major antimicrobial peptides secreted by Paneth cells in the human small intestine. HD-5 is produced and stored as a propeptide in Paneth cell granules, secreted in response to stimulation by cholinergic reagents or bacterial antigens. The activation process by trypsin occurs in the intestinal lumen to produce mature HD-5. This study evaluated the difference between proHD-5 and mature HD-5 in bactericidal activity and induction of chemokine secretion in vitro. Mature HD-5 showed bactericidal activities against all bacterial strains. Though, proHD-5 without enzymatic cleavage possessed less antimicrobial ability against Salmonella typhimurium and Escherichia coli but not against Staphylococcus aureus. Mature HD-5 also induced intestinal epithelial cells to increase the protein and mRNA levels of interleukin-8. Furthermore, the peptides were applied to dextran sulfate sodium-induced mouse colitis. The expression of endogenous mouse defensins was not changed in the small intestine, and the additional injection of exogenous HD-5 improved mortality (p < 0.05). This study demonstrated the multifunctional roles of the activation process in human defensin and the possibility of using antimicrobial peptides for the treatment of inflammatory bowel diseases in future applications.
Localisation and gene expression of Human {beta}-defensin 9 at the human ocular surface epithelium in response to pathogen-associated molecular patterns (PAMPs) and Interleukin-1 beta.
Mohammed I, Suleman H, Otri AM, Kulkarni BB, Chen P, Hopkinson A, Dua HS
Division of Ophthalmology & Visual Sciences, University of Nottingham, Nottingham, United Kingdom.
Invest Ophthalmol Vis Sci. 2010 Sep;51(9):4677-82.
PURPOSE: Antimicrobial peptides (AMPs) are multifunctional host defense molecules. Human beta-defensin 9 (HBD9) has previously been shown to be downregulated during ocular surface (OS) infection or inflammation. Here, the authors aimed to study localization of HBD9 protein in different OS regions and to determine the role of Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors, and proinflammatory cytokines in HBD9 expression. METHODS: Immunolocalization of HBD9 protein was carried out on the normal human OS regions (cornea, limbus, and conjunctiva). Quantitative PCR analysis of HBD9 mRNA was performed in SV40-transformed human corneal epithelial cells (hCECs) treated for different durations with synthetic pathogen-associated molecular patterns (PAMPs) and recombinant cytokines. RESULTS: HBD9 protein was constitutively expressed on OS epithelia. Corneal and limbal epithelia and corneal stroma demonstrated modest levels of HBD9, whereas conjunctival epithelium demonstrated high levels of HBD9 protein. TLR02, TLR03, TLR04, and TLR05 were shown to modulate HBD9 mRNA in hCECs. Similarly, NOD2 and IL-1beta were also shown to alter HBD9 in a time-dependent manner. In response to infection-related PAMPs and inflammatory cytokines, an initial increase in HBD9 mRNA levels was observed, followed by a significant downregulation. CONCLUSIONS: This is the first demonstration of HBD9 protein expression at different OS regions. The authors also determined the role of various innate immune receptors in HBD9 mRNA modulation. Further understanding of the signaling mechanisms involved in the initial response of HBD9 to infection or inflammation is likely to indicate future therapeutic directions with this AMP.
The antimicrobial peptide DEFB1 is associated with caries.
Ozturk A, Famili P, Vieira AR
Department of Periodontics and Preventive Dentistry, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
J. Dent. Res. 2010 Jun;89 (6):631-6
Genetics is an important component in the determination of individual susceptibility to caries and periodontal diseases. Since beta defensin 1 (DEFB1) localizes in the oral cavity, we tested if variation in DEFB1 is associated with caries and periodontitis. We analyzed 3 single-nucleotide polymorphisms in DEFB1 in DNA samples from unrelated individuals. Carrying a copy of the variant allele of the DEFB1 marker rs11362 (G-20A) increased the DMFT and DMFS scores more than five-fold. Also, carrying a copy of the variant allele of the DEFB1 marker rs179946 (G-52A) correlated with low DMFT scores. We found a high-caries-experience haplotype (GCA), which increased DMFT scores two-fold, and a low- caries-experience haplotype (ACG), which decreased DMFT scores two-fold, in the DEFB1 promoter. No association between DEFB1 genetic markers and periodontal disease was found. Our results suggest that functional polymorphisms of DEFB1 are potential markers for caries.
Scaling and self-organized criticality in proteins: Lysozyme c.
Phillips JC
Department of Physics and Astronomy, Rutgers University, Piscataway, New Jersey 08854, USA.
Phys Rev E Stat Nonlin Soft Matter Phys 2009 Nov;80 (5 Pt 1):051916
Proteins appear to be the most dramatic natural example of self-organized criticality (SOC), a concept that explains many otherwise apparently unlikely phenomena. Protein functionality is often dominated by long-range hydro(phobic/philic) interactions, which both drive protein compaction and mediate protein-protein interactions. In contrast to previous reductionist short-range hydrophobicity scales, the holistic Moret-Zebende hydrophobicity scale [Phys. Rev. E 75, 011920 (2007)] represents a hydroanalytic tool that bioinformatically quantifies SOC in a way fully compatible with evolution. Hydroprofiling identifies chemical trends in the activities and substrate binding abilities of model enzymes and antibiotic animal lysozymes c , as well as defensins, which have been the subject of tens of thousands of experimental studies. The analysis is simple and easily performed and immediately yields insights not obtainable by traditional methods based on short-range real-space interactions, as described either by classical force fields used in molecular-dynamics simulations, or hydrophobicity scales based on transference energies from water to organic solvents or solvent-accessible areas.