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Last updated: 13th August 2010

Literature
Lucifensin, the long-sought antimicrobial factor of medicinal maggots of the blowfly Lucilia sericata.
Cerovsk V, Zdrek J, Fuck V, Monincov L, Voburka Z, Bm R
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nm. 2, 166 10, Prague 6, Czech Republic, cerovsky@uochb.cas.cz.
Cell Mol Life Sci. 2010 Feb;67(3):455-66.
Abstract
A novel homologue of insect defensin designated lucifensin (Lucilia defensin) was purified from the extracts of various tissues (gut, salivary glands, fat body, haemolymph) of green bottle fly (Lucilia sericata) larvae and from their excretions/secretions. The primary sequence of this peptide of 40 residues and three intramolecular disulfide bridges was determined by ESI-QTOF mass spectrometry and Edman degradation and is very similar to that of sapecin and other dipteran defensins. We assume that lucifensin is the key antimicrobial component that protects the maggots when they are exposed to the highly infectious environment of a wound during the medicinal process known as maggot therapy. We also believe that lucifensin is that long-sought larger molecular weight antimicrobial factor of the Lucilia sericata excretions/secretions believed to be effective against pathogenic elements of the wound microbial flora.
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Constitutive Expression of the Antimicrobial Peptide RNase 7 Is Associated with Staphylococcus aureus Infection of the Skin.
Zanger P, Holzer J, Schleucher R, Steffen H, Schittek B, Gabrysch S
Institut fr Tropenmedizin and 2Universitts-Hautklinik, Eberhard Karls Universitt, Tbingen, Germany; and 3London School of Hygiene and Tropical Medicine, London, United Kingdom.
J. Infect. Dis. 2009 Dec;200 (12):1907-1915
Abstract
Background. Staphylococcus aureus infections of the skin are a public health problem of growing importance. Antimicrobial peptides in human skin are believed to play an important role in innate defense against intruding pathogens. This study aimed to clarify whether their baseline expression influences the propensity of healthy individuals to develop S. aureus-positive skin infections. Methods. Using real-time polymerase chain reaction technique and a prospective case-control design, we determined the expression of messenger RNA coding for human beta-defensin 2 and 3 as well as RNase 7 in unaffected skin of 20 travelers returning with Staphylococcus aureus-positive skin infection (case patients) relative to levels in 40 matched control subjects. Results. Expression of RNase 7 was found to be 64% higher in unaffected skin of control subjects, compared with unaffected skin of case patients (95% confidence interval, 17%-131%; [Formula: see text]). This association remained stable after controlling for S. aureus nasal carriage, smoking, level of accommodation, and history of allergy. No such association was present for human beta-defensin 2 or 3. Conclusions. In conjunction with the existing evidence from in vitro studies, these findings suggest that antimicrobial peptides found at high baseline levels in healthy skin, such as RNase 7, confer protection against S. aureus infection of the skin.
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A novel biologic immunomodulator, HDFx, protects against lethal hemorrhage, endotoxins and traumatic injury: potential relevance to emerging diseases.
Altura BM, Gebrewold A, Carella A
International journal of clinical and experimental medicine 2009 ;2 (3):266-79
Abstract
For more than 125 years, it has been known that the RES, macrophages and the innate immune system play fundamental roles in host defense against pathogenic infections, trauma, hemorrhage, and combined injuries. Some years ago, we and others reported that the RES-macrophage system was intimately connected to resistance to these bodily stressors, among other injuries. We tested the hypothesis that induction of tolerance (either spontaneous, RES-stimulated, or drug-induced) might be associated with production of a yet-to-be-identified biologic host defense factor, which we have termed HDFx. The results presented, herein, demonstrate for the first time that: 1) the MW of this protein, HDFx, is approximately 35-40 KDa , larger than known defensin peptides and much smaller than the larger MW fibronectins and complement products; 2) we describe some of HDFx's physico-chemical characteristics; 3) approximately 80 % of HDFx's plasma biological activity is derived from macrophages; 4) about 15-20 % of its activity is derived from natural killer (NK) cells; 5) polymorphonuclear leukocytes are not a source of HDFx synthesis or release; 6) known stimulants of the RES-macrophage system (i.e., denatured human serum albumin, triolein, and choline chloride) effect phagocytic stimulation of macrophages and protection against endotoxins, trauma, and hemorrhage via synthesis and release of HDFx; 7) adaptation to lethal trauma is dependent on the biological activity of HDFx; and 8) repeated administration of purified HDFx to rats, over several months, does not produce any detectable pathologies. Lastly, the release of cytokines (i.e., IL-2,IL-6,IFN-gamma) from lymphocytes, after hemorrhage and trauma, at least in rodents, appears to be dependent on the available plasma levels of HDFx. Since it is present also in mice, guinea-pigs, and rabbits, we are tempted to speculate that HDFx could prove (if found in humans) to be useful against potential biothreats, new emerging diseases, high -risk surgical procedures, hospital-borne infections, and burn injuries, where the chances for superimposed bacterial infections present great risk.
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Differential expression pattern of genes encoding for anti-microbial peptides in the fetal membranes of patients with spontaneous preterm labor and intact membranes and those with preterm prelabor rupture of the membranes.
Erez O, Romero R, Tarca AL, Chaiworapongsa T, Kim YM, Than NG, Vaisbuch E, Draghici S, Tromp G
Perinatology Research Branch, NICHD, NIH, DHHS, Detroit, Michigan, USA.
J. Matern. Fetal. Neonatal. Med. 2009 Dec;22 (12):1103-15
Abstract
OBJECTIVE: Increased amniotic fluid concentrations of anti-microbial peptides, components of the innate immune system, have been reported in patients with preterm labor (PTL) with intact membranes and intra-amniotic infection and/or inflammation (IAI), as well as in patients with preterm prelabor rupture of the membranes (PPROM). This study was designed to confirm these results using a targeted approach, detecting DEFA1, DEFB1, GNLY, and S100A9 gene expression in the choriamniotic membranes in pregnancies complicated with PTL and intact membranes or PPROM, with and without histologic chorioamnionitis. STUDY DESIGN: Human fetal membranes were obtained from patients in the following groups: (1) PTL with intact membranes (n = 15); (2) PTL with intact membranes with histologic chorioamnionitis (n = 12); (3) PPROM (n = 17); and (4) PPROM with histologic chorioamnionitis (n = 21). The mRNA expression of alpha-defensin-1, beta-defensin-1, calgranulin B and granulysin in the fetal membranes was determined by qRT-PCR. RESULTS: (1) The expression of alpha-defensin-1 mRNA in the fetal membranes was higher in patients with PTL and intact membranes with histologic chorioamnionitis, than those without chorioamnionitis (19.4-fold, p < 0.001); (2) Among patients with histologic chorioamnionitis, patients with PTL and intact membranes had a higher alpha-defensin-1 mRNA expression than those with PPROM (5.5-fold, p = 0.003); (3) Histologic chorioamnionitis was associated with a higher calgranulin B mRNA expression in the chorioamniotic membranes of patients with both PTL and intact membranes (7.9-fold, p = 0.03) and PPROM (7.6-fold, p < 0.0001); (4) The expression of calgranulin B mRNA in the fetal membranes was higher in patients with PTL and intact membranes without histologic chorioamnionitis than in those with PPROM without histologic chorioamnionitis (2.7-fold, p = 0.03); (5) There were no differences in the expression of beta-defensin-1 and granulysin in the chorioamniotic membranes between the study groups even in the presence of histologic chorioamnioniotis. CONCLUSIONS: (1) Among patients with histologic chorioamnionitis, the mRNA expression of alpha-defensin-1 and calgranulin B in the fetal membranes of patients with PTL and intact membranes as well as that of calgranulin B in the fetal membranes of patients with PPROM is higher than in the membranes of those without histologic chorioamnionitis; (2) histologic chorioamnionitis is associated with differences in the pattern of alpha-defensin-1 mRNA expression in the fetal membranes in patients with PTL and intact membranes and those with PPROM.
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A Molecular Dynamics Study of Human Defensins HBD-1 and HNP-3 in Water.
Sharadadevi A, Nagaraj R
Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Uppal Road, Hyderabad 500 007, INDIA. nraj@ccmb.res.in.
J. Biomol. Struct. Dyn. 2010 Feb;27 (4):541-50
Abstract
Mammalian defensins are crucial components of the innate immune system. They are characterized by three disulfide bridges and exhibit broad spectrum antibacterial activity. The spacing between the cysteines and disulfide connectivities in the two classes of defensins, the alpha- and beta-forms, are different. The structural motif of 3 beta-strands appears to be conserved in alpha- and beta-defensins despite differences in disulfide connectivities and spacing between cysteines. In this study, Molecular Dynamics Simulations (MDS) have been carried out to study the conformational behavior of alpha- andbeta-defensins with and without disulfide bridges. Our results indicate that beta-strands in the C-terminal region of HBD-1 and HNP-3 do not unfold during the course of MDS. The segment adopting alpha-helix in HBD-1 unfolds early during the simulations. The backbone hydrogen bonds in HBD-1 and HNP-3 are broken during MDS. When the disulfide bonds are absent, the N-terminal beta- strand unfolds by 20 ns but beta-strands are observed in the C-terminal region of HNP-3. HBD-1, without disulfide bridges, unfolds to a greater extent during the course of the MDS. Examination of distances between sulfur atoms of cysteines without disulfide bridges during the simulations indicate that there is no specific preference for native disulfide bridges, which could be the reason for the experimental observation of non-native disulfide bridge formation during chemical synthesis of human alpha- and beta-defensins. Since defensins with non-native disulfide bridges are biologically active, the exact three dimensional structures observed for native HBD-1 and HNP-3 does not appear to be essential for exhibiting antibacterial activity.
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The bacterial defensin resistance protein MprF consists of separable domains for lipid lysinylation and antimicrobial peptide repulsion.
Ernst CM, Staubitz P, Mishra NN, Yang SJ, Hornig G, Kalbacher H, Bayer AS, Kraus D, Peschel A
Cellular and Molecular Microbiology Division, Interfaculty Institute of Microbiology and Infection Medicine, University of Tbingen, Tbingen, Germany.
PLoS Pathog. 2009 Nov;5 (11):e1000660
Abstract
Many bacterial pathogens achieve resistance to defensin-like cationic antimicrobial peptides (CAMPs) by the multiple peptide resistance factor (MprF) protein. MprF plays a crucial role in Staphylococcus aureus virulence and it is involved in resistance to the CAMP-like antibiotic daptomycin. MprF is a large membrane protein that modifies the anionic phospholipid phosphatidylglycerol with l-lysine, thereby diminishing the bacterial affinity for CAMPs. Its widespread occurrence recommends MprF as a target for novel antimicrobials, although the mode of action of MprF has remained incompletely understood. We demonstrate that the hydrophilic C-terminal domain and six of the fourteen proposed trans-membrane segments of MprF are sufficient for full-level lysyl-phosphatidylglycerol (Lys-PG) production and that several conserved amino acid positions in MprF are indispensable for Lys-PG production. Notably, Lys-PG production did not lead to efficient CAMP resistance and most of the Lys-PG remained in the inner leaflet of the cytoplasmic membrane when the large N-terminal hydrophobic domain of MprF was absent, indicating a crucial role of this protein part. The N-terminal domain alone did not confer CAMP resistance or repulsion of the cationic test protein cytochrome c. However, when the N-terminal domain was coexpressed with the Lys-PG synthase domain either in one protein or as two separate proteins, full-level CAMP resistance was achieved. Moreover, only coexpression of the two domains led to efficient Lys-PG translocation to the outer leaflet of the membrane and to full-level cytochrome c repulsion, indicating that the N-terminal domain facilitates the flipping of Lys-PG. Thus, MprF represents a new class of lipid-biosynthetic enzymes with two separable functional domains that synthesize Lys-PG and facilitate Lys-PG translocation. Our study unravels crucial details on the molecular basis of an important bacterial immune evasion mechanism and it may help to employ MprF as a target for new anti-virulence drugs.
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Pyrosequencing the Manduca sexta larval midgut transcriptome: messages for digestion, detoxification and defence.
Pauchet Y, Wilkinson P, Vogel H, Nelson DR, Reynolds SE, Heckel DG, Ffrench-Constant RH
School of Biosciences, University of Exeter, Cornwall campus, Penryn, UK.
Insect Mol Biol. 2010 Feb 1;19(1):61-75.
Abstract
The tobacco hornworm Manduca sexta is an important model for insect physiology but genomic and transcriptomic data are currently lacking. Following a recent pyrosequencing study generating immune related expressed sequence tags (ESTs), here we use this new technology to define the M. sexta larval midgut transcriptome. We generated over 387 000 midgut ESTs, using a combination of Sanger and 454 sequencing, and classified predicted proteins into those involved in digestion, detoxification and immunity. In many cases the depth of 454 pyrosequencing coverage allowed us to define the entire cDNA sequence of a particular gene. Many new M. sexta genes are described including up to 36 new cytochrome P450s, some of which have been implicated in the metabolism of host plant-derived nicotine. New lepidopteran gene families such as the beta-fructofuranosidases, previously thought to be restricted to Bombyx mori, are also described. An unexpectedly high number of ESTs were involved in immunity, for example 39 contigs encoding serpins, and the increasingly appreciated role of the midgut in insect immunity is discussed. Similar studies of other tissues will allow for a tissue by tissue description of the M. sexta transcriptome and will form an essential complimentary step on the road to genome sequencing and annotation.
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Peptide thioester synthesis through N-->S acyl-transfer: application to the synthesis of a beta-defensin.
Kang J, Reynolds NL, Tyrrell C, Dorin JR, Macmillan D
Department of Chemistry, University College London, 20 Gordon Street, London, UK WC1H 0AJ.
Org. Biomol. Chem. 2009 Dec;7 (23):4918-23
Abstract
Peptide thioesters readily prepared through N-->S acyl transfer of a specific C-terminal motif provide access to biologically active mini-proteins using native chemical ligation.
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Human gammadelta T cells produce the protease inhibitor and antimicrobial peptide elafin.
Marischen L, Wesch D, Schrder JM, Wiedow O, Kabelitz D
Institute of Immunology, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
Scand. J. Immunol. 2009 Dec;70 (6):547-52
Abstract
Human gammadelta T cells rapidly secrete pro-inflammatory cytokines in response to T cell receptor-dependent recognition of pyrophosphates produced by many bacteria and parasites. In further support of an important role of gammadelta T cells in the immune defence against infection, human gammadelta T cells have been shown to produce the antimicrobial peptide LL37/cathelicidin. In this study, we have investigated whether gammadelta T cells can produce additional antimicrobial peptides. To this end, we have screened human gammadelta T cell clones by RT-PCR for mRNA expression of a broad range of antimicrobial peptides. While alpha-defensins were absent and beta-defensins (HBD1) present only in rare gammadelta T cell clones, elafin mRNA was induced by supernatant of Pseudomonas aeruginosa grown under static conditions. Elafin is a protease inhibitor that also displays antimicrobial activity. Constitutive intracellular expression of elafin was demonstrated by flow cytometry and Western blot analysis. Furthermore, trappin-2 (pre-elafin) could be immunoprecipitated in cell lysates but also in the supernatant of gammadelta T cells stimulated by Ps. aeruginosa supernatant. Taken together, our studies reveal a novel effector function of gammadelta T cells which might be important for local immune defence.
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Defective Paneth Cell-Mediated Host Defense in Pediatric Ileal Crohn's Disease.
Perminow G, Beisner J, Koslowski M, Lyckander LG, Stange E, Vatn MH, Wehkamp J
Department of Pediatrics, Akershus University Hospital and Oslo University Hospital, Oslo, Norway.
Am J Gastroenterol. 2010 Feb;105(2):452-9.
Abstract
OBJECTIVES:Adult ileal Crohn's disease (CD) is characterized by a specific decrease in ileal Paneth cell alpha-defensins. In addition to NOD2, we previously identified a disturbance of the Wnt-signaling transcription factor TCF-4 as a major mechanism for this deficiency. The aim of this study was to evaluate human alpha-defensin-5 (HD-5) and TCF-4 in an independent cohort of pediatric CD patients.METHODS:Expression levels of HD-5 and TCF-4 mRNA were quantified by real-time PCR in biopsies from newly diagnosed untreated pediatric CD patients (<18 years, n=36) and age-matched symptomatic non-inflammatory bowel disease controls with a histologically normal gut (n=29). To assess the influence of current inflammation, mucosal interleukin-8 (IL-8) and fecal calprotectin levels were determined.RESULTS:Small intestinal HD-5 and TCF-4 mRNA were significantly reduced in pediatric ileal CD (L1+L3) (P=0.022 and P=0.0005, respectively) and were significantly correlated (r=0.499; P=0.0001). In ileal but not colonic CD, TCF-4 was also reduced in the colon (P=0.005). Importantly, both HD-5 and TCF-4 were independent of inflammation, as measured by IL-8 expression or fecal calprotectin. In contrast to the small intestine, colonic Paneth cell HD-5 mRNA was significantly elevated in colonic CD (L2) (P=0.026) and was correlated with fecal calprotectin levels (r=0.481; P=0.020).CONCLUSIONS:In this study, we describe a specific decrease in HD-5 and TCF-4 mRNA expression levels in children with ileal CD. In the small intestine, this decrease was independent of current inflammation, whereas inflammation seems to induce Paneth cell metaplasia in the colon. Our data extend the hypothesis of an important role of antimicrobial host defense in pediatric CD patients.Am J Gastroenterol advance online publication, 10 November 2009; doi:10.1038/ajg.2009.643.
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