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Genomics information relating to human body lice is surprisingly scarce, and this has constrained studies of their physiology, immunology and vector biology. To identify novel body louse genes, we used engorged adult lice to generate a cDNA library. Initially, 1152 clones were screened for inserts, edited for removal of vector sequences and base pairs of poor quality, and viewed for splicing variations, gene families and polymorphism. Computational methods identified 506 inferred open reading frames including the first predicted louse defensin. The inferred defensin aligns well with other insect defensins and has highly conserved cysteine residues, as are known for other defensin sequences. Two cysteine and five serine proteinases were categorized according to their inferred catalytic sites. We also discovered seven putative ubiquitin-pathway genes and four iron metabolizing deduced enzymes. Finally, glutathione-S-transferases and cytochrome P450 genes were among the detoxification enzymes found. Results from this first systematic effort to discover human body louse genes should promote further studies in Phthiraptera and lice.
Insect Biochem Mol Biol 2003 Nov
PMID:Transcriptome identification of putative genes involved in protein catabolism and innate immune response in human body louse (Pediculicidae: Pediculus humanus). 1456 64

Fat body and hemocytes play a central role in cellular and humoral responses for systemic infections in invertebrates, similar to the mammalian liver and blood cells. Epithelial surfaces, in particular the midgut, participate in the initial local immune responses in order to aid in the generation of the terminal cytotoxic molecules that mediate non-self recognition. Here, we describe for the first time the immune responses of a cluster of cells at the foregut/midgut junction--known as proventriculus (cardia) in the medically and agriculturally important insect, tsetse fly (Diptera: Glossinidae). We provide evidence for the transcriptional induction of the antimicrobial peptides attacin and defensin as well as for the reactive nitrogen intermediate (RNI) nitric oxide synthase (NOS) upon microbial challenge by either microinjection or feeding. Proventriculus from immune challenged flies also has higher NOS and nitric oxide (NO) activities as well as increased levels of the reactive oxygen intermediate (ROI), hydrogen peroxide (H2O2). In several vector pathogen systems, including tsetse flies and African trypanosomes, stimulation of systemic responses prior to pathogen acquisition has been shown to reduce disease transmission. Furthermore, the induction of systemic immune responses has been documented while pathogens are still differentiating within the midgut environment. While evidence for a close molecular communication between the local and systemic responses is accumulating, the molecular signals that mediate these interactions are at present unknown. Reactive intermediates such as NO or H2O2 may function as immunological signals for mediating the molecular communication between the different insect compartments. We discuss the putative role of the proventriculus in invertebrate immunity and specifically speculate on its significance for trypanosome transmission in tsetse.
Insect Biochem Mol Biol 2003 Nov
PMID:Proventriculus (cardia) plays a crucial role in immunity in tsetse fly (Diptera: Glossinidiae). 1456 66

beta-Defensin genes encode broad spectrum antimicrobial cationic peptides. We have analysed the largest murine and human clusters of these genes, which localise to mouse and human chromosome 8. Using hidden Markov models, we identified novel mouse and human beta-defensin genes. We subsequently found full-length expressed transcripts for these novel genes. Expression in the mouse was high in brain and reproductive tissues. Fourteen murine beta-defensins could be grouped into two clear sub-groups by virtue of their position and high signal sequence (exon 1 encoded) identity. In contrast, there was a very low level of sequence conservation in the exon 2 region encoding the mature antimicrobial peptide. Evolutionary analysis revealed strong evidence that following gene duplication, exon 1 and surrounding non-coding DNA show little divergence within subfamilies. The focus for rapid sequence divergence is localised in the DNA encoding the mature peptide and this is driven by accelerated positive selection. In the human we also conclude that the locus has evolved by successive rounds of duplication followed by substantial divergence involving positive selection, to produce a diverse cluster of paralogous genes prior to human-baboon divergence. This mechanism of adaptive evolution is consistent with the role of this gene family as defence against bacterial pathogens. In order to look at function of these rapidly evolving genes, we characterised one of the novel mouse beta-defensin genes. This gene deviates from the canonical six cysteine motif present in the mature functional peptide of all other beta defensins. This defensin related gene (Defr1) is most highly expressed in testis and heart and the genomic organisation is highly similar to Defb3-6. A synthetic Defr1 peptide was shown to exist as a dimer and yet displayed both antimicrobial and chemotactic activity. The antimicrobial activity of Defr1 against S. aureus, E. coli and B. cepacia was found to be reduced in raised concentration of NaCl, but its action against P. aeruginosa was independent of NaCl concentration. These data have major implications on the structure and functions of these important host defence molecules.
Mol Immunol 2003 Nov
PMID:Rapid sequence divergence in mammalian beta-defensins by adaptive evolution. 1456 87

Evidence for the central role that intestinal beta-defensins play in maintaining gut health continues to accumulate within the literature. Two epithelially-derived enteric beta-defensins, hBD1 and hBD2, have been identified thus far and the following chapter reviews our current understanding of how the expression and secretion of these endogenous antimicrobial, chemotactic and adjuvant peptides is regulated within the context of the most microbe-rich of mucosal environments, the gastrointestinal tract. The agonists and microbial moieties identified as being responsible for the direct receptor-mediated induction of enteric epithelial beta-defensins, the signaling and nuclear events that are triggered as a consequence and which drive defensin gene transcription, the potential antimicrobial and immunomodulatory consequences of beta-defensin release within the luminal and mucosal aspects of the alimentary tract thereafter and the validity of animal models for the study of these key immune effector molecules in vivo are discussed. These significant and recent discoveries have provided much in the way of momentum for the pace with which this exciting and dynamic area of mucosal immunology research continues to move forward.
Mol Immunol 2003 Nov
PMID:Regulation of expression of beta-defensins: endogenous enteric peptide antibiotics. 1456 90

The human intestinal tract is constantly exposed to an enormous indigenous bacterial flora. It has recently been recognised that antimicrobial peptides of the defensin family likely play a role in protection against microbial invasion at a variety of mucosal epithelial surfaces, including that of the intestinal tract. To date, six alpha-defensins have been identified in humans. Four of these, designated Human Neutrophil Peptides (HNP) 1,2,3 and 4, form part of the armoury of neutrophils, where they participate in systemic innate immunity. The remaining two, Human Defensin (HD) 5 and 6, are expressed in intestinal Paneth cells, and probably contribute to innate defense of the GI mucosal surface. Murine intestinal alpha-defensins (the 'cryptdins') have been extensively studied, but less is known about their human counterparts. The putative mature HD-5 was chemically synthesised and used to raise polyclonal antiserum. Using this anti-HD-5 antiserum, the expression of HD-5 in normal and inflamed intestinal mucosal samples was studied using immunohistochemistry. HD-5 is expressed in Paneth cells and also in some villous epithelial cells in normal duodenum, jejunum and ileum. HD-5 is not expressed in the normal stomach or colon. In cases of gastritis, colonic Crohn's disease and ulcerative colitis, HD-5 is expressed in metaplastic Paneth cells. Utilizing the anti-HD-5 antiserum, native HD-5 was isolated and purified from acid extracts of normal terminal ileal mucosal epithelial cells using cation exchange and reverse phase high pressure liquid chromatography. The purified peptide was characterised using N-terminal amino acid sequence and mass spectral analysis. Antimicrobial activity of the peptide was assessed using a sensitive colony forming unit antimicrobial assay. HD-5 is stored in the predicted precursor form in Paneth cells, and this form does not have antimicrobial activity against a defensin sensitive Salmonella. Potential processing of the precursor form of the HD-5 peptide into a mature active form, was studied by stimulating Paneth cell granule secretion in freshly isolated, cultured ileal crypts. A truncated form of the precursor form of HD-5, but not the predicted mature form, was present in the culture supernatant. Recently published studies suggest that further processing of the molecule occurs in vivo. The expression of HNP 1-3 in the normal intestinal mucosa and in cases of inflammatory bowel disease was studied. In the normal intestinal mucosa, HNP are expressed only in sparse lamina propria neutrophils, and not in Paneth cells. In cases of active ulcerative colitis and Crohn's disease, scattered surface epithelial cells, as well as numerous lamina propria neutrophils, were seen to express HNP. In conclusion, HD-5 is stored only in its precursor form in normal ileal Paneth cells, and partial processing of the peptide to a mature form occurs during and/or after secretion. In inflammatory bowel disease, HD-5 is expressed in metaplastic Paneth cells in the colon, and HNP is expressed by some surface epithelial cells. These studies suggest that antimicrobial defensin peptides may be important in protection of the host against microbial invasion in states of intestinal inflammation.
Mol Immunol 2003 Nov
PMID:Alpha-defensins in the gastrointestinal tract. 1456 93

Defensins are thought to play a major role in the defence of small intestinal crypts against colonisation by potential pathogens. In humans two alpha-defensins, HD5 and HD6 and two beta-defensins, hBD1 and hBD2, probably contribute to the antimicrobial barrier, but there are no data to indicate how the expression of these defensin genes might vary in individuals and in populations. To begin to address this question we developed a competitive reverse transcriptase polymerase chain reaction (RT-PCR) assay to quantify HD5 and HD6 mRNA and used it to measure transcripts in small intestinal biopsy tissue from adults living in London, UK, or in Lusaka, Zambia. We also measured alpha- and beta-defensin mRNA in biopsies collected in London from different regions of the small intestine. Jejunal biopsies (n=169) from 83 adults in Lusaka contained approximately one order of magnitude less HD5 and HD6 mRNA than biopsies (n=33) obtained from 27 adults in London. HD5 and HD6 transcript levels were high throughout duodenum, jejunum and ileum. hBD1 and hBD2 mRNA were detected in some, but not all, biopsies from normal small intestine. These data suggest that alpha-defensin expression is down-regulated in tropical populations, and that there are distinct pathways regulating transcription of alpha- and beta-defensins.
Mol Immunol 2003 Nov
PMID:Intestinal defensin gene expression in human populations. 1456 94

An insect defensin, named Galleria defensin, was purified from the larval haemolymph of Galleria mellonella immunized against E. coli. The peptide was composed of forty-three amino acid residues containing six cysteines that might be engaged in intramolecular disulphide bridges. The primary structure of Galleria defensin shared about 90.7% identity to that of heliomicin, which was an insect defensin isolated from Heliothis virescens. The full-length cDNA encoding Galleria defensin was cloned from the fat body of the immunized G. mellonella larvae. Northern blot analysis revealed that Galleria defensin was expressed not only in the fat body but also in the midgut against invading bacteria into haemocoel. This is the first report presenting cDNA and expression of an insect defensin in the lepidopteran species.
Insect Mol Biol 2004 Feb
PMID:Purification, cDNA cloning and expression of an insect defensin from the great wax moth, Galleria mellonella. 1472 68

In order to obtain information on genes specifically expressed in the ectomycorrhizal symbiosis, 3,555 expressed sequence tags (ESTs) were analyzed from a cDNA library constructed from ectomycorrhiza formed between the basidiomycete Paxillus involutus and birch (Betula pendula). cDNA libraries from saprophytically growing fungus (3,964 ESTs) and from axenic plants (2,532 ESTs) were analyzed in parallel. By clustering all the EST obtained, a nonredundant set of 2,284 unique transcripts of either fungal or plant origin were identified. The expression pattern of these genes was analyzed using cDNA microarrays. The analyses showed that the plant and fungus responded to the symbiosis by altering the expression levels of a number of enzymes involved in carbon metabolism. Several plant transcripts with sequence similarities to genes encoding enzymes in the tricarboxylic cycle and electron transport chain were down regulated as compared with the levels in free-living roots. In the fungal partner, a number of genes encoding enzymes in the lipid and secondary metabolism were down regulated in mycorrhiza as compared with the saprophytically growing mycelium. A substantial number of the ESTs analyzed displayed significant sequence similarities to proteins involved in biotic stress responses, but only a few of them showed differential expression in the mycorrhizal tissue, including plant and fungal metallothioneins and a plant defensin homologue. Several of the genes that were differentially expressed in the mycorrhizal root tissue displayed sequence similarity to genes that are known to regulate growth and development of plant roots and fungal hyphae, including transcription factors and Rho-like GTPases.
Mol Plant Microbe Interact 2004 Feb
PMID:Transcriptional responses of Paxillus involutus and Betula pendula during formation of ectomycorrhizal root tissue. 1496 34

Defensin is the predominant inducible immune peptide in Aedes aegypti. In spite of its activity against Gram-positive bacteria in vitro, defensin expression is detected in mosquitoes inoculated with Gram-positive or negative bacteria, or with filarial worms. Defensin transcription and expression are dependent upon bacterial dose; however, translation is inconsistent with transcription because peptide is detectable only in mosquitoes inoculated with large doses. In vitro translation assays provide further evidence for post-transcriptional regulation of defensin. Clearance assays show that a majority of bacteria are cleared before defensin is detected. In gene silencing experiments, no significant difference in mortality was observed between defensin-deficient and control mosquitoes after bacteria inoculation. These studies suggest that defensin may have an alternative function in mosquito immunity.
Insect Mol Biol 2004 Apr
PMID:Reassessing the role of defensin in the innate immune response of the mosquito, Aedes aegypti. 1505 59

Antimicrobial peptides (AMPs) are essential components of host defences against infectious microrganisms. In chelicerate organisms they have been implicated in three alternative defensive systems: one is defined by the immediate up-regulation of genes encoding AMPs, another is characterized by the inducible systemic release of AMPs from cellular reservoirs and the third alternative is the systemic constitutive production of AMPs. In this work we used a differential high-performance liquid chromatography and mass spectrometry approach to show that septic injury elicits an immune response in the haemolymph of the Mexican scorpion Centruroides limpidus limpidus. We isolated several haemolymph components, one of which was characterized extensively (amino acid sequence, disulphide pairing, cDNA and genomic clones) and demonstrated to be a novel member of the invertebrate defensin family and consequently named C. limpidus limpidus defensin-like peptide (Cll-dlp). This peptide accumulates in the haemolymph in response to septic injury, independently of transcriptional regulation.
Cell Mol Life Sci 2004 Jun
PMID:Antimicrobial peptide induction in the haemolymph of the Mexican scorpion Centruroides limpidus limpidus in response to septic injury. 1519 74


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