Antimicrobial Peptides (Advances in Molecular and Cellular Biology Series)

Immune System and Its Relationships with Pathogens: Structure, Physiology, and Molecular Biology
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The antimicrobial activity includes especially strong antifungal effects. Because peptide antibiotics are host defense substances with antimicrobial activity as well as a mediator function, their expression is tightly regulated.


The regulation of antimicrobial peptides has been described in detail for murine, human, and bovine molecules. The expression of hBD-1 has been found to be constitutive [ 20 , 34 ]. In contrast, hBD-2 expression has been detected to be upregulated by infectious and inflammatory stimuli in cell cultures as well as in human studies. In human material, hBD-2 transcripts and peptide levels in the airways were upregulated during infection [ 35 ].

The mechanism of induction of the antimicrobial peptide and the nature of the corresponding receptors and signalling pathways are speculative at present. Airway epithelial cells express several molecules that qualify as receptors to detect infection or inflammation reviewed in [ 38 ]. It has been shown that these cells synthesize the receptor panel to detect bacterial LPS, including CD14 and Toll-like receptors 1—9 [ 39 ], and R Bals, unpublished data.

The airway epithelium is an immune organ with the capabilities of detecting microorganisms and inducing an inflammatory and host defense response, including the secretion of antimicrobial peptides as effector molecules. Antimicrobial peptides of the respiratory tract might be induced by different stimuli and signalling pathways, and could have different functions as effector molecules. This concept of a large family of antimicrobial peptides with differential functions against diverse classes of microorganisms has been demonstrated for the host defense system of Drosophila [ 40 ] and should also be applicable to humans.

The antimicrobial activity of peptide antibiotics was deduced from tests in vitro assaying purified substances against microorganisms. Antimicrobial peptides, including defensins, cathelicidins and histatins, have a broad spectrum of activity against Gram-positive and Gram-negative bacteria as well as against fungi and enveloped viruses. The minimal inhibitory concentrations of the peptides are in the range 0. Antimicrobial peptides show synergistic activity with other host defense molecules such as lysozyme and lactoferrin.

The microbicidal activity of defensins stems from the permeabilization of anionic lipid bilayers and the subsequent release of cellular contents and the destruction of the membrane's electrode potential Fig. Activities of antimicrobial peptides.

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As well as their antimicrobial function 1 , antimicrobial peptides have other potential roles in inflammation and infection 2,3. The mechanism of the antimicrobial activity is explained in the insert. After electrostatic interactions between the negatively charged bacterial wall and the positively charged peptides a , the peptide associates with the membranes, either by insertion as pores b or by forming carpet-like structures that lead to a destabilization of the membrane.

The sources 1 of antimicrobial peptides in the airways are epithelial cells and inflammatory cells. Defensins and LL have a feedback mediator function that targets these cell types 2,3 , influencing the release of mediators and other cellular processes such as proliferation and chemoattraction. The first step of the interaction between the cationic peptide and the anionic microbial cell membrane is thought to involve electrostatic attraction, which is inhibited by high concentrations of salt in the solution.

The second step is the permeabilization of the membrane. One mechanism of permeabilization is thought to involve the formation of ion pores. The existence of pores, their dimensions and electrical properties have been described for model bilayers and various cell types [ 41 , 42 ]. Additionally, defensin-related cell death has been related to interference with protein synthesis or DNA damage.

Functional studies on antimicrobial activity have primarily been restricted to experiments in vitro with purified components. In fact, the evidence that defensins actually contribute to innate immunity in vivo is largely indirect. In addition to their antimicrobial activity, defensins and cathelicidins can bind to lipopolysaccharide and inactivate the biological functions of this endotoxin. Bacterial resistance to antimicrobial peptides is a rare phenomenon.

Mechanisms that result in the development of resistance involve modifications of outer cell wall components, such as lipopolysaccharide [ 45 ], teichoic acids [ 46 ], or phosphoicholine [ 47 ], and the modulation of efflux pumps [ 48 ]. Beside their role as endogenous antibiotics, antimicrobial peptides have functions in inflammation, wound repair, and regulation of the adaptive immune system Fig.

Human neutrophil defensins have been described as being cytotoxic to various cell types [ 49 ], as inducing cytokine synthesis in airway epithelial cells [ 50 ], monocytes [ 51 ], and T lymphocytes [ 52 ], as increasing the release of SLPI from respiratory epithelial cells [ 53 ], and as decreasing intracellular glutathione concentration [ 54 ].

Further, they increase the binding of bacteria to epithelial cells [ 55 ] and induce the liberation of histamine from mast cells. On the basis of their activity in vitro , their patterns of expression and gene regulation, and their involvement in pathways of innate immunity, there is strong suggestive evidence that antimicrobial peptides serve as host defense substances not only by direct antimicrobial activity but also as mediators.

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Animal experiments with the use of a human bronchial xenograft model with the genetic depletion of hBD-1 by antisense oligonucleotides [ 17 ], overexpression of antimicrobial peptides in animal models of infection [ 30 ], or the above-mentioned experiments with matrilysin knockout mice [ 12 ] support this view. An assessment of the relative contribution of individual proteins or peptides to the host defense is difficult to accomplish.

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The concentrations of antimicrobial peptides and proteins at the site of action e. A functional analysis of purified peptides and proteins in vitro does not reflect the complexity of component interactions, such as synergism and antagonism between multiple substances. The story of cystic fibrosis CF research over the past decade has provided important lessons about the relation between a defect in an ion channel and a breach of the host defense system of the airways.

An obvious defect of the host defense system of the respiratory tract is evident from clinical studies and was evaluated in several models in vitro or ex vivo [ 17 , 59 ]. The link between the defect in ion transport and decreased host defense is less obvious and remains speculative at present reviewed in [ 60 ].

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Buy Antimicrobial Peptides [OP]: Discovery, Design and Novel Therapeutic Strategies Series: Advances in Molecular and Cellular Microbiology (Book 18). Part of the Advances in Experimental Medicine and Biology book series Antimicrobial Peptides of Multicellular Organisms: My Perspective Peptides ( SALPs) as Effective Inhibitors of Pathogen-Associated Molecular Patterns ( PAMPs).

Antimicrobial peptides might have a role in this pathogenesis, either by being inactivated by increased salt concentration in secretions of CF airways or by being absent from the ASF owing to alteration of the secretory apparatus caused by the dysfunctional CF transmembrane conductance regulator CFTR. Beside their host defense function during infections, the proinflammatory activity of antimicrobial peptides is likely to have negative consequences too. On the basis of the activities of antimicrobial peptides, it is obvious that these substances affect the inflammatory process Fig.

Owing to the lack of detailed knowledge of their functional spectrum in vivo , it is hard to decide which peptide antibiotic in which concentration results in a proinflammatory or anti-inflammatory activity. On the one hand, defensins attract inflammatory cells such as neutrophils, B-cells, and macrophages, and activate these and other cell types, including epithelial cells. Defensins might lead to an imbalance of the redox system by reducing glutathione levels in epithelial airway cells and might disturb the protease-antiprotease system by binding to proteinase inhibitor serpin family members.

On the other hand, defensins might also exhibit anti-inflammatory activities by induction of the secretion of IL [ 61 ] or SLPI [ 53 ], or by facilitating the binding of microorganisms to epithelia with subsequent clearance of the microorganisms by a bactericidal activity of the cell. It is also likely that antimicrobial peptides in the airway secretions modulate the cytokine profile of lymphocytes towards T helper type 1 or 2 cells. This could have a direct effect on the development of bronchial hyper-responsiveness. Additionally, defensins have been shown to release histamine from mast cells and might induce hyper-responsiveness by their cationic charge [ 62 ]. These experimental results do not draw a complete picture of the functions that antimicrobial peptides have in inflammatory or infectious disease; however, they indicate that they fulfil not only an epiphenomenal bystander role but are linked to the underlying pathogenetic processes.

The intriguing idea of developing antimicrobial peptides as innovative antibiotics has been followed up by several biotechnological companies. With the use of protein-biochemical methods and recombinant DNA technology, the structures of naturally occurring peptides serve as starting points for the development of new drugs. Several derivatives of antimicrobial peptides have been through the pharmaceutical process, including human phase I-III studies.

The use of human antimicrobial peptides as drugs is restricted so far by the still unknown biological function of these molecules and the high costs of the generation of sufficient amounts. On the basis of their functions that have been elucidated so far, antimicrobial peptides might not serve only as antibiotics, but also as modulators of inflammation or anti-LPS medication. Antimicrobial peptides have emerged as effector substances of the innate immune system involving activities not only as endogenous antibiotics but also as mediators of inflammation.

Several important topics will have to be addressed in the future:. The identification of novel antimicrobial peptides. It is likely that human families of antimicrobial peptides consist of multiple molecules. Progress in the Human Genome Project will also reveal ways of shortcutting conventional bioscreening procedures for the identification of host defense substances.

Epithelial antimicrobial peptides in host defense against infection

Analysis of the biologically relevant functions of antimicrobial peptides. Beside experiments in vitro that give the first molecular insight into the function of peptide antibiotics, a broader approach involving genetic animal models is necessary to interpret results in vitro in the context of a whole organism.

Evaluation of the function of antimicrobial peptides in airway and other diseases will provide insights into the corresponding pathogenesis.

Development of antimicrobial peptides as drugs. JavaScript is currently disabled, this site works much better if you enable JavaScript in your browser. Presents the latest findings on antimicrobial peptides Elucidates their mechanisms of antimicrobial action Examines AMP activities beyond antimicrobial action Discusses the progress made, and obstacles to, their clinical application see more benefits. Buy eBook. Buy Hardcover. FAQ Policy. About this book This book presents an overview of antimicrobial peptides AMPs , their mechanisms of antimicrobial action, other activities, and various problems that must still be overcome regarding their clinical application.

Show all. In various species, cystatins are implicated in several functions related to immune response, epidermal homeostasis, antigen presentation, and inflammation [ 83 , 84 , 85 ]. In mammals, cystatin C is involved in the defense against pathogen [ 86 ]. Currently, cystatin sequence has been found in ticks, from cDNA library obtained from salivary glands of Ixodes scapularis [ 82 , 87 , 88 , 89 , 90 ].

The cystatin sialostatin L obtained from I. Moreover, SI-alostatin L, during tick blood feeding, has an important role as anti-inflammatory and in the inhibition of cytotoxic T-cell proliferation, contributing to feeding and pathogen transmission. On the other hand, cystatin RNAi-mediated silencing assay demonstrated that Amblyomma americanum reduced the ability to feed and evade the host immune response [ 87 ].

Moreover, in hard tick R. However, a possible role of the cystatin in several tissues in ticks still remains unknown. In this regard, novel cystatins from midgut were described in Haemaphysalis longicornis that show inhibitory activity against cysteine proteases [ 90 ]. In this regard, some assays demonstrate that Babesis gibsoni LPS injection is capable to increase the expression in the midgut in adult and larval ticks.

The nitric oxide NO is an unstable radical, capable to act with a key factor in several physiological and pathological pathways, and it is synthesized by the nitric oxide synthase NOS [ 91 ]. In invertebrates, including ticks, NO is related with a cytotoxic action against pathogens from hemocytes, derivates to phagocyte process during microbial infection [ 92 ].

Currently, the gene that codified for NOS has been identified and cloned from the insects: Drosophila melanogaster, Anopheles stephensi, Anopheles gambiae , and Rhodnius prolixus , suggesting the NO activity is present in these arthropods [ 94 , 95 , 96 , 97 , 98 ]. Likewise, Litopenaeus vannamei shrimp is capable of producing nitric oxide, in response to Vibrio harveyi inoculation, derivates to NOS activity [ 93 ].

In ticks, the activity of eNOS enzyme was reported in Dermacentor variabilis salivary glands, and by in silico analysis, the presence of NOS gene sequence was demonstrated in Ixodes scapularis embryonated eggs [ 91 , ]. In hematophagous arthropods, blood ingestion is the determinant of survival. However, during feeding and digestion, several toxic molecules are produced, such as reactive nitrogen species RNOS and reactive oxygen species ROS [ ].

The protection against nitrosative and oxidative stress is carried out by detoxification agents, produced largely by the midgut epithelial cells. In many insects, enzymes such as peroxiredoxins, catalases, and many members of antioxidant peroxidase family function as antioxidant agents. However, in arthropods, as in many organisms, the microbial infections are capable to induce oxidative stress.

Antimicrobial Peptides

Interestingly, many arthropods have the capacity of enhancing ROS and RNOS against pathogen infection while simultaneously protecting their tissue cells with antioxidants. Moreover, the glutathione S-transferases GST family plays an important role during oxidative stress caused by pathogens, through detoxification enzyme reactions and, in turn, removing the formatted ROS and RNOS [ ]. In midgut from D. In ticks, other detoxification enzymes have been reported, such as glutaredoxins, glutathione peroxidases, phospholipid-hydroperoxidases, thioredoxins, and one superoxide dismutase [ , , ].

However, in ticks, the precise role in antimicrobial control of detoxification agents is still unclear. In arthropods, mechanical injury or the presence of foreign objects including pathogens results in melanin deposition around the damaged tissue or around the foreign object that in turn forms a capsule isolating the foreign particle.

Melanins are molecules produced in the hemolymph by different types of hemocytes.

The key enzyme for the melanization process is the phenol oxidase PO. The metabolic pathway is initiated by hydroxylation of phenylalanine to tyrosine, followed by a series of reactions, resulting in 5,6-indolquinones, synthesized to phenol quinones, and these quinones polymerize to form melanin.

The signaling pathway starts with a hemocyte prophenol oxidase enzyme PPO synthesis PO inactive form that results in the conversion of the PPO into the active form by serine protease cascade [ ]. The intermediary components of this pathway, such as semiquinones, ROS, and melanin, are all very toxic to pathogens [ ].

However, at the present, some studies in Amblyomma americanum, Dermacentor variabilis , and Ixodes scapularis ticks report the presence of genes involved in the PPO-PO pathway; however, the enzymatic activity has not been reported [ 29 ]. In the tick O. However, currently, the presence of PO in ticks is controversial.

The innate immune systems represent one aspect in a generalized response to several pathogens and are composed of individual factors. This variability has a particular behavior in each tick. The principal components are the hemolymph and hemocytes; however, they are not the only factors. The response depends on the pathogen type, tissue, sex, life cycle phases, and tick species, among others.

In this regard, innate immunity starts when membrane receptors recognize component characteristics of bacterial cell surfaces as peptidoglycans or lipoteichoic acid, which leads to synthesis of antimicrobial peptides AMPs as defensins, cecropins, attacins, and lysozyme that disrupt the cell wall structure, leading to cell death [ 2 ]. Other components in the fungi cell wall are betaglucans and beta mannose or 2-ketodeoxyoctonate LPS, characteristic of Gram-negative bacteria, leading to soluble lectin synthesis [ 2 ].

These cell wall components and foreign molecular structures are known as pathogen-associated molecular patterns PAMPs [ 2 , ]. In sexual term, transcriptome analysis in the male reproductive structures of this tick showed seven contigs related to a dual reproductive and immune response [ ].

However, the complete role of these peptides is still unknown, but their presence in seminal fluids suggests a role in the clearing of bacteria introduced during mating [ ]. In the tissues, the immune response includes several factors such as AMPs, peritrophic membrane, proteases, and protease inhibitors, lectins, detoxificant proteins, and oxidative stress [ 3 ].

Transcriptome analyses in D. Moreover, transcriptome analyses of tick salivary glands found AMPs, proteases, and protease inhibitors related to innate immune response [ , , ]. The synganglion transcriptome of D. To identify the pathogen type, the hemocyte cells need to be activated, using specific receptors that result in a specific signaling pathway [ ].

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On the other hand, among the invertebrates, the insects have received most attention, compared to arachnids. All invertebrates have an immune system, composed of both humoral and cellular response that results as effective defense to different pathogen attack. Large-scale manufacture of peptide therapeutics by chemical synthesis. Serpins may be found in plasma hemolymph and small cytoplasm granules [ 76 ]; however, in R. Article Google Scholar

The fruit fly D. In Drosophila model, the fungal pathogens and Gram-positive bacteria activate the Toll cascade, which is composed of different Toll-like receptors TLRs capable of recognizing diverse types of PAMPs [ 2 , , , ]. After pathogen recognition, intermediate effectors such as myeloid differentiation factor 88 MyDD88 , Tube, and Pelle are activated followed by activation of transcription factor Dorsal homolog of NF-kB and Dorsal-related immunity factor Dif that translocates into the nucleus and regulates the AMP synthesis [ ].

From the Imd pathway, Dredd, Caspar, and Relish have been found. Recently, the RNA interference RNAi pathway has been described that regulates the immune system in arthropods including ticks. This process is crucial in the innate response to viruses that infect and are transmitted by ticks [ ].

In Drosophila , the RNAi mechanism is related to a virus penetration and regulation of innate immune response in the midgut. The RNAi pathway in ticks is unknown; however, its components are described in some ticks [ ], as RNAi has been used to silence genes involved in several mechanisms, suggesting that RNAi pathway is active in some tick species, which would explain the different capacity of ticks to transfer several viruses [ ]. Advances in gene identification and expression in tick tissues are being achieved by the use of expressed sequence tag EST.

The EST analyses correspond to partial sequence of acid nucleic from different random clones included in a cDNA library, obtained from the interest tissue mRNA [ ]. The analyses include the translation of EST sequence to amino acid sequence and compared with a public genome database. Interestingly, salivary gland genes of ticks show differential expression during blood ingestion, suggesting that processes are involved in homeostasis, tissue remodeling, immune defenses, angiogenesis, and the facilitation of the transmissible pathogen establishment [ ].

The EST library from unfed hard tick larvae of R. On the other hand, R. A meta-analysis was done, which describes the transcripts from salivary glands of several species of ticks, including the salivary gland transcripts from unfed male of I. All tick groups analyzed were from different ages and different feeding times, or unfed. Interestingly, transposable elements were found in 0.

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In the exclusive case of females, differential gene expressions of transcripts were showed. The unfed female showed no change in expression, while fed female showed the highest number of overexpressed variants. All biologically relevant genes are likely redundant and encode antigenic variants, in turn identifying gene families involved in hemostatic deregulation.

Other identified genes include cystatins, lectins, cysteine and glycine-rich peptides, and protease inhibitors [ , , , , ]. A very important finding in R. In this regard, no significant differences were found in the expressed transcripts of ESTs from salivary glands of R. Currently, the genome sequence of several arthropod vectors including ticks is under development, and partial results of I. It is remarkable that cattle tick genome is more than twice the size of the human genome that contains 3—2 Gbp [ ]; furthermore, the cattle tick genomes are larger than most insect species genomes.

The ever-increasing knowledge of the immune system biology of vertebrates represents an important foundation in the research and development of advanced vaccines, new drugs, as well as the search for new targets for chemical or drug treatments of infectious diseases, which have contributed to the control of several human and livestock pathogens. Unfortunately, the immune system of invertebrates, especially, arthropod vectors like ticks, and their relationship with their pathogens, and infectious diseases they transmit, have been little explored.

In this regard, the knowledge of mechanisms, molecules, and cells, as well as the regulation of immune response signaling pathways, represents an advance in designing control strategies that will contribute to improve livestock production and animal health. Now, all transcriptome analyses and whole-genome sequencing represent powerful methodologies for understanding the biology, evolutionary relationships, and host-vector-pathogen interaction.

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