抗菌肽在宿主防御中作用

抗菌肽广泛地存在于自然界中,其中许多抗菌肽具有直接抗微生物活性,能作用于G-、 G+细菌、真菌、寄生虫甚至是包膜病毒,并且在宿主先天免疫和适应性反应中有重要的调节作用。近来,越来越多的证据表明抗菌肽是有效的免疫辅助因子,能够与其他的众多免疫效应子协同作用,从而起始适应性免疫,促进伤口愈合,抑制前炎症反应以及诱导和调节细胞因子和趋化因子的产生。另外,随着抗菌肽作用机理逐渐被揭开,将这些内源性肽及其衍生物制成抗感染治疗药剂将会有广阔的应用前景。     

The role of antimicrobial peptides in cardiovascular physiology and disease

Antimicrobial peptides are natural peptide antibiotics, existing ubiquitously in both plant and animal kingdoms. They exhibit broad-spectrum antimicrobial activity and play an important role in host defense against invading microbes. Recently, these peptides have been shown to possess activities unrelated to direct microbial killing and be involved in the complex network of immune responses and inflammation. Thus, their role has now broadened beyond that of endogenous antibiotics. Because of their wide involvement in inflammatory response and the emerging role of inflammation in atherosclerosis, antimicrobial peptides have been proposed to represent an important link between inflammation and the pathogenesis of atherosclerotic cardiovascular diseases. This review highlights recent findings that support a role of these peptides in cardiovascular physiology and disease.     

Defensins in innate immunity

The innate immune system is the first line of defense against many common microorganisms, which can initiate adaptive immune responses to provide increased protection against subsequent re-infection by the same pathogen. As a major family of antimicrobial peptides, defensins are widely expressed in a variety of epithelial cells and sometimes in leukocytes, playing an important role in the innate immune system due to their antimicrobial, chemotactic and regulatory activities. This review introduces their structure, classification, distribution, synthesis, and focuses on their biological activities and mechanisms, as well as clinical relevance. These studies of defensins in the innate immune system have implications for the prevention and treatment of a variety of infectious diseases, including bacterial ocular disease.     

宿主防御肽抗病毒感染机制研究进展

宿主防御肽是一类广泛存在于脊椎动物的小分子多肽,具有广谱的抗菌活性以及抗炎、细胞趋化、促进血管生成和修复损伤等免疫调节功能。以往的研究多集中在宿主防御肽抗细菌和真菌感染的研究上。近年来大量研究发现,宿主防御肽也具有广泛的抗病毒活性,在临床各类病毒病的预防和治疗上具有潜在的应用前景。本文围绕宿主防御肽直接杀伤病毒、调节病毒感染过程和参与宿主抗病毒天然免疫调节这3个方面的作用机制进行综述,为宿主防御肽抗病毒相关研究和相关抗病毒生物药物的研发提供参考和借鉴。     

Macrophages acquire neutrophil granules for antimicrobial activity against intracellular pathogens

A key target of many intracellular pathogens is the macrophage. Although macrophages can generate antimicrobial activity, neutrophils have been shown to have a key role in host defense, presumably by their preformed granules containing antimicrobial agents. Yet the mechanism by which neutrophils can mediate antimicrobial activity against intracellular pathogens such as Mycobacterium tuberculosis has been a long-standing enigma. We demonstrate that apoptotic neutrophils and purified granules inhibit the growth of extracellular mycobacteria. Phagocytosis of apoptotic neutrophils by macrophages results in decreased viability of intracellular M. tuberculosis. Concomitant with uptake of apoptotic neutrophils, granule contents traffic to early endosomes, and colocalize with mycobacteria. Uptake of purified granules alone decreased growth of intracellular mycobacteria. Therefore, the transfer of antimicrobial peptides from neutrophils to macrophages provides a cooperative defense strategy between innate immune cells against intracellular pathogens and may complement other pathways that involve delivery of antimicrobial peptides to macrophages.     

Staphylococcal resistance to antimicrobial peptides of mammalian and bacterial origin

Antimicrobial host defense peptides, such as defensins, protegrins, and platelet microbicidal proteins are deployed by mammalian skin, epithelia, phagocytes, and platelets in response to Staphylococcus aureus infection. In addition, staphylococcal products with similar structures and activities, called bacteriocins, inhibit competing microorganisms. Staphylococci have developed resistance mechanisms, which are either highly specific for certain host defense peptides or bacteriocins or which broadly protect against a range of cationic antimicrobial peptides. Experimental infection models can be used to study the molecular mechanisms of antimicrobial peptides, the peptide resistance strategies of S. aureus, and the therapeutic potential of peptides in staphylococcal diseases.     

鲎源抗菌肽的研究及其潜在应用价值

鲎血细胞来源的抗菌肽,在鲎天然免疫中起至关重要的作用,它对外源病原菌具有抗性作用,降低了外源病原菌对鲎活体的致病性,增强了鲎的天然免疫能力。鲎源抗菌肽有一些不同于其他来源的抗菌肽的优势,对鲎源抗菌肽的研究有很重要的实用意义。概述了鲎源抗菌肽的性质、分子结构、基因序列及其制备,并对它们的潜在应用价值进行了论述。     

Antibiotic peptides from higher eukaryotes: biology and applications.

Gene-encoded antibiotic peptides are increasingly being recognized as effector molecules of host defense in plants and animals. Studies of antimicrobial peptides are providing new insights into the dynamic interactions between microbes and their hosts, and are generating new paradigms for the pathogenesis and treatment of diseases. Because antimicrobial peptides of higher eukaryotes differ structurally from conventional antibiotics produced by bacteria and fungi, they offer novel templates for pharmaceutical compounds that could be effective against increasingly resistant microbes.     

Medicinal signaling cells: A potential antimicrobial drug store

Medicinal signaling cells (MSCs) are multipotent cells derived from mammalian bone marrow and periosteum that can be extended in culture. They can keep their ability in vitro to form a variety of mesodermal phenotypes and tissues. Over recent years, there has been great attention over MSCs since they can impact the organ transplantation as well as autoimmune and bacterial diseases. MSCs can secrete different bioactive factors such as growth factors, antimicrobial peptides/proteins and cytokines that can suppress the immune system and prevent infection via direct and indirect mechanisms. Moreover, MSCs are able to increase bacterial clearance in sepsis models by producing antimicrobial peptides such as defensins, cathelicidins, lipocalin and hepcidin. It is the aim of the present review to focus on the antibacterial effector functions of MSCs and their mechanisms of action against the pathogenic microbes.     

Role of antimicrobial peptides in host defense against mycobacterial infections

Worldwide, tuberculosis remains the most important infectious disease causing morbidity and death. Currently, at least one-third of the world's population is infected with Mycobacterium tuberculosis. In addition, the World Health Organization estimates that about 8-10 million new tuberculosis cases occur annually worldwide and this incidence is currently increasing. Moreover, multidrug-resistant tuberculosis has been increasing in incidence in many areas during the past decade. These situations underscore the importance of the development of new therapeutic agents against mycobacterial infectious diseases. In this article, it is review current progress in the understanding of antimicrobial peptides as potential candidates to develop an alternative/adjunct therapeutic strategy against tuberculosis. This immunoadjunctive therapy might be evaluated in the context of possible drug resistance. This review also summarizes the knowledge about the functions of antimicrobial peptides in the pulmonary innate host defense system and their role in mycobacterial infection, and at the same time outlines recent advances in our understanding of the combined effect of antimicrobial peptides and anti-tuberculosis drugs against intracellular mycobacteria. A concerted effort should now focus on the clinical application of antimicrobial peptides for their practical use.     

Correlation between simulated physicochemical properties and hemolycity of protegrin-like antimicrobial peptides: predicting experimental toxicity

The therapeutic, antibiotic potential of antimicrobial peptides can be prohibitively diminished because of the cytotoxicity and hemolytic profiles they exhibit. Quantifying and predicting antimicrobial peptide toxicity against host cells is thus an important goal of AMP related research. In this work, we present quantitative structure activity relationships for toxicity of protegrin-like antimicrobial peptides against human cells (epithelial and red blood cells) based on physicochemical properties, such as interaction energies and radius of gyration, calculated from molecular dynamics simulations of the peptides in aqueous solvent. The hypothesis is that physicochemical properties of peptides, as manifest by their structure and interactions in a solvent and as captured by atomistic simulations, are responsible for their toxicity against human cells. Protegrins are beta-hairpin peptides with high activity against a wide variety of microbial species, but in their native state are toxic to human cells. Sixty peptides with experimentally determined toxicities were used to develop the models. We test the resulting relationships to determine their ability to predict the toxicity of several protegrin-like peptides. The developed QSARs provide insight into the mechanism of cytotoxic action of antimicrobial peptides. In a subsequent blind test, the QSAR correctly ranked four of five protegrin analogues newly synthesized and tested for toxicity.     

The role of natural antimicrobial peptides during infection and chronic inflammation

Natural antimicrobial peptides (AMPs), a family of small polypeptides that are produced by constitutive or inducible expression in organisms, are integral components of the host innate immune system. In addition to their broad-spectrum antibacterial activity, natural AMPs also have many biological activities against fungi, viruses and parasites. Natural AMPs exert multiple immunomodulatory roles that may predominate under physiological conditions where they lose their microbicidal properties in serum and tissue environments. Increased drug resistance among microorganisms is occurring far more quickly than the discovery of new antibiotics. Natural AMPs have shown promise as ‘next generation antibiotics’ due to their broad-spectrum curative effects, low toxicity, the fact that they are not residual in animals, and the low rates of resistance exhibited by many pathogens. Many types of synthetic AMPs are currently being tested in clinical trials for the prevention and treatment of various diseases such as chemotherapy-associated infections, diabetic foot ulcers, catheter-related infections, and other conditions. Here, we provide an overview of the types and functions of natural AMPs and their role in combating microorganisms and different infectious and inflammatory diseases.     

Antimicrobial activity of marine sponge Clathria indica (Dendy, 1889)

Sponges are sessile filter feeders that have developed efficient defense mechanisms against foreign invaders such as viruses, bacteria or eukaryotic organisms. Antimicrobial peptides are known as major components of the innate immune defense system in marine invertebrates. The aim of the present work was to study the antimicrobial properties of the Indian sponge Clathria indica with special reference to the identification of antimicrobial peptides. Crude methanolic extract and its chloroform, n-butanol and aqueous fractions were tested against 16 human pathogens which include eleven bacteria with four of them being multidrug resistant and five pathogenic fungi. All fractions showed effective antibacterial activity against common and multidrug-resistant Salmonella typhi and antifungal activity against C. albicans and C. neoformans. However, they were ineffective against Escherichia coli, Pseudomonas aeruginosa, Streptococcus pyogenes and Staphylococcus aureus. Chloroform fraction being the most potent among the fractions tested on chemical investigation was indicative of the presence of peptides as evidenced by ninhydrin positive spots on TLC and presence of peptide bonds by NMR. Its ESI-MS showed presence of several peptides in the range of m/z 850 to 980. Structure of three peptides has been tentatively assigned by ESI-MS/MS or tandem mass analysis, on the basis of the amino acid sequence established. The results clearly show that the sponge C. indica represent an interesting source of marine invertebrates-derived antimicrobial peptides in the development of new strategies to treat various infectious diseases.     

The Presence of Arginine in the Pro-Arg-Pro Motif Augments the Lethality of Proline Rich Antimicrobial Peptides of Insect Source

Antimicrobial peptides are emerging as alternate drug candidates over couple of decades. The diversity exists in amino acid sequence, conformation and mechanism of action of these peptides. Cationic antimicrobial peptides constitute major class which is further classified depending on abundance of amino acid. Insect originated cationic proline rich antimicrobial peptides do not destabilize bacterial cell membrane but have intracellular targets. Some of the peptides belonging to proline rich class such as Apidaecins and Drosocin have unique tripeptide, Pro-Arg-Pro motif which is absent in Formaecin I of same group. Earlier we have designed a non-glycosylated analog of Formaecin I which contains a Pro-Lys-Pro motif. In this report, we have shown that substitution of lysine to arginine in Pro-Lys-Pro motif increases lethal action of this peptide against all the tested bacterial strains without affecting its structural, cytotoxic and membrane permeabilization properties. Importance of arginine in Pro-Arg-Pro motif is reemphasized when substitution of arginine to lysine in Pro-Arg-Pro, tripeptide sequence of Apidaecin and Drosocin results into decrease in their activity. Maintaining overall charge, this substitution indicates the role of arginine beyond providing cationicity.     

Cell Wall-active Bacteriocins and Their Applications Beyond Antibiotic Activity

Microorganisms synthesize several compounds with antimicrobial activity in order to compete or defend themselves against others and ensure their survival. In this line, the cell wall is a major protective barrier whose integrity is essential for many vital bacterial processes. Probably for this reason, it represents a ??hot spot?? as a target for many antibiotics and antimicrobial peptides such as bacteriocins. Bacteriocins have largely been recognized by their pore-forming ability that collapses the selective permeability of the cytoplasmic membrane. However, in the last few years, many bacteriocins have been shown to inhibit cell wall biosyntheis alone, or in a concerted action with pore formation like nisin. Examples of cell wall-active bacteriocins are found in both Gram-negative and Gram-positive bacteria and include a wide diversity of structures such as nisin-like and mersacidin-like lipid II-binding bacteriocins, two-peptide lantibiotics, and non-modified bacteriocins. In this review, we summarize the current knowledge on these antimicrobial peptides as well as the role, composition, and biosynthesis of the bacterial cell wall as their target. Moreover, even though bacteriocins have been a matter of interest as natural food antimicrobials, we propose them as suitable tools to provide new means to improve biotechnologically relevant microorganisms.     

Structural congruence among membrane-active host defense polypeptides of diverse phylogeny

A requisite for efficacious host defense against pathogens and predators has prioritized evolution of effector molecules thereof. A recent multidimensional analysis of physicochemical properties revealed a novel, unifying structural signature among virtually all classes of cysteine-containing antimicrobial peptides. This motif, termed the gamma-core, is seen in host defense peptides from organisms spanning more than 2.6 billion years of evolution. Interestingly, many toxins possess the gamma-core signature, consistent with discoveries of their direct antimicrobial activity. Many microbicidal chemokines (kinocidins) likewise contain iterations of the gamma-core motif, reconciling their antimicrobial efficacy. Importantly, these polypeptide classes have evolved to target and modulate biomembranes in protecting respective hosts against unfavorable interactions with potential pathogens or predators. Extending on this concept, the current report addresses the hypothesis that antimicrobial peptides, kinocidins, and polypeptide toxins are structurally congruent and share a remarkably close phylogenetic relationship, paralleling their roles in host-pathogen relationships. Analyses of their mature amino acid sequences demonstrated that cysteine-stabilized antimicrobial peptides, kinocidins, and toxins share ancient evolutionary relatedness stemming from early precursors of the gamma-core signature. Moreover, comparative 3-D structure analysis revealed recurring iterations of antimicrobial peptide gamma-core motifs within kinocidins and toxins. However, despite such congruence in gamma-core motifs, the kinocidins diverged in overall homology from microbicidal peptides or toxins. These findings are consistent with observations that chemokines are not toxic to mammalian cells, in contrast to many antimicrobial peptides and toxins. Thus, specific functions of these molecular effectors may be governed by specific configurations of structural modules associated with a common gamma-core motif. These concepts are consistent with the hypothesis that the gamma-core is an archetype determinant in polypeptides that target or regulate with biological membranes, with specific iterations optimized to unique or cognate host defense contexts. Quantitative and qualitative data suggest these protein families emerged through both parallel and divergent processes of modular evolution. Taken together, the current and prior findings imply that the gamma-core motif contributes to conserved structures and functions of host defense polypeptides. The presence of this unifying molecular signature in otherwise diverse categories of membrane-active host defense peptides implies an ancient and essential role for such a motif in effector molecules governing host-pathogen relationships.     

Human antimicrobial peptides: analysis and application

Antimicrobial peptides are innate host defense molecules that have a direct effect on bacteria, fungi and enveloped viruses. They are found in evolutionarily diverse species ranging from prokaryotes and plants to invertebrate and vertebrate animals. Humans express several families of antimicrobial peptides in myeloid cells and on various epithelial surfaces where they are poised to defend against pathogens. Recently, antimicrobial peptides from animals and plants have served as templates for the design of new therapeutic antibiotics. This review provides an introduction to the biology of human antimicrobial peptides, followed by a more detailed discussion of their isolation from tissues and biological fluids, their purification by gel electrophoresis and chromatography and assays of their antimicrobial activities.     

Advances in antimicrobial peptide immunobiology

Antimicrobial peptides are ancient components of the innate immune system and have been isolated from organisms spanning the phylogenetic spectrum. Over an evolutionary time span, these peptides have retained potency, in the face of highly mutable target microorganisms. This fact suggests important coevolutionary influences in the host-pathogen relationship. Despite their diverse origins, the majority of antimicrobial peptides have common biophysical parameters that are likely essential for activity, including small size, cationicity, and amphipathicity. Although more than 900 different antimicrobial peptides have been characterized, most can be grouped as belonging to one of three structural classes: (1) linear, often of alpha-helical propensity; (2) cysteine stabilized, most commonly conforming to beta-sheet structure; and (3) those with one or more predominant amino acid residues, but variable in structure. Interestingly, these biophysical and structural features are retained in ribosomally as well as nonribosomally synthesized peptides. Therefore, it appears that a relatively limited set of physicochemical features is required for antimicrobial peptide efficacy against a broad spectrum of microbial pathogens.During the past several years, a number of themes have emerged within the field of antimicrobial peptide immunobiology. One developing area expands upon known microbicidal mechanisms of antimicrobial peptides to include targets beyond the plasma membrane. Examples include antimicrobial peptide activity involving structures such as extracellular polysaccharide and cell wall components, as well as the identification of an increasing number of intracellular targets. Additional areas of interest include an expanding recognition of antimicrobial peptide multifunctionality, and the identification of large antimicrobial proteins, and antimicrobial peptide or protein fragments derived thereof. The following discussion highlights such recent developments in antimicrobial peptide immunobiology, with an emphasis on the biophysical aspects of host-defense polypeptide action and mechanisms of microbial resistance.     

Defensins' offensive play: exploiting a viral achilles' heel

Vertebrates rely on antimicrobial peptides as a front-line defense against invading pathogens. Certain cationic antimicrobial peptides, such as human alpha-defensins, have traditionally been thought to destroy invading microbes by disrupting their lipid membranes. In this issue of Cell Host & Microbe, Smith and Nemerow reveal that alpha-defensins can inactivate adenoviruses, which lack lipid membranes, through direct binding of the defensin to the virus's naked protein shell.