Macrophage lectins in host defence

Macrophage lectins contribute to host defence by a variety of mechanisms. The best characterised, mannose receptor (MR) and complement receptor three (CR3), are both able to mediate phagocytosis of pathogenic microbes and induce intracellular killing mechanisms. The regulation of the effector functions induced via MR is complex, and may involve both host and microbial factors. Therefore, MR is likely to play a dynamic role in the response to infection; it may act as a classical pattern recognition receptor in phagocytosis, whereas other poorly characterised factors may make a more decisive contribution to its function in physiologic settings. In contrast, the lectin site of CR3 appears to lack host-derived ligands and may be a true pattern recognition receptor. Further studies are required to evaluate the roles of other macrophage lectins in recognition of and responses to microbes.     

Alcohol, host defence and society

Impaired health caused by alcohol abuse has been known throughout recorded history. Over the past century, alcohol abuse has been clearly linked to host susceptibility to infectious disease, particularly bacterial pneumonia. Recently, both acute and chronic alcohol intake have been shown to result in specific defects in innate and adaptive immunity; these could, in principle, be subjected to specific modulation to overcome the immunosuppressive effects of the most commonly abused substance in the Western world.     

Cytokine gene expression--part of host defence in pulpitis

Analyses of cytokines mediating inflammatory reactions are key to understanding the etiopathology of various diseases. This study investigated differences in cytokine gene expression between pulps from healthy virgin teeth and from symptomatic vital teeth with severe caries lesions in a group of young, healthy individuals. The mRNA levels of IL-1alpha, IL-1beta, IL-6, IL-8, and IL-18 were measured concomitantly by quantitative real-time RT-PCR. IL-1alpha and IL-1beta were not expressed at significantly higher levels in symptomatic versus clinically healthy pulps, while the difference was significant for the other cytokines (log-rank test, P<0.05). A concordance test for independence revealed significant correlation between IL-1alpha and IL-1beta, and between IL-6, IL-8, and IL-18 mRNA levels (P<0.05). The cytokine-specific differences revealed a differential significance of gene expression in cytokine regulation. The hypothesis that increase of cytokine mRNA expression is part of host reaction in pulpitis was corroborated by our observation.     

Parasitism, host immune defence and dispersal

Host-parasite interactions have been hypothesized to affect the evolution of dispersal by providing a possibility for hosts to escape debilitating parasites, and by influencing the level of local adaptation. We used a comparative approach to investigate the relationship between a component of host immune function (which reflects the evolutionary history of parasite-induced natural selection) and dispersal in birds. We used a sample of 46 species of birds for which we had obtained field estimates of T-cell response for nestlings, mainly from our own field studies in Denmark and Spain. Bird species with longer natal, but not with longer breeding dispersal distances had a stronger mean T-cell-mediated immune response in nestlings than species with short dispersal distances. That was also the case when controlling for the potentially confounding effect of migration from breeding to wintering area, which is known from previous studies to be positively associated with dispersal distance. These relationships held even when controlling for similarity among species because of common ancestry. Avian hosts with a larger number of different breeding habitats had weaker mean T-cell-mediated immune responses than habitat specialists. This relationship held even when controlling for similarity among species because of common ancestry. Therefore, T-cell-mediated immunity is an important predictor of evolutionary changes in dispersal ability among common European birds.     

Unifying themes in DNA replication: reconciling single molecule kinetic studies with structural data on DNA polymerases

Structural data suggest that DNA polymerases, from at least three different families, employ common strategies for carrying out DNA replication. Universal features include a large conformational change in the enzyme-template complex and a conserved active-site geometry that imposes a sharp kink at the 5 end of the template strand. Recent single molecule experiments have shown that stretching the DNA template markedly alters the rate of DNA synthesis catalyzed by these motor enzymes. From these data, it was previously inferred that T7 DNA polymerase and two related enzymes convert two or four (depending on the enzyme) single-stranded (ss) template bases to double helix geometry in the polymerase active site during each catalytic cycle. We discuss structural data on related DNA polymerases, which suggest that only one (ss) template base is contracted to dsDNA geometry during the rate-limiting step of each replication cycle. Previous interpretations relied upon the global stretching curves for DNA polymers alone (with no reference to the enzyme or the structure of the transition state). In contrast, we present a structurally guided model that presumes the force dependence of the replication rate is governed chiefly by local interactions in the immediate vicinity of the enzyme s active site. Our analysis reconciles single molecule kinetic studies with structural data on DNA polymerases.     

Brood parasitism selects for no defence in a cuckoo host

In coevolutionary arms races, like between cuckoos and their hosts, it is easy to understand why the host is under selection favouring anti-parasitism behaviour, such as egg rejection, which can lead to parasites evolving remarkable adaptations to ‘trick’ their host, such as mimetic eggs. But what about cases where the cuckoo egg is not mimetic and where the host does not act against it? Classically, such apparently non-adaptive behaviour is put down to evolutionary lag: given enough time, egg mimicry and parasite avoidance strategies will evolve. An alternative is that absence of egg mimicry and of anti-parasite behaviour is stable. Such stability is at first sight highly paradoxical. I show, using both field and experimental data to parametrize a simulation model, that the absence of defence behaviour by Cape bulbuls (Pycnonotus capensis) against parasitic eggs of the Jacobin cuckoo (Clamator jacobinus) is optimal behaviour. The cuckoo has evolved massive eggs (double the size of bulbul eggs) with thick shells, making it very hard or impossible for the host to eject the cuckoo egg. The host could still avoid brood parasitism by nest desertion. However, higher predation and parasitism risks later in the season makes desertion more costly than accepting the cuckoo egg, a strategy aided by the fact that many cuckoo eggs are incorrectly timed, so do not hatch in time and hence do not reduce host fitness to zero. Selection will therefore prevent the continuation of any coevolutionary arms race. Non-mimetic eggs and absence of defence strategies against cuckoo eggs will be the stable, if at first sight paradoxical, result.     

Post-translational modification of host proteins in pathogen-triggered defence signalling in plants

Microbial plant pathogens impose a continuous threat to global food production. Similar to animals, an innate immune system allows plants to recognize pathogens and swiftly activate defence. To activate a rapid response, receptor-mediated pathogen perception and subsequent downstream signalling depends on post-translational modification (PTM) of components essential for defence signalling. We discuss different types of PTMs that play a role in mounting plant immunity, which include phosphorylation, glycosylation, ubiquitination, sumoylation, nitrosylation, myristoylation, palmitoylation and glycosylphosphatidylinositol (GPI)-anchoring. PTMs are rapid, reversible, controlled and highly specific, and provide a tool to regulate protein stability, activity and localization. Here, we give an overview of PTMs that modify components essential for defence signalling at the site of signal perception, during secondary messenger production and during signalling in the cytoplasm. In addition, we discuss effectors from pathogens that suppress plant defence responses by interfering with host PTMs.     

Wolbachia infection suppresses both host defence and parasitoid counter-defence

Endosymbiotic bacteria in the genus Wolbachia have been linked to several types of reproductive parasitism, which enhance their own transmission, while their direct effects on the host vary from beneficial to neutral or detrimental. Here, we report negative effects of infection on immunity-related traits of Drosophila simulans and the parasitoid wasp Leptopilina heterotoma. Infected D. simulans showed a reduced ability to encapsulate parasitoid eggs, compared to a tetracycline-treated, bacterium-free line. Challenging the two lines with a fungal pathogen, Beauveria bassiana, on the other hand, revealed no differences in survival. Moreover, elimination of Wolbachia was beneficial for the parasitoid wasp, as eggs laid by uninfected females suffered significantly lower encapsulation rates. We discuss possible origins of these fitness costs and their implications for infection dynamics and the interactions between host species.     

Function and therapeutic potential of host defence peptides.

Cationic host defence (antimicrobial) peptides are an important component of the innate immune systems of a wide variety of plants, animals, and bacteria. Although most of these compounds have direct antimicrobial activities under specific conditions, a greater appreciation for the diversity of functions of these molecules is beginning to develop in the field. In addition to their directly antimicrobial activities, they also have a broad spectrum of activity on the host immune system, with both pro-inflammatory and anti-inflammatory effects being invoked. Increasingly sophisticated approaches to understand the role of host defence peptides in modulating innate immunity are already serving to guide the development of novel therapeutics.     

Characterisation of host defence proteins in milk using a proteomic approach

Besides providing nutrition to the newborn, milk also protects the neonate and the mammary gland against infection. As well as the six major proteins, bovine milk contains minor proteins, not all of which have been characterized. In this study, we have subjected bovine skim milk, whey, and milk fat globule membrane (MFGM) fractions to both direct liquid chromatography-tandem mass spectrometry (LC-MS/MS), and two-dimensional electrophoresis (2-DE) followed by matrix assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry (MS) of individual protein spots to better characterize the repertoire of minor milk proteins, particularly those involved with host defense. Milk from peak lactation as well as during the period of colostrum formation and during mastitis were analyzed to gain a more complete sampling of the milk proteome. In total, 2903 peptides were detected by LC-MS and 2770 protein spots by 2-DE. From these, 95 distinct gene products were identified, comprising 53 identified through direct LC-MS/MS and 57 through 2-DE-MS. The latter were derived from a total of 363 spots analyzed with 181 being successfully identified. At least 15 proteins were identified that are involved in host defense. These results demonstrate that the proteome of milk is more complex than has previously been reported and a significant fraction of minor milk proteins are involved in protection against infection.     

Adrenomedullin and mucosal defence: interaction between host and microorganism

Many surface epithelial cells express adrenomedullin (AM) and it is postulated that it may have an important protective role. This peptide has many properties in common with other cationic antimicrobial peptides including the human beta-defensins. Antimicrobial activity against members of the human skin, oral, respiratory tract and gastric microflora has been demonstrated. Both pathogenic and commensal strains of bacteria are sensitive; Gram-positive and Gram-negative bacteria being equally susceptible. No activity against the yeast Candida albicans was observed. Minimum inhibitory and minimum bacteriocidal concentrations range from 7.75 x 10(-4) to 12.5 and 0.003 to >25.0 microg ml(-1), respectively. On exposure of oral, skin and gastric epithelial cells to whole cells and culture supernatants from bacteria isolated from these sites an increase in AM peptide and gene expression has been observed. No upregulation was detected with C. albicans. In cultured cells and an animal infection model increased AM peptide and gene expression has been demonstrated using immunohistochemical and in situ hybridization techniques. These collective findings suggest that AM represents a new category of antimicrobial peptide, which contributes to the mucosal host defence system.     

Synthetic oligoureas of metaphenylenediamine mimic host defence peptides in their antimicrobial behaviour

Oligomeric ureas of m-phenylenediamine target anionic DMPG (dimyristoylphosphatidylglycerol) and possess promise as antimicrobial agents. Their similar size, shape and hydrophobicity to helical antimicrobial peptides (AMPs) may be important for activity to exist and the ability of these compounds to insert into a well ordered lipid environment.     

Persistence of host defence behaviour in the absence of avian brood parasitism

The fate of host defensive behaviour in the absence of selection from brood parasitism is critical to long-term host-parasite coevolution. We investigated whether New World Bohemian waxwings Bombycilla garrulus that are allopatric from brown-headed cowbird Molothrus ater and common cuckoo Cuculus canorus parasitism have retained egg rejection behaviour. We found that egg rejection was expressed by 100 per cent of Bohemian waxwings. Our phylogeny revealed that Bohemian and Japanese waxwings Bombycilla japonica were sister taxa, and this clade was sister to the cedar waxwing Bombycilla cedrorum. In addition, there was support for a split between Old and New World Bohemian waxwings. Our molecular clock estimates suggest that egg rejection may have been retained for 2.8-3.0 Myr since New World Bohemian waxwings inherited it from their common ancestor with the rejecter cedar waxwings. These results support the 'single trajectory' model of host-brood parasite coevolution that once hosts evolve defences, they are retained, forcing parasites to become more specialized over time.     

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.     

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 γ-core, is seen in host defense peptides from organisms spanning more than 2.6 billion years of evolution. Interestingly, many toxins possess the γ-core signature, consistent with discoveries of their direct antimicrobial activity. Many microbicidal chemokines (kinocidins) likewise contain iterations of the γ-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 γ-core signature. Moreover, comparative 3-D structure analysis revealed recurring iterations of antimicrobial peptide γ-core motifs within kinocidins and toxins. However, despite such congruence in γ-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 γ-core motif. These concepts are consistent with the hypothesis that the γ-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 γ-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.     

The role of Dectin-1 in the host defence against fungal infections

Dectin-1 is an innate immune pattern recognition receptor (PRR) that, through its ability to bind β-glucans, is involved in the recognition of several pathogenic fungi. Dectin-1 can stimulate a variety of cellular responses via the Syk/CARD9 signalling pathway, including phagocytosis, cytokine production and the respiratory burst. Several advances in our understanding of Dectin-1 immunobiology have been made in recent years, including characterisation of additional signalling pathways and demonstration of its ability to directly induce the development of adaptive immunity. However, the physiological role of many of the functions of this receptor is still unclear. This review aims to provide an update on Dectin-1 and its role within antifungal immune responses, focussing on progress made in the last two years.     

Role of natural killer T cells in host defence against cryptococcal infection

Cryptococcosis is an opportunistic fungal infectious disease that often occurs in severely immunocompromised patients. Host defence against the causative microorganism is largely mediated by cellular immunity, and Th1 cytokines, such as IFN-gamma, play central roles in the host protective responses. IL-12 and IL-18 activate the synthesis of IFN-gamma by innate immune cells, including NK, NKT and gamma delta T cells and promote the differentiation of Th1-type acquired immune responses. Recently, NKT cells, which are involved in the recognition of glycolipid antigens, have attracted much attention based on their potent immunomodulating activities. Several studies have reported the role of this particular component of innate immune responses in tumor immunity and pathogenesis of autoimmune diseases. In this review, I outline the recent findings on the role of NKT cells in host defence against infectious microorganisms, with a special focus on our data emphasizing the importance of this subset of immunocytes in the development of acquired as well as early host protection against cryptococcal infection.