Activation Of Host Defense Mechanisms Research Articles

Biologically Active Compounds in Seaweed Extracts - the Prospects for the Application

The paper covers the latest developments in research on the utilitarian properties of algal extracts. Their appli- cation as the components of pharmaceuticals, feeds for animals and fertilizers was discussed. The classes of various bio- logically active compounds were characterized in terms of their role and the mechanism of action in an organism of hu- man, animal and plant. Recently, many papers have been published which discuss the methods of manufacture and the composition of algal ex- tracts. The general conclusion is that the composition of extracts strongly depends on the raw material (geographical loca- tion of harvested algae and algal species) as well as on the extraction method. The biologically active compounds which are transferred from the biomass of algae to the liquid phase include polysaccharides, proteins, polyunsaturated fatty ac- ids, pigments, polyphenols, minerals, plant growth hormones and other. They have well documented beneficial effect on humans, animals and plants, mainly by protection of an organism from biotic and abiotic stress (antibacterial activity, scavenging of free radicals, host defense activity etc.) and can be valuable components of pharmaceuticals, feed additives and fertilizers.

Interleukin-18: The Master Regulator Driving Destructive and Remodeling Processes in the Lungs of Patients with Chronic Obstructive Pulmonary Disease?

Interleukin-18: The Master Regulator Driving Destructive and Remodeling Processes in the Lungs of Patients with Chronic Obstructive Pulmonary Disease?

Pregnancy status and choline intake alter DNA integrity, epigenetic marks and gene expression

This study sought to systemically elucidate the effects of pregnancy and maternal choline intake on genomic markers. Healthy third trimester pregnant (n=26, wk 27 gestation) and non‐pregnant (n=21) women were randomized to controlled choline intakes of 480 or 930 mg/day for 12‐wk. Leukocyte samples were acquired at wk 0 and 12. Pregnant women had higher DNA damage compared to non‐pregnant women (P < 0.001), suggesting insufficient defense against oxidative stress. Genome‐wide transcript profiling revealed the up‐regulation of genes related to immune response, consistent with an activated host defense system towards the end of pregnancy. Pregnant women responded to the higher choline intake with increased (P < 0.05) histone 3 lysine 4 di‐methylation (H3K4me2), a marker of transcription activation. In sum, pregnancy altered markers of genomic stability and modulated the expression of immune‐related genes in leukocytes. The epigenetic modification of histones among pregnant women consuming varied choline intakes may have downstream effects on chromatin restructuring and gene transcription.Grant Funding Source: Funded in part by USDA, ENC and the Beef Checkoff through NCBA

Fungi infecting cultivated moss can also cause diseases in crop plants

AbstractBryophytes (mosses) are non‐vascular plants inhabited by a large number of fungal species, but whether mosses can act as reservoirs of fungal pathogens of crop plants has gained little attention. A few moss species including the Sunagoke moss (Racomitrium japonicum; family Grimmiaceae) are found to have modern economical applications in uses such as greening of urban environments. In a previous study, we identified fungi causing symptoms of varying severity in the commercially grown Sunagoke moss. The aim of this study was to test whether the same fungal isolates are pathogenic to vascular plants. An isolate of Fusarium avenaceum lethal to the Sunagoke moss caused root and crown rot in barley (Hordeum vulgare) and reduced germination of tomato (Solanum lycopersicum) and carrot (Daucus carota) grown in the infested soil. An isolate of Cladosporium oxysporum causing mild symptoms in moss reduced growth and caused reddening and premature death of carrot seedlings. On the other hand, isolates of Alternaria alternata and Fusarium oxysporum lethal to the Sunagoke moss caused no detectable symptoms in any tested vascular plant, suggesting specialisation of these isolates to moss. Chloroplast repositioning was observed in the neighbouring cells towards the initially infected cell following infection with F. avenaceum and A. alternata in Physcomitrella patens (family Funariaceae), a model moss used to study microscopic symptoms. Infection of P. patens with a non‐virulent Apiospora montagnei isolate induced formation of papillae in the moss cells, indicating activation of host defence as described in vascular plants. Results suggest that mosses and vascular plants may be linked by a common microbial interface constituted by pathogenic fungi. The findings have epidemiological implications that have gained little previous attention.

An NLRP7-Containing Inflammasome Mediates Recognition of Microbial Lipopeptides in Human Macrophages

Cytosolic pathogen- and damage-associated molecular patterns are sensed by pattern recognition receptors, including members of the nucleotide-binding domain and leucine-rich repeat-containing gene family (NLR), which cause inflammasome assembly and caspase-1 activation to promote maturation and release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 and induction of pyroptosis. However, the contribution of most of the NLRs to innate immunity, host defense, and inflammasome activation and their specific agonists are still unknown. Here we describe identification and characterization of an NLRP7 inflammasome in human macrophages, which is induced in response to microbial acylated lipopeptides. Activation of NLRP7 promoted ASC-dependent caspase-1 activation, IL-1β and IL-18 maturation, and restriction of intracellular bacterial replication, but not caspase-1-independent secretion of the proinflammatory cytokines IL-6 and tumor necrosis factor-α. Our study therefore increases our currently limited understanding of NLR activation, inflammasome assembly, and maturation of IL-1β and IL-18 in human macrophages.

Genome-Wide RNAi Screen in IFN-γ-Treated Human Macrophages Identifies Genes Mediating Resistance to the Intracellular Pathogen Francisella tularensis

Interferon-gamma (IFN-γ) inhibits intracellular replication of Francisella tularensis in human monocyte-derived macrophages (HMDM) and in mice, but the mechanisms of this protective effect are poorly characterized. We used genome-wide RNA interference (RNAi) screening in the human macrophage cell line THP-1 to identify genes that mediate the beneficial effects of IFN-γ on F. tularensis infection. A primary screen identified ∼200 replicated candidate genes. These were prioritized according to mRNA expression in IFN-γ-primed and F. tularensis-challenged macrophages. A panel of 20 top hits was further assessed by re-testing using individual shRNAs or siRNAs in THP-1 cells, HMDMs and primary human lung macrophages. Six of eight validated genes tested were also found to confer resistance to Listeria monocytogenes infection, suggesting a broadly shared host gene program for intracellular pathogens. The F. tularensis-validated hits included ‘druggable’ targets such as TNFRSF9, which encodes CD137. Treating HMDM with a blocking antibody to CD137 confirmed a beneficial role of CD137 in macrophage clearance of F. tularensis. These studies reveal a number of important mediators of IFN-γ activated host defense against intracellular pathogens, and implicate CD137 as a potential therapeutic target and regulator of macrophage interactions with Francisella tularensis.

Host-defense activities of cyclotides.

Cyclotides are plant mini-proteins whose natural function is thought to be to protect plants from pest or pathogens, particularly insect pests. They are approximately 30 amino acids in size and are characterized by a cyclic peptide backbone and a cystine knot arrangement of three conserved disulfide bonds. This article provides an overview of the reported pesticidal or toxic activities of cyclotides, discusses a possible common mechanism of action involving disruption of biological membranes in pest species, and describes methods that can be used to produce cyclotides for potential applications as novel pesticidal agents.

Syk Kinase-Coupled C-type Lectin Receptors Engage Protein Kinase C-δ to Elicit Card9 Adaptor-Mediated Innate Immunity

SummaryC-type lectin receptors (CLRs) that couple with the kinase Syk are major pattern recognition receptors for the activation of innate immunity and host defense. CLRs recognize fungi and other forms of microbial or sterile danger, and they induce inflammatory responses through the adaptor protein Card9. The mechanisms relaying CLR proximal signals to the core Card9 module are unknown. Here we demonstrated that protein kinase C-δ (PKCδ) was activated upon Dectin-1-Syk signaling, mediated phosphorylation of Card9 at Thr231, and was responsible for Card9-Bcl10 complex assembly and canonical NF-κB control. Prkcd−/− dendritic cells, but not those lacking PKCα, PKCβ, or PKCθ, were defective in innate responses to Dectin-1, Dectin-2, or Mincle stimulation. Moreover, Candida albicans-induced cytokine production was blocked in Prkcd−/− cells, and Prkcd−/− mice were highly susceptible to fungal infection. Thus, PKCδ is an essential link between Syk activation and Card9 signaling for CLR-mediated innate immunity and host protection.

Biological Effects of Chicken Type III Interferon on Expression of Interferon-Stimulated Genes in Chickens: Comparison with Type I and Type II Interferons

Interferons (IFNs) are key mediators that activate host defense mechanisms against viruses. The recently identified mammalian Type III IFN has biological effects similar to type I IFN. However, the biological effects of type III IFN have not yet been characterized in birds. We compared the effects of chicken type III IFN (IFN-λ) with type I (IFN-β) and type II (IFN-γ) IFNs on IFN-stimulated genes (ISGs) using recombinant proteins expressed in Escherichia coli. Recombinant chicken IFN-λ inhibited influenza virus replication and induced the mRNA expression of the ISGs, Mx and OAS, in chicken embryonic fibroblasts (CEFs) in a dose-dependent manner. However, the effective dose of IFN-λ was higher than that of IFN-β and IFN-γ. Furthermore, the effect of IFN-λ on induction of Mx and OAS was lesser than that of IFN-β, but comparable to that of IFN-γ. These results indicate that chicken IFN-λ has the potential to induce ISGs and inhibit viral replication in chicken cells.

Provocative exhibits at the Seventeen Gallery

Two studies identify a tissue-autonomous innate immune mechanism whereby infection provokes epithelial cells to produce IL-17C that engages an epithelial receptor composed of IL-17RA and IL-17RE chains, which promotes host defense and immune activation.

Toll-Like Receptor–Gut Microbiota Interactions: Perturb at Your Own Risk!

The well-being of the intestine and its host requires that this organ execute its complex function amid colonization by a large and diverse microbial community referred to as the gut microbiota. A myriad of interacting mechanisms of mucosal immunity permit the gut to corral the microbiota in such a way as to maximize the benefits and to minimize the danger of living in close proximity to this large microbial biomass. Toll-like receptors and Nod-like receptors, collectively referred to as pattern recognition receptors (PRRs), recognize a variety of microbial components and, hence, play a central role in governing the interface between host and microbiota. This review examines mechanisms by which PRR-microbiota interactions are regulated so as to allow activation of host defense when necessary while preventing excessive inflammation, which can have a myriad of negative consequences for the host. Analysis of published studies performed in human subjects and a variety of murine disease models reveals the central theme that PRRs play a key role in maintaining a healthful stable relationship between the intestine and its microbiota. In contrast, although select genetic ablations of PRR signaling may protect against some chronic diseases, the overriding theme of studies performed to date is that perturbations of PRR-microbiota interactions are more likely to promote disease states associated with inflammation.

The Pathogen-Actin Connection: A Platform for Defense Signaling in Plants

The cytoskeleton, a dynamic network of cytoplasmic polymers, plays a central role in numerous fundamental processes, such as development, reproduction, and cellular responses to biotic and abiotic stimuli. As a platform for innate immune responses in mammalian cells, the actin cytoskeleton is a central component in the organization and activation of host defenses, including signaling and cellular repair. In plants, our understanding of the genetic and biochemical responses in both pathogen and host that are required for virulence and resistance has grown enormously. Additional advances in live-cell imaging of cytoskeletal dynamics have markedly altered our view of actin turnover in plants. In this review, we outline current knowledge of host resistance following pathogen perception, both in terms of the genetic interactions that mediate defense signaling, as well as the biochemical and cellular processes that are required for defense signaling.

Molecular Characterization of the Host Defense Activity of the Barrier to Autointegration Factor against Vaccinia Virus

The barrier to autointegration factor (BAF) is an essential cellular protein with functions in mitotic nuclear reassembly, retroviral preintegration complex stability, and transcriptional regulation. Molecular properties of BAF include the ability to bind double-stranded DNA in a sequence-independent manner, homodimerize, and bind proteins containing a LEM domain. These capabilities allow BAF to compact DNA and assemble higher-order nucleoprotein complexes, the nature of which is poorly understood. Recently, it was revealed that BAF also acts as a potent host defense against poxviral DNA replication in the cytoplasm. Here, we extend these observations by examining the molecular mechanism through which BAF acts as a host defense against vaccinia virus replication and cytoplasmic DNA in general. Interestingly, BAF rapidly relocalizes to transfected DNA from a variety of sources, demonstrating that BAF's activity as a host defense factor is not limited to poxviral infection. BAF's relocalization to cytoplasmic foreign DNA is highly dependent upon its DNA binding and dimerization properties but does not appear to require its LEM domain binding activity. However, the LEM domain protein emerin is recruited to cytoplasmic DNA in a BAF-dependent manner during both transfection and vaccinia virus infection. Finally, we demonstrate that the DNA binding and dimerization capabilities of BAF are essential for its function as an antipoxviral effector, while the presence of emerin is not required. Together, these data provide further mechanistic insight into which of BAF's molecular properties are employed by cells to impair the replication of poxviruses or respond to foreign DNA in general.

Alternative Spliced CD1D Transcripts in Human Bronchial Epithelial Cells

CD1d is a MHC I like molecule which presents glycolipid to natural killer T (NKT) cells, a group of cells with diverse but critical immune regulatory functions in the immune system. These cells are required for optimal defence against bacterial, viral, protozoan, and fungal infections, and control of immune-pathology and autoimmune diseases. CD1d is expressed on antigen presenting cells but also found on some non-haematopoietic cells. However, it has not been observed on bronchial epithelium, a site of active host defence in the lungs. Here, we identify for the first time, CD1D mRNA variants and CD1d protein expression on human bronchial epithelial cells, describe six alternatively spliced transcripts of this gene in these cells; and show that these variants are specific to epithelial cells. These findings provide the basis for investigations into a role for CD1d in lung mucosal immunity.

Lung Surfactant Protein A (SP-A) Interactions with Model Lung Surfactant Lipids and an SP-B Fragment

Surfactant protein A (SP-A) is the most abundant protein component of lung surfactant, a complex mixture of proteins and lipids. SP-A performs host defense activities and modulates the biophysical properties of surfactant in concerted action with surfactant protein B (SP-B). Current models of lung surfactant mechanism generally assume SP-A functions in its octadecameric form. However, one of the findings of this study is that when SP-A is bound to detergent and lipid micelles that mimic lung surfactant phospholipids, it exists predominantly as smaller oligomers, in sharp contrast to the much larger forms observed when alone in water. These investigations were carried out in sodium dodecyl sulfate (SDS), dodecylphosphocholine (DPC), lysomyristoylphosphatidylcholine (LMPC), lysomyristoylphosphatidylglycerol (LMPG), and mixed LMPC + LMPG micelles, using solution and diffusion nuclear magnetic resonance (NMR) spectroscopy. We have also probed SP-A’s interaction with Mini-B, a biologically active synthetic fragment of SP-B, in the presence of micelles. Despite variations in Mini-B’s own interactions with micelles of different compositions, SP-A is found to interact with Mini-B in all micelle systems and perhaps to undergo a further structural rearrangement upon interacting with Mini-B. The degree of SP-A–Mini-B interaction appears to be dependent on the type of lipid headgroup and is likely mediated through the micelles, rather than direct binding.

More than Inflammation: Interleukin-1β Polymorphisms and the Lipid Metabolism

More than Inflammation: Interleukin-1β Polymorphisms and the Lipid Metabolism

Sensing of viral nucleic acids by RIG-I: From translocation to translation

The innate immune system is a first layer of defense against infection by pathogens. It responds to pathogens by activating host defense mechanisms via interferon and inflammatory cytokine expression. Pathogen associated molecular patterns (PAMPs) are sensed by specific pattern recognition receptors. Among those, the ATP dependent helicase related RIG-I like receptors RIG-I, MDA5 and LGP2 sense the presence of viral RNA in the cytoplasm of host cells. While the precise PAMPs and functions of MDA5 or LGP2 are still unclear, RIG-I senses predominantly viral RNA containing a 5′-triphosphate along with dsRNA regions. Here we review our current knowledge of how these PAMPs are sensed and integrated by RIG-I, and how RIG-I's innate immune function can be used in translational medical approaches.

Pathogens Drop the Hint: Don't Forget Phytoalexin Pathways

Many effectors secreted by pathogenic bacteria suppress host signal transduction pathways that activate host defense responses. In this issue of Cell Host & Microbe, Zhou etal. (2011) now broaden that theme by demonstrating that HopZ1b from Pseudomonas syringae pv. glycinea causes degradation of a host enzyme directly involved in the synthesis of antimicrobial phytoalexin compounds.

Methodology Identification of 18 genes encoding necrosis-inducing proteins from the plant pathogen Phytophthora capsici (Pythiaceae: Oomycetes)

Phytophthora capsici is an aggressive plant pathogen that affects solanaceous and cucurbitaceous hosts. Necrosis-inducing Phytophthora proteins (NPPs) are a group of secreted toxins found particularly in oomycetes. Several NPPs from Phytophthora species trigger plant cell death and activate host defense gene expression. We isolated 18 P. capsici NPP genes, of which 12 were active during hypha growth from a Phytophthora stain isolated from pepper (Capsicum annuum) plants in China. The 18 predicted proteins had a sequence homology of 46.26%. The 18 Pcnpp sequences had a conserved GHRHDWE motif and fell into two groups. Eleven sequences in group 1 had two conserved cysteine residues, whereas the other seven sequences in group 2 lacked these two cysteine residues. A phylogenetic tree was constructed on the basis of the alignment of the predicted protein sequences of 52 selected NPP genes from oomycetes, fungi and bacteria from Genbank. The tree did not rigorously follow the taxonomic classification of the species; all the NPPs from oomycetes formed their own clusters, while fungal sequences were grouped into two separate clades, indicating that based on NPPs, we can separate oomycetes from fungi and bacteria, and that expansion of the NPP family was a feature of Phytophthora evolution.

CTRP-3: Blocking a Toll Booth to Obesity-Related Inflammation

Over the last decade, our understanding of adipose tissue has changed significantly, and where it was once thought of as a simple energy storage site, it is now considered an important and immunologically active endocrine organ (1–3). Adipose tissue is composed of both metabolically and immunologically active cells that include adipocytes, preadipocytes, macrophages, endothelial cells, fibroblasts, and leukocytes; and in the omentum, this also includes omental mesothelial cells (1, 4). A network of blood vessels surrounds these cells and allows them to communicate with systemic sites. This coupling of metabolism and immunity in adipose tissue is a clever biological organization that allows efficient cross talk between these two pathways. This allows the host to make rapid metabolic changes in response to activation of host defense mechanisms against pathogens. This cross talk is achieved by more than 100 proinflammatory, antiinflammatory, and immunomodulating proteins and peptides (3). These include adipokines, such as leptin, adiponectin, visfatin, omentin, and resistin, as well as inflammatory cytokines TNF , monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1. The newly identified adipokine C1q/TNF-related protein (CTRP)-3 is a member of the recently described family of proteins called the CTRP superfamily. This family of proteins has developed by divergence from a common ancestor of the innate immune system (5). As such, they all contain a unique globular C1q domain and a common three-dimensional structure. Thus, CTRP family proteins are suitably designed to provide cross talk between the metabolic pathwayandtheinnateimmunesystem.Indeed,adipocyte-secreted CTRP-3 plays a role in regulating adipokine secretion (6). In this issue of Endocrinology, Kopp et al. (7) probe the function and mechanism of CTRP-3 in adipocytes and monocytes and show that it acts as an endogenous antagonist of the toll-like receptor (TLR)-4 pathway. CTRP-3 was initially identified as a TGF -responsive gene in cartilage (8), and it has since been shown to stimulate the proliferation of mesenchymal chondroprogenitor cells (9) and exhibit an antiinflammatory activity in monocytes (10). However, there is limited information on CTRP-3 and its role in adipocyte biology. Given that CTRP-3 is paralog of adiponectin and a potent antiinflammatory regulator of monocytes, Kopp et al. (7) proposed that CTRP-3 may also have antiinflammatory properties in adipocytes. The authors provide evidence that CTRP-3 acts through a toll-like receptor pathway in adipocytes and monocytes (7). Toll-like receptors are innate immune receptors that recognize conserved microbial signature patterns called pathogen-associated molecular patterns. They initiate proinflammatory signaling pathways important for host defense (11). Adipocytes and monocytes express a broad spectrum of TLRs, including TLR-4, which is the main sensor of pathogenic lipopolysaccharide (LPS) (12). LPS activation of TLR-4 leads to a potent stimulation of proinflammatory cytokine (TNF and IL-6) release from adipocytes (Fig. 1) (13). Importantly, and with respect to obesity-related inflammation, TLR-4 is also stimulated by saturated fatty acids in adipocytes and monocytes (14). As such, TLR-4 could provide cross talk between innate immunity and metabolism. It has become evident that proinflammatory adipocytokines such as TNF , IL-6, and MCP-1 contribute to obesity, type2diabetes, and insulin resistance (15–18).Theydosoby causing chronic low-grade systemic inflammation. Interestingly, mice lacking TLR-4 that are fed a high-fat diet are protected from obesity (19). Moreover these mice have de-