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PubMed2007

Structural insights into the innate immune recognition specificities of L- and H-ficolins.

Innate immunity relies critically upon the ability of a few pattern recognition molecules to sense molecular markers on pathogens, but little is known about these interactions at the atomic level. Human L- and H-ficolins are soluble oligomeric defence proteins with lectin-like activity, assembled from collagen fibers prolonged by fibrinogen-like recognition domains. The X-ray structures of their trimeric recognition domains, alone and in complex with various ligands, have been solved to resolutions up to 1.95 and 1.7 A, respectively. Both domains have three-lobed structures with clefts separating the distal parts of the protomers. Ca(2+) ions are found at sites homologous to those described for tachylectin 5A (TL5A), an invertebrate lectin. Outer binding sites (S1) homologous to the GlcNAc-binding pocket of TL5A are present in the ficolins but show different structures and specificities. In L-ficolin, three additional binding sites (S2-S4) surround the cleft. Together, they define an unpredicted continuous recognition surface able to sense various acetylated and neutral carbohydrate markers in the context of extended polysaccharides such as 1,3-beta-D-glucan, as found on microbial or apoptotic surfaces.

Acetylation↗
PubMed2004

Innate immune responses of a lepidopteran insect, Manduca sexta.

Many innate immune mechanisms are conserved throughout the animal kingdom. Manduca sexta, a widely used model for insect biochemical research, employs these mechanisms to defend against invading pathogens and parasites. We have isolated from M. sexta hemolymph a group of proteins (hemolin, peptidoglycan recognition proteins, beta-1,3-glucan recognition proteins, and C-type lectins), which serve as a surveillance mechanism by binding to microbial surface molecules (e.g. peptidoglycan, lipopolysaccharide, lipoteichoic acid, and beta-1,3-glucan). The binding triggers diverse responses such as phagocytosis, nodule formation, encapsulation, melanization, and synthesis of anti-microbial peptides/proteins. Some of these responses are mediated and coordinated by serine proteinase cascades, analogous to the complement system in mammals. Our current research is focused on the proteolytic activation of prophenoloxidase (proPO)--a reaction implicated in melanotic encapsulation, wound healing, and protein cross-linking. We have isolated three proPO-activating proteinases, each of which requires serine proteinase homologs as a cofactor for generating active phenoloxidase. The proteinases and proteinase-like molecules, containing one to two clip domains at their amino-terminus, are acute-phase proteins induced upon an immune challenge. Inhibitory regulation of the proteinases by serpins and association of the proteinase homologs with a bacteria-binding lectin are important for ensuring a localized defense response. Additional serine proteinases expressed in M. sexta hemocytes and fat body have been discovered. Future research efforts will be aimed at elucidating the proteinase cascade for proPO activation and investigating the roles of proteinases in other immune responses such as processing of plasmatocyte-spreading peptide.

Animals↗
PubMed2004

[Innate immunity in hemodialysis and continuous ambulatory peritoneal dialysis patients: impaired cytokine synthetic response to ex-vivo stimuli in mononuclear cells].

Dialysis patients are weak in immune host defense, which is associated with their high morbidity of infection. Polymorphonuclear leukocytes (PMNLs) and mononuclear cells play a key role in innate host defense. PMNLs and monocytes have bactericidal activity through the process of phagocytosis. Monocytes and lymphocytes contribute to the development of innate immunity by their cytokine actions. We studied the intracellular cytokine syntheses in response to ex-vivo stimuli, which may reflect the potential reactivity of immune cells in cytokine syntheses when pathogens invade humans. Furthermore, phagocytic activity was assessed in granulocytes and monocytes. Twenty HD, 15 CAPD, and 10 age-matched controls were enrolled in this study. One milliliter of whole blood from each subject was incubated with lipopolysaccharides (LPS) or mitogens for 4 hours at 37 degrees C. Monoclonal antibodies to CD14+ and CD4+ were used for identifying monocytes and helper T cells, respectively. Intracellular cytokines were stained using FASTIMMUNE staining kits. Interleukin-1beta and TNF-alpha syntheses were examined in monocytes, which are the most important early-response cytokines in innate immunity. IFN-gamma and IL-4 syntheses were examined in helper T cells to observe their polarization into Th1 and Th2 cells. IFN-gamma is a key factor in establishing innate immunity. The percentage of cells that stained positive for each cytokine was analyzed using a flow cytometer. The following results were obtained: 1) In CAPD patients, IL-1beta and TNF-alpha response to LPS in monocytes were significantly reduced, as compared to other subjects. Polarization of helper T cells was reduced, resulting in a significant decrease in Th1 cells. 2) In HD patients, monokine responses were not altered, but polarization of helper T cells was skewed toward a Th1 type. Phagocytic activities were not impaired in both dialysis groups. In conclusion, mononuclear cells from CAPD patients have the potential to exhibit failure of a cytokine response to ex-vivo stimuli in terms of innate immunity.

Cytokines↗
PubMed2003

Innate immunity and pathogen-host interaction.

The skin and contiguous mucosal surfaces define the primary locus of interaction between host and micro-organisms. In this review, we focus on the innate immune system in the mucosa, which manages to deal with invading pathogens, the mechanisms that organisms have evolved in order to circumvent this primary defensive barrier and, finally, potential therapeutic manipulation of the innate immune system that was the focus of meeting at a Euroconference/Workshop on "Novel Strategies of Mucosal Immunisation through Exploitation of Mechanisms of Innate Immunity in Pathogen-Host Interaction", which was held in Siena, Italy, November 2002.

Animals↗
PubMed2001

The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5.

The innate immune system recognizes pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, but not on the host. Toll-like receptors (TLRs) recognize PAMPs and mediate the production of cytokines necessary for the development of effective immunity. Flagellin, a principal component of bacterial flagella, is a virulence factor that is recognized by the innate immune system in organisms as diverse as flies, plants and mammals. Here we report that mammalian TLR5 recognizes bacterial flagellin from both Gram-positive and Gram-negative bacteria, and that activation of the receptor mobilizes the nuclear factor NF-kappaB and stimulates tumour necrosis factor-alpha production. TLR5-stimulating activity was purified from Listeria monocytogenes culture supernatants and identified as flagellin by tandem mass spectrometry. Expression of L. monocytogenes flagellin in non-flagellated Escherichia coli conferred on the bacterium the ability to activate TLR5, whereas deletion of the flagellin genes from Salmonella typhimurium abrogated TLR5-stimulating activity. All known TLRs signal through the adaptor protein MyD88. Mice challenged with bacterial flagellin rapidly produced systemic interleukin-6, whereas MyD88-null mice did not respond to flagellin. Our data suggest that TLR5, a member of the evolutionarily conserved Toll-like receptor family, has evolved to permit mammals specifically to detect flagellated bacterial pathogens.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Staphylococcal innate immune evasion.

Upon entering the human body, bacteria are confronted with the sophisticated innate defense mechanisms of the human host. From work in recent years it has become obvious that a new and growing family of small and excreted proteins can counteract the antibacterial effects of innate immunity. These highly selective proteins pick out crucial elements of our immune system and inhibit their function. In Staphylococcus aureus these proteins act on specific cellular receptors, on antimicrobial peptides and especially on the complement system. The combined action of this growing group of essential virulence factors ascertains efficient innate immune evasion.

Humans↗
PubMed2002

Neuronal oxidative damage from activated innate immunity is EP2 receptor-dependent.

Increase in prostaglandin (PG) E2 levels and oxidative damage are associated with diseases of brain that involve activation of innate immunity. We tested the hypothesis that cerebral oxidative damage resulting from activation of innate immunity with intracerebroventricular (icv) lipopolysaccharide (LPS) is dependent on PGE2-mediated signaling. We measured two quantitative in vivo biomarkers of lipid peroxidation: F2-isoprostanes (IsoPs) that derive from arachidonic acid (AA) that is uniformly distributed in all cell types in brain, and F4-neuroprostanes (NeuroPs) that derive from docosahexaenoic acid (DHA) that is highly concentrated in neuronal membranes. LPS stimulated delayed elevations in cerebral F2-IsoPs and F4-NeuroPs that were completely suppressed by indomethacin or ibuprofen pre-treatment. LPS-induced cerebral oxidative damage was abolished by disruption of subtype 2 receptor for PGE2 (EP2). In contrast, initial oxidative damage from icv kainic acid (KA) was more rapid than with LPS also was completely suppressed by indomethacin or ibuprofen pre-treatment but was independent of EP2 receptor activation. The protective effect of deleting the EP2 receptor was not associated with changes in cerebral eicosaniod production, but was partially related to reduced induction of nitric oxide synthase (NOS) activity. These results suggest the EP2 receptor as a therapeutic target to limit oxidative damage from activation of innate immunity in cerebrum.

Animals↗
PubMed2005

Opposing and hierarchical roles of leukotrienes in local innate immune versus vascular responses in a model of sepsis.

The 5-lipoxygenase (5-LO)-derived leukotrienes (LTs) influence both local innate immunity and vascular responses, but the relative importance of effects on these two processes in sepsis is unknown. In a cecal ligation and puncture model of peritonitis with severe sepsis, 5-LO(-/-) mice showed a reduction in peritoneal neutrophil accumulation and an increase in the number of bacteria in the peritoneal cavity. Despite this impairment of local innate immunity, the null mice exhibited a marked improvement in survival, and this protection was also seen in wild-type animals treated with the LT synthesis inhibitor MK 886. A survival advantage in severe sepsis was also observed in mice treated with the cysteinyl-LT receptor antagonist MK 571, but not with the LTB(4) receptor antagonist CP 105, 696. Protection in the 5-LO(-/-) mice was associated with reduced vascular leak and serum lactate levels. Moreover, wild-type mice treated with MK 571 exhibited less sepsis-induced hypotension. These data demonstrate opposing effects of cysteinyl-LTs on innate immune vs hemodynamic responses, demonstrating protective effects on local immunity and deleterious effects on the vasculature. They also suggest the possible therapeutic utility of targeting vascular events in sepsis with cysteinyl-LT blockade.

Acidosis, Lactic↗
PubMed2004

Innate immunity of the gut: mucosal defense in health and disease.

The intestine is an important immune organ consisting of a complex cellular network, secreted peptides and proteins and other host defenses. Innate immunity plays a central role in intestinal immune defense against invading pathogens. It also serves as a bridge to the activation of the adaptive immune system. Pattern recognition molecules of microorganisms are an essential component for identifying invading pathogens. Toll-like receptors (TLRs), CARD15/NOD2 and scavenger receptors all serve as the pattern recognition receptors in the innate immune defense system. Secreted bactericidal peptides or defensins produced by the intestinal epithelia represent another crucial element of innate mucosal immune defense. Mutations in pattern recognition receptors and dysfunction of secretory bactericidal peptides may impair host immune defenses leading to an invasion of pathogens resulting in chronic inflammation of the gut. This review updates our current understanding of innate immunity of the gastrointestinal tract.

Humans↗
PubMed2003

TLR-induced negative regulatory circuits: role of suppressor of cytokine signaling (SOCS) proteins in innate immunity.

Recognition of pathogen-associated molecular pattern (PAMP) by PAMP receptors of innate immune cells leads to activation and initiation of innate and adaptive immune responses. While the initial steps have been elucidated recently, the mechanisms how innate immune responses are controlled and regulated are only poorly understood. Suppressor of cytokine signaling (SOCS) proteins seem to play an important role in this process. It has been recognized that SOCS proteins not only regulate JAK/STAT-dependent cytokine signaling pathways but are also induced by TLR stimuli and in addition might also regulate TLR signaling.

Animals↗
PubMed2005

Innate immunity processes in organ allografting--their contribution to acute and chronic rejection.

The innate immune processes proceeding in organ allografts and their contribution to acute and chronic rejection have been described. Ischemia/reperfusion phenomenon with damage of the endothelial and parenchymal cells and reaction of granulocytes and macrophages as well as humoral factors including complement, coagulation factors, free radicals, nitrous oxide have an impact on late function of the transplanted organs. Participation of granulocytes and macrophages in acute allogeneic rejection is another example of the role of the innate system in transplant damage. Recurrent basic disease, diabetes, hyperlipidemia, adverse effects of immunosuppressive drugs in allograft recipients are factors evoking reaction of the innate system. Investigations of the innate immune system have shown an essential role, beside of the adaptive system stimulated by allogeneic mismatch, in organ graft rejection.

Acute Disease↗
PubMed1998

Evolution and phylogeny of defense molecules associated with innate immunity in horseshoe crab.

This short review describes the molecular evolution and phylogeny of various defense molecules participating in the host defense of horseshoe crab. It is well known that invertebrate animals, which lack adaptive immune systems, have developed various defense systems, so called innate immunity, that respond to common antigens on the surface of potential pathogens. The systems include hemolymph coagulation, melanization, cell agglutination, antimicrobial action, active oxygen formation, and phagocytic action. Among them, hemolymph coagulation and phenoloxidase-mediated melanization, in addition to cell agglutination, are directly induced by foreign substances, that result in the engulfment of invading microbes. The immobilized invaders are finally killed by antimicrobial substances released mainly from many kinds of hemocytes. In the past two decades, we have investigated biochemically various defense molecules, using horseshoe crab as a model animal, and established extensively their molecular structures. These results now make it possible to discuss evolution and phylogeny of the defense molecules at a molecular level, in comparison with those derived from vertebrate animals. Here, the authors will describe the present state of our knowledge concerning molecules mainly associated with innate immunity.

Amino Acid Sequence↗
PubMed2005

Innate immune responses and chronic obstructive pulmonary disease: "Terminator" or "Terminator 2"?

Innate immune responses appear to be partially responsible for maintaining inflammation and tissue destruction in chronic obstructive pulmonary disease. In the early stages of the disease in smokers, the airways are bombarded with large quantities of particulate material, and activation of phagocytic cells results in the release of many of the mediators believed to remodel the airways. Ironically, failure of the innate immune defense system, either by inherited deficiency or as a result of chronic smoke inhalation, is likely to result in increased susceptibility to infectious disease and exacerbations of chronic obstructive pulmonary disease. It is well known that deficiencies in the production of collectins, pentraxins, and complement can lead to increased infections, and several studies indicate that deficiency in one or another innate defense component is associated with increased exacerbations. Corticosteroids reduce exacerbations in part because of their ability to boost the production of innate host-defense molecules. Therapeutic approaches that stimulate the generation of antimicrobial molecules in the lungs might be able to reduce disease exacerbations.

Acute-Phase Proteins↗
PubMed2006

C1q and MBL, components of the innate immune system, influence monocyte cytokine expression.

It has recently been recognized that the innate immune response, the powerful first response to infection, has significant influence in determining the nature of the subsequent adaptive immune response. C1q, mannose-binding lectin (MBL), and other members of the defense collagen family of proteins are pattern recognition molecules, able to enhance the phagocytosis of pathogens, cellular debris, and apoptotic cells in vitro and in vivo. Humans deficient in C1q inevitably develop a lupus-like autoimmune disorder, and studies in C1q knockout mice demonstrate a deficiency in the clearance of apoptotic cells with a propensity for autoimmune responses. The data presented here show that under conditions in which phagocytosis is enhanced, C1q and MBL modulate cytokine production at the mRNA and protein levels. Specifically, these recognition molecules of the innate immune system contribute signals to human peripheral blood mononuclear cells, leading to the suppression of lipopolysaccharide-induced proinflammatory cytokines, interleukin (IL)-1alpha and IL-1beta, and an increase in the secretion of cytokines IL-10, IL-1 receptor antagonist, monocyte chemoattractant protein-1, and IL-6. These data support the hypothesis that defense collagen-mediated suppression of a proinflammatory response may be an important step in the avoidance of autoimmunity during the clearance of apoptotic cells.

Animals↗
PubMed2006

Antiviral innate immunity pathways.

Recent studies have uncovered two signaling pathways that activate the host innate immunity against viral infection. One of the pathways utilizes members of the Toll-like receptor (TLR) family to detect viruses that enter the endosome through endocytosis. The TLR pathway induces interferon production through several signaling proteins that ultimately lead to the activation of the transcription factors NF-kappaB, IRF3 and IRF7. The other antiviral pathway uses the RNA helicase RIG-I as the receptor for intracellular viral double-stranded RNA. RIG-I activates NF-kappaB and IRFs through the recently identified adaptor protein MAVS, a CARD domain containing protein that resides in the mitochondrial membrane. MAVS is essential for antiviral innate immunity, but it also serves as a target of Hepatitis C virus (HCV), which employs a viral protease to cleave MAVS off the mitochondria, thereby allowing HCV to escape the host immune system.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Copy number polymorphisms are not a common feature of innate immune genes.

Extensive copy number polymorphism was recently reported for innate immunity-related alpha-defensin genes DEFA1 and DEFA3 and beta-defensin genes DEFB4, DEFB103, and DEFB104. To establish whether such polymorphisms are a common feature of innate immune genes we used quantitative real-time PCR to determine the copy numbers of seven genes whose products have important innate immune functions. The genes encoding lysozyme, lactoferrin, cathelicidin antimicrobial peptide (hCAP18/LL-37), cathepsin G, bactericidal/permeability-increasing protein, azurocidin (CAP37/heparin-binding protein), and neutrophil elastase were each found to be single copy per haploid genome. These findings, along with the recent observation that defensin genes DEFA4, DEFA5, DEFA6, and DEFB1 are single copy, suggest that copy number polymorphisms are not a common feature of the innate immune genome but are restricted to a small subset of innate immunity-related genes.

Antimicrobial Cationic Peptides↗
PubMed2001

Augmented age-associated innate immune responses contribute to negative inotropic and lusitropic effects of lipopolysaccharide and interferon gamma.

Innate immunity not only mediates early host defenses to infection, but also contributes to septic hemodynamic compromise through nitric oxide synthase (NOS2) induction and inhibition of cardiovascular adrenergic responses. Because of increased age-related susceptibility to sepsis, we hypothesized that hearts from old (28-29 months) adult rats would exhibit greater beta-adrenergic hyporesponsiveness than young (6-8 months) following lipopolysaccharide (LPS, 6 mg/kg) with and without interferon gamma (INF-gamma, 5000 units). LPS/INF-gamma depressed baseline +dP/dt and isoproterenol-stimulated inotropy in both old and young hearts. beta-adrenergic inotropic (+dP/dt) and lusitropic responses were more depressed in old v young LPS/INF-gamma hearts. Additionally isoproterenol-stimulated cAMP elaboration was less in old (1950+/-160 fmol/min/g) v young (2440+/-170 fmol/min/g, P=0.05) LPS/INF-gamma hearts. LPS alone also depressed basal +dP/dt and prolonged myocardial relaxation in old and young hearts, but suppressed isoproterenol +dP/dt responses only in old hearts. Depressed beta-adrenergic inotropic responses were augmented with the selective NOS2 inhibitor N-iminoethyl-L-lysine. To establish biochemical mechanisms for this, we tested whether induction of NOS2 and innate immune system receptors (CD14 and Toll-like receptor 4, TLR4) were enhanced in old v young hearts. Induction of myocardial NOS2 and CD14 (not present in control) by LPS/INF-gamma was approximately 2-3-fold greater in old compared to young animals. TLR4 was constitutively expressed in old and young hearts and was unaffected by LPS/INF-gamma. These findings indicate that advanced age is associated with augmented cardiac beta-adrenergic depression and enhanced CD14-NOS2 signaling in response to cytokines. Upregulation of cardiovascular innate immunity may have clinical implications for increased mortality in older individuals with systemic inflammatory response syndromes.

Adrenergic beta-Agonists↗