innate immune response Research Papers (original) (raw)

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- Immunology, Immune response, Cytokines, Inflammation

Al though the aetiology of inflammatory bowel disease (IBD) remains unknown, the pathogenesis is gradually being unravelled, seeming to be the result of a combination of environmental, genetic, and immunological factors in which an uncontrolled immune response within the intestinal lumen leads to inflammation in genetically predisposed individuals. Multifactorial evidence suggests that a defect of innate immune response to microbial agents is involved in IBD. This editorial outlines the immunopathogenesis of IBD and their current and future therapy. We present IBD as a result of dysregulated mucosal response in the intestinal wall facilitated by defects in epithelial barrier function and the mucosal immune system with excessive production of cytokines growth factors, adhesion molecules, and reactive oxygen metabolites, resulting in tissue injury. Established and evolving therapies are discussed in the second part of this editorial and at the end of this section we review new therapi...

- by M. Torres
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- Genetics, Immune response, Probiotics, Cytokines

Although innate immunity is crucial to pulmonary host defense and can initiate immune and inflammatory responses independent of adaptive immunity, it remains unstudied in the context of transplant rejection. To investigate the role of... more

- by David Howell
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- Innate immunity, Inflammatory Immune Response, Adaptive Immunity, American

Background Trypanosomosis is the most economically important disease constraint to livestock productivity in Africa. A number of trypanotolerant cattle breeds are found in West Africa, and identification of the genes conferring trypanotolerance could lead to effective means of genetic selection for trypanotolerance. In this context, high resolution mapping in mouse models are a promising approach to identifying the genes associated with trypanotolerance. In previous studies, using F2 C57BL/6J × A/J and C57BL/6J × BALB/cJ mouse resource populations, trypanotolerance QTL were mapped within a large genomic intervals of 20-40 cM to chromosomes MMU17, 5 and 1, and denoted Tir 1, Tir 2 and Tir 3 respectively. Subsequently, using F6 C57BL/6J × A/J and C57BL/6J × BALB/cJ F6 advanced intercross lines (AIL), Tir 1 was fine mapped to a confidence interval (CI) of less than 1 cM, while Tir 2 and Tir 3, were mapped within 5-12 cM. Tir 1 represents the major trypanotolerance QTL. Results In order...

- by Joseph Nganga
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- Biology, Innate immunity, Medicine, Biological Sciences

The factors that govern the development of tuberculosis disease are incompletely understood. We hypothesized that some strains of Mycobacterium tuberculosis (M. tuberculosis) are more capable of causing disseminated disease than others and may be associated with polymorphisms in host genes responsible for the innate immune response to infection. We compared the host and bacterial genotype in 187 Vietnamese adults with tuberculous meningitis (TBM) and 237 Vietnamese adults with uncomplicated pulmonary tuberculosis. The host genotype of tuberculosis cases was also compared with the genotype of 392 cord blood controls from the same population. Isolates of M. tuberculosis were genotyped by large sequence polymorphisms. The hosts were defined by polymorphisms in genes encoding Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) and Toll-like receptor-2 (TLR-2). We found a significant protective association between the Euro-American lineage of M. tuberculosis and pulmonary rather than meningeal tuberculosis (Odds ratio (OR) for causing TBM 0.395, 95% confidence intervals (C.I.) 0.193-0.806, P = 0.009), suggesting these strains are less capable of extrapulmonary dissemination than others in the study population. We also found that individuals with the C allele of TLR-2 T597C allele were more likely to have tuberculosis caused by the East-Asian/Beijing genotype (OR = 1.57 [95% C.I. 1.15-2.15]) than other individuals. The study provides evidence that M. tuberculosis genotype influences clinical disease phenotype and demonstrates, for the first time, a significant interaction between host and bacterial genotypes and the development of tuberculosis.

- by Nguyen Thi Quynh Nhu (FPL HCM_K16)
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- Microbiology, Immunology, Polymorphism, Medical Microbiology

Background— Circulating levels of acute phase reactant proteins such as plasma C-reactive protein (CRP) are likely influenced by multiple genes regulating the innate immune response. Methods and Results— We screened a set of 16 inflammation-related genes for association with CRP in a large population-based study of healthy young adults (n=1627). Results were validated in 2 independent studies (n=1208 and n=4310), including a pooled analysis of all 3 studies. In the pooled analysis, the minor allele of IL1RN 1018 (rs4251961) within the gene encoding interleukin (IL)-1 receptor antagonist (IL-1RA) was significantly associated with higher mean plasma log(CRP) level ( P <1×10 −4 ). The same IL1RN 1018 allele was associated with higher mean plasma log(IL-6) levels ( P =0.004). In the pooled analysis, the minor allele of IL1RN 13888 (rs2232354) was associated with higher fibrinogen, ( P =0.001). The IL1RN 1018 and 13888 variant alleles tag a clade of IL1RN haplotypes linked to allele 1...

- by Gail Jarvik
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- Gene regulation, Biology, Inflammation, Medicine

Functionally, the innate immune system of immature chickens is inefficient during the first week posthatch. This immunological inefficiency enables pathogens such as Salmonella enterica serovar Enteritidis (SE) to invade and colonize the visceral organs of immature chickens. The objective of this study was to evaluate the effect of purified h-glucan as an immunomodulator of the innate immune response. h-glucan, as a feed additive, significantly provided protection against SE organ invasion in young chickens (Pb0.05). The functional efficiency of heterophils isolated from neonatal chickens fed a hglucan ration was significantly (Pb0.05) up-regulated when compared to heterophils isolated from chickens fed a control ration as determined with an array of functional assays. Phagocytosis, bactericidal killing, and oxidative burst were significantly increased in heterophils isolated from chickens fed the purified h-glucan ration (Pb0.05). To our knowledge, this is the first report of a purified h-glucan feed additive significantly decreasing the incidence of SE organ invasion in immature chickens and up-regulating the functional abilities of heterophils isolated from immature chickens against an invading pathogen, SE.

- by Michael Kogut
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- Microbiology, Biology, Industrial Biotechnology, Innate immunity

Innate immunity represents the first line of defence to pathogens besides the physical barrier and seems to play a role in protection against HIV/SIV infection and disease progression. High production of beta-chemokines and CD8+ T cell anti-viral factors in naive as well as in vaccinated macaques has been associated with complete or partial protection against SIV infection indicating that genetic or environmental factors may influence their production. This innate immunity may help in generating HIV/SIV-specific responses upon the first exposure to HIV/SIV. SIV subunit vaccines given by the targeted iliac lymph node route have been shown to induce an increased production of CD8+ T cell suppressor factors and beta-chemokines. Only a few vaccine studies have focused on enhancing the innate immune response against HIV/SIV. The use of unmethylated CpG motifs, HSP and GM-CSF as adjuvants in SIV vaccines has been shown to induce production of HIV/SIV-inhibiting cytokines and beta-chemokines, which seem to be important in modulating and steering the adaptive immune responses. HSP has also been shown to induce gammadelta+ T cells, which contribute to the innate immunity. More knowledge about the interplay between the innate and adaptive immune responses is important to develop new HIV/SIV vaccine strategies.

- by Raija Ahmed
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- Genetics, Immunology, Biology, Cytokines

The present work investigated whether polyamines play a role in the control of the innate immune response in the brain. The first evidence that these molecules may be involved in such a process was based on the robust increase in the expression of the first and rate-limiting enzyme of biosynthesis of polyamines during immune stimuli. Indeed, systemic lipopolysaccharide (LPS) administration increased ornithine decarboxylase (ODC) mRNA and protein within neurons and microglia across the mouse central nervous system (CNS). This treatment was also associated with a robust and transient transcriptional activation of genes encoding pro-inflammatory cytokines and toll-like receptor 2 (TLR2) in microglial cells. The endotoxin increased the cerebral activity of ODC, which was abolished by a suicide inhibitor of ODC. The decrease in putrescine levels largely prevented the ability of LPS to trigger tumor necrosis factor α and TLR2 gene transcription in the mouse brain. In contrast, expression ...

- by Denis Soulet
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- Enzyme Inhibitors, Cell Biology, Polyamines, Biological Sciences

Dysregulation of host immune responses plays a critical role in the pathogenesis of severe 2009 pandemic H1N1 infection. Whether H1N1 virus could escape innate immune defense in vivo remains to be investigated. The aim of this study was... more

- by cosmo del borgo
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- Immune response, Cytokines, Innate immunity, Multidisciplinary

The horseshoe crab is often referred to as a “living fossil,” representative of the oldest classes of arthropods, almost identical to species in existence more than 500 million years ago. Comparative analyses of the defense mechanisms used by the horseshoe crab that allowed it to survive mostly unchanged throughout the millennia reveal a common ancestry of the coagulation and innate immune systems that are totally integrated—indeed, almost inseparable. In human biology, we traditionally view the hemostatic pathways and those regulating innate immune responses to infections and tissue damage as entirely separate entities. But are they? The last couple of decades have revealed a remarkable degree of interplay between these systems, and the linking cellular and molecular mechanisms are rapidly being delineated. In this review, we present some of the major points of intersection between coagulation and innate immunity. We attempt to highlight the potential impact of these findings by id...

- by Edward Conway
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- Hematology, Immune response, Innate immunity, Blood

DGKs (diacylglycerol kinases) are members of a unique and conserved family of intracellular lipid kinases that phosphorylate DAG (diacylglycerol), catalysing its conversion into PA (phosphatidic acid). This reaction leads to attenuation of DAG levels in the cell membrane, regulating a host of intracellular signalling proteins that have evolved the ability to bind this lipid. The product of the DGK reaction, PA, is also linked to the regulation of diverse functions, including cell growth, membrane trafficking, differentiation and migration. In multicellular eukaryotes, DGKs provide a link between lipid metabolism and signalling. Genetic experiments in Caenorhabditis elegans, Drosophila melanogaster and mice have started to unveil the role of members of this protein family as modulators of receptor-dependent responses in processes such as synaptic transmission and photoreceptor transduction, as well as acquired and innate immune responses. Recent discoveries provide new insights into ...

- by Isabel Mérida
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- Biochemistry, Genetics, Caenorhabditis elegans, Cancer
- by David Knipe
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- Immune response, Virology, Biological Sciences, Cell line

In response to viral infection, RIG-I-like RNA helicases bind to viral RNA and activate the mitochondrial protein MAVS, which in turn activates the transcription factors IRF3 and NF-kB to induce type I interferons. We have previously shown that RIG-I binds to unanchored lysine-63 (K63) polyubiquitin chains and that this binding is important for MAVS activation; however, the mechanism underlying MAVS activation is not understood. Here, we show that viral infection induces the formation of very large MAVS aggregates, which potently activate IRF3 in the cytosol. We find that a fraction of recombinant MAVS protein forms fibrils that are capable of activating IRF3. Remarkably, the MAVS fibrils behave like prions and effectively convert endogenous MAVS into functional aggregates. We also show that, in the presence of K63 ubiquitin chains, RIG-I catalyzes the conversion of MAVS on the mitochondrial membrane to prion-like aggregates. These results suggest that a prion-like conformational switch of MAVS activates and propagates the antiviral signaling cascade.

- by Qiu-Xing Jiang
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- Biology, Mitochondria, Innate immunity, Medicine
- by Alfonso Alba
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- HUMAN PAPILLOMAVIRUS, Antibodies, Cervical Cancer, Immune system

Gene silencing through RNA interference (RNAi) has revolutionized the study of gene 98 function, particularly in non-model insects. However, in Lepidoptera (moths and butterflies) 99 RNAi has many times proven to be difficult to achieve. Most of the negative results have been 100 anecdotal and the positive experiments have not been collected in such a way that they are 101 possible to analyze. In this review, we have collected detailed data from more than 150 102 experiments including all to date published and many unpublished experiments. Despite a 103 large variation in the data, trends that are found are that RNAi is particularly successful in the 104 family Saturniidae and in genes involved in immunity. On the contrary, gene expression in 105 epidermal tissues seems to be most difficult to silence. In addition, gene silencing by feeding 106 dsRNA requires high concentrations for success. Possible causes for the variability of success 107 in RNAi experiments in Lepidoptera are discussed. The review also points to a need to further 108 investigate the mechanism of RNAi in lepidopteran insects and its possible connection to the 109 innate immune response. Our general understanding of RNAi in Lepidoptera will be further 110 aided in the future as our public database at http://insectacentral.org/RNAi will continue to 111 gather information on RNAi experiments.

- by Manchikatla Rajam
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- Physiology, Zoology, Research Design, Insect Physiology

Mast cells and neutrophils play a major role in the innate immune response. Following invasion of the host by microorganisms, these immune cells become activated and release anti-microbial cytotoxic granules in an effort to destroy invading microorganisms in a process termed degranulation. By-products from the degradation of microorganisms can also activate G-protein-coupled receptors (GPCRs), which can further activate immune cells. While degranulation of basophils has been extensively characterized for IgE receptors, the signaling pathways initiated by GPCRs that lead to degranulation and the regulation of these pathways during the degranulation response are areas of active study. This review summarizes the current understanding of the mechanisms involved in the regulation of degranulation through GPCRs.

- by Charlotte Vines
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- Mast Cells, Biological Sciences, G protein-coupled receptors, Endocytosis

Background Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), belong to the autoimmune disorders in the sense that an excessive response of the immune system(both innate and acquired) towards commensal microbial flora of the intestinal mucosa is involved in their pathogenesis. The progress of IBD is unknown, characterized by periods of exacerbation and quiescence. Depression and

- by Ilias Vlachos
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- Psychology, Inflammatory Bowel Disease, Intestinal Mucosa, Ulcerative colitis

The innate immune response, and in particular the alpha/beta interferon (IFN-/ß) system, plays a critical role in the control of viral infections. Interferons and ß exert their antiviral effects through the induction of hundreds of... more

- by Stephen Chiweshe
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- Virology, Cytokines, Biological Sciences, Mice
- by Tomas Santalucia
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- Innate immunity, RNA interference, Lipids, Mice

Adenosine is a purine nucleoside, which is produced inside the body under metabolic stress like hypoxic conditions, acute or chronic inflammatory tissue insults. The synthesis of adenosine involves the catabolism of adenine nucleotides (ATP, ADP and AMP) by the action of extracellular ectonucleotidases i.e. CD39 or nucleoside triphosphate dephosphorylase (NTPD) and CD73 or 5′-ectonucleotidase. Once adenosine is released in the extracellular environment, it binds to different types of adenosine (i.e. adenosine A 1 , A 2A , A 2B and A 3 receptors) receptors expressed on various innate immune cells [Neutrophils, macrophages, mast cells, dendritic cells and natural killer cells]. Thus, depending on the type of adenosine receptor to which it binds, adenosine modulates innate immune response during various inflammatory conditions [i.e. chronic (cancer, asthma) as well as acute (sepsis, acute lung injury) inflammatory diseases]. This review summarizes the effect of adenosine on innate immunity and the use of adenosine receptor specific agonists or antagonists in various immunologic disorders (asthma, cancer, HIV-1 infection) as future immunomodulatory therapeutics.

- by Vijay Kumar
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- Biology, Treatment, Innate immunity, Medicine

The common neurotrophin receptor P75NTR, its co-receptor sortilin and ligand proNGF, have not previously been investigated in Natural Killer (NK) cell function. We found freshly isolated NK cells express sortilin but not significant amounts of P75NTR unless exposed to interleukin-12 (IL-12), or cultured in serum free conditions, suggesting this receptor is sequestered. A second messenger associated with p75NTR, neurotrophin-receptor-interacting-MAGE-homologue (NRAGE) was identified in NK cells. Cleavage-resistant proNGF123 killed NK cells in the presence of IL-12 after 20h and without IL-12 in serum free conditions at 48h. This was reduced by blocking sortilin with neurotensin. However, we found no evidence that NK cells produce endogenous proNGF or NGF. We conclude that proNGF induced apoptosis of NK cells may have important implications for limiting the innate immune response.

- by Robert Rush
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- Neurology, Immunology, Flow Cytometry, Biology

- by Raija Ahmed
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- Genetics, Immunology, Biology, Cytokines

The objectives of this study were to compare innate immune responses of calves weaned early (EW; n=23; weaned at 23.7 ± 2.3 d of age) with those of conventionally weaned calves (CW; n=22; weaned at 44.7 ± 2.3 d of age). All calves were fed 3.8L of colostrum within 12h of birth and were subsequently fed milk replacer twice daily. The weaning process began by withdrawal of the afternoon milk-replacer feeding. Milk was fully withdrawn, and the calf was considered completely weaned when it consumed 900 g of calf starter as-fed for 2 consecutive days. Blood samples were collected from all calves at 24, 27, 31, 45, 48, 52, and 66 ± 2.3 d of age. Early weaned calves took a variable amount of time to completely wean from milk replacer; therefore, data were also analyzed by comparing calves grouped by latency to completely weaned (fast=1 to 5 d; intermediate=6 to 8 d; slow=15 to 17 d). Slow-EW calves weighed less than either the fast- or intermediate-EW calves before initiating weaning. At 2...

- by L. Hulbert
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- Animal Science, Dairy Science, Biology, Medicine

Objectives: To investigate whether inhalable microparticles containing two anti-tuberculosis agents, isoniazid and rifampicin, evoke host-defence strategies in macrophages in addition to targeting the incorporated drugs. Methods: Microparticles were prepared by spray-drying a homogeneous solution of drugs and poly (lactic acid) (PLA; apparent viscosity 1.1 cP). Four parts PLA and three parts rifampicin were dissolved in dichloromethane. One part isoniazid was dissolved in methanol. The two solutions were mixed in the ratio 22: 3 at which none of the solutes precipitated. These were administered as ‘nose-only ’ inha-lations to mice or exposed to cultured J774 mouse macrophages. Targeting to lung macrophages was investigated by transmission electron microscopy. Reactive oxygen species (ROS) were estimated by a cytochrome c assay and flow cytometry. Reactive nitrogen intermediates (RNI) were assayed using Griess reagent. Cytokines in culture supernatants were estimated by ELISA. Result...

- by Rolee Sharma
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- Microbiology, Medical Microbiology, Biology, Cytokines

Antimicrobial peptides (AMPs) are important components of the host's innate immune response against microbial invasion. The cysteinerich AMPs such as defensin and hepcidin have been extensively studied, but the recently identified cysteine-rich liver-expressed antimicrobial peptide 2 (LEAP-2) has been characterized from only a few organisms. Here we cloned and sequenced the LEAP-2 cDNAs from both Channel catfish and Blue catfish. The LEAP-2 gene from Channel catfish was also sequenced and characterized. Channel catfish LEAP-2 gene consists of two introns and three exons that encode a peptide of 94 amino acids with a 28 amino acid signal peptide and a mature peptide of 41 amino acids. The amino acid sequences and gene organization were conserved between catfish and other organisms. The Channel catfish LEAP-2 gene is expressed in a wide range of tissues except brain and stomach. Its expression is developmentally regulated with no detection of mature mRNA in early stages of development. It appears that the catfish LEAP-2 gene is regulated at the level of splicing; it is constitutively transcribed, but remains unspliced until 6 days after hatching. The expression of LEAP-2 was induced in a tissue-specific manner. Its expression was upregulated in the spleen, but not in the liver and head kidney, after challenge with Edwardsiella ictaluri, the causative agent of enteric septicemia of catfish (ESC).

- by Zhanjiang Liu
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- Immunology, Biology, Fish Diseases, Innate immunity

The variable array of pattern receptor expression in different cells of the innate immune system explains the induction of distinct patterns of arachidonic acid (AA) metabolism. Peptidoglycan and mannan were strong stimuli in neutrophils, whereas the fungal extract zymosan was the most potent stimulus in monocyte-derived dendritic cells since it induced the production of PGE2, PGD2, and several cytokines including a robust IL-10 response. Zymosan activated κB-binding activity, but inhibition of NF-κB was associated with enhanced IL-10 production. In contrast, treatments acting on CREB (CRE binding protein), including PGE2, showed a direct correlation between CREB activation and IL-10 production. Therefore, in dendritic cells zymosan induces il10 transcription by a CRE-dependent mechanism that involves autocrine secretion of PGE2, thus unraveling a functional cooperation between eicosanoid production and cytokine production.

- by REBOZA Mario
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- Immunology, Biology, Polysaccharides, Macrophages

Cyclooxygenase-2 (COX-2) is a cellular enzyme in the eicosanoid synthetic pathway that mediates the synthesis of prostaglandins from arachidonic acid. The eicosanoids function as critical regulators of a number of cellular processes, including the acute and chronic inflammatory response, hemostasis, and the innate immune response. Human cytomegalovirus (HCMV), which does not encode a viral COX-2 isoform, has been shown to induce cellular COX-2 expression. Importantly, although the precise role of COX-2 in CMV replication is unknown, COX-2 induction was shown to be critical for normal HCMV replication. In an earlier study, we identified an open reading frame (Rh10) within the rhesus cytomegalovirus (RhCMV) genome that encoded a putative protein (designated vCOX-2) with high homology to cellular COX-2. In the current study, we show that vCOX-2 is expressed with early-gene kinetics during RhCMV infection, resulting in production of a 70-kDa protein. Consistent with the expression of a ...

- by Cary Rue
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- Microbiology, Kinetics, Comparative Genomics, Biological Sciences

A small animal model of localised candidiasis is needed for the evaluation of new antifungal compounds. Mammary glands of immunocompetent (BALB/cJ) and immunodeficient (SCID and athymic nude) mice were infected with a wild-type of Candida albicans. Some of the animals were treated with amphotericin B (AmB) while others were treated with saline and acted as controls. The histologic changes of infected mammary gland tissues and a number of other organs were evaluated. Complement (C) activation was analysed by immunoelectrophoretic quantification of molecules with C3c epitopes (C3, C3b, iC3b, and C3c) in serum. In all animals the organisms were confined to the mammary glands. Serum C3c levels were significantly higher (P 6 0.05) in infected untreated BALB/cJ and SCID mice, which also had severe mammary gland tissue inflammation, compared with control mice treated with AmB (4 mg kg 31 i.p. once daily for 4 days). Both treated and control nude mice showed less tissue inflammation compared to BALB/cJ and SCID mice, and revealed insignificant activation of the complement system. It is concluded that innate immune response is important in the control of candidiasis and that the murine mastitis model is useful for immunopathological studies as well as evaluation of potential antifungal compounds.

- by Faisal Guhad
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- Immune response, Complement activation, Mastitis, Biological Sciences

Uric acid has historically been viewed as a purine metabolic waste product excreted by the kidney and gut that is relatively unimportant other than its penchant to crystallize in joints to cause the disease gout. In recent years, however, there has been the realization that uric acid is not biologically inert but may have a wide range of actions, including being both a pro-and anti-oxidant, a neurostimulant, and an inducer of inflammation and activator of the innate immune response. In this paper, we present the hypothesis that uric acid has a key role in the foraging response associated with starvation and fasting. We further suggest that there is a complex interplay between fructose, uric acid and vitamin C, with fructose and uric acid stimulating the foraging response and vitamin C countering this response. Finally, we suggest that the mutations in ascorbate synthesis and uricase that characterized early primate evolution were likely in response to the need to stimulate the foraging "survival" response and might have inadvertently had a role in accelerating the development of bipedal locomotion and intellectual development. Unfortunately, due to marked changes in the diet, resulting in dramatic increases in fructose-and purine-rich foods, these identical genotypic changes may be largely responsible for the epidemic of obesity, diabetes and cardiovascular disease in today's society.

- by Takahiko Nakagawa
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- Physiology, Cardiovascular disease, Comparative, Metabolic syndrome

The effect of Suaeda maritima enriched diet on blood physiology, innate immune response, and disease resistance in olive flounder Paralichythys olivaceus against Miamiensis avidus on weeks 1, 2, and 4 was investigated. Feeding with any enriched diet and then challenging with M. avidus significantly increased white blood cells (WBC) on weeks 2 and 4; the red blood cells (RBC) significantly increased with 0.1% and 1.0% enriched diets on week 4. The hemoglobin (Hb) and hematocrit (Ht) levels significantly increased when fed with 0.1% and 1.0% supplementation diets on weeks 2 and 4. The mean corpuscular volume (MCV) did not significantly vary with any diet and time; however the mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) significantly increased with 0.1% and 1.0% supplementation diets on weeks 2 and 4. The leukocytes such as lymphocytes (Lym), monocytes (Mon), neutrophils (Neu) and biochemical parameters such as total protein (TP), glucose (GLU), and calcium (CAL) levels significantly increased in 0.1% and 1.0% supplementation diet fed groups on weeks 2 and 4. The serum lysozyme activity was significantly enhanced in 0.1% and 1.0% supplementation diet fed groups from weeks 1 to 4 when compared to the control (0% herbal extract enriched diet). The scuticocidal activity and respiratory burst activity were significantly enhanced when fish were fed with 0.1% and 1.0% supplementation diets from weeks 2 and 4. The protective effect in terms of cumulative mortality (50% and 40%) was low in groups on being fed with 0.1% and 1.0% supplemented diet. Therefore the present study suggested that 0.1% and 1.0% S. maritime-supplemented diets protect the hematological and biochemical parameters, improving the innate immunity, affording protection disease from M. avidus infection in olive flounder.

- by Dharaneedharan Subramanian
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- Microbiology, Diet, Fish Diseases, Innate immunity

The invertebrate pattern-recognition protein named coelomic cytolytic factor (CCF) and the mammalian cytokine tumor necrosis factor (TNF) share functional analogies that are based on a similar saccharide recognition specificity. In particular, CCF and TNF have been shown to interact with ion channels on the surface of vertebrate cells via N,N#-diacetylchitobiose lectin-like activity. In the present study, we show that CCF-induced membrane depolarization results in the release of TNF, IL-6 and nitric oxide (NO) by macrophages via nuclear factor-kB signaling. Interestingly, our data suggest that TNF contributes, through lectin-saccharide interaction, to the secretion of IL-6 and NO induced by CCF. This experimental non-physiological setting based on the interaction of an invertebrate defense lectin with vertebrate cells involved in the innate immune response may have highlighted an evolutionarily ancient mechanism of macrophage activation in vertebrates.

- by Alain Beschin
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- Immunology, Pattern Recognition, Ion Channels, Signal Transduction

The natural niche of Streptococcus pneumoniae is the nasopharyngeal mucosa and nasopharyngeal carriage of pneumococci is widely prevalent. Pneumolysin (Ply), a pore-forming protein produced by S. pneumonia, may be important in driving the innate immune response of the nasopharynx. We studied the Ply-induced production of CXCL8 by nasopharyngeal cells and further analysed the mechanism of this induction. Detroit nasopharyngeal cells were stimulated with supernatants derived from bacterial cultures of Ply-deficient, wild-type pneumococci and recombinant Ply, and CXCL8 measured by ELISA. The role of MAP kinase family members in Ply-induced CXCL8 production was analysed using specific inhibitors, NF-kB activity was measured by immunoblot and Ply-mediated TLR4 activation analysed by a CXCL8 promotor luciferase assay. Ply significantly increased production of CXCL8 in Detroit and primary nasal cells. Flow cytometric analysis showed that Detroit cells express cell surface TLR4. CXCL8 production was dependent on changes in the intracellular Ca 2þ levels and also by NF-kB via activation of TLR4, and MAP kinase signalling. Ply induces production of CXCL8 by nasopharyngeal cells using signalling mechanisms involving Ca 2þ mobilisation and activation of MAPK and NF-kB via TLR4. This may be important in regulating nasopharyngeal immunity against pneumococcal colonization.

- by Tim Mitchell
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- Microbiology, Immunology, Medical Microbiology, Calcium
- by Carmen Pedemonte Mendoza
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- Biology, Medicine, Gene expression, Signal Transduction
- by Robert Tighe
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- Genetics, Immunology, Biology, Innate immunity

Telomeres are specialised structures located at the end of eukaryotic chromosomes, that get short during progressive cell divisions. Therefore, telomere may be an indicator of the mitotic history of a cell and it is also a determining factor for the residual cell life span. One mechanism, compensating for the telomere erosion, involves the induction of telomerase, a ribonucleoprotein-enzyme able to synthesize telomeric DNA repeats. In this study, old subjects of two consecutive decades were compared with a group of young controls to investigate whether ageing-related modifications differently affects telomere length and telomerase activity of human peripheral blood CD8 T and CD16 NK lymphocytes. Telomeres in individual cells were measured by flow-FISH and telomerase activity was determined using the TeloTAGGG telomerase PCR ELISA PLUS kit. Both CD8 T and NK lymphocytes showed an age-associated loss of telomeres at rates that were different between the subsets together with an age-associated reduction of telomerase activity that was progressive in CD8 and late in NK lymphocytes. We can assume that preserved innate immune response in the elderly is due to the negligible telomere shortening and the maintained telomerase expression that could allow NK cells of octogenarians to delay replicative senescence.

- by Alessandra Meneghetti
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- Aging, Biology, Adolescent, Medicine
- by S Umair Ahmad
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- Engineering, Physics, Chemistry, Model Checking

The innate immune response in fishes includes both cellular (phagocytes) and humoral (complement system mainly) components. In fish, as in mammals, reactive oxygen metabolites (ROM) are involved in the respiratory burst of phagocytes and three pathways of complement activation can be discerned. The aim of this study was to analyze the innate immune response of fish using parameters such as respiratory burst of phagocytes and the complement activity of plasma of the common carp (Cyprinus carpio, Cyprinidae). Samples from a total of 160 individuals were collected in five periods of the year (early summer, late summer, autumn, winter and spring). Respiratory burst activity of a constant blood volume was measured luminometrically and also calculated per phagocyte number. A trend of negative relation between respiratory burst activity and water temperature was observed, thus the respiratory activity reached the lowest values in summer. Total complement activity of plasma was determined as bacteriolytic activity against bioluminescent bacteria. The highest total complement activity was observed in autumn, it decreased in summer and winter and the lowest activity was detected in spring. The highest activity of alternative pathway of complement activation was detected in spring, which decreased in autumn and the lowest values were found in winter and in summer. To evaluate the effect of steroid hormones, the level of 11-ketotestosterone was analyzed in males and the maximum was found in spring. A negative correlation was found between 11-ketotestosterone and both respiratory burst and total complement activity. Our results indicate that the measured parameters of innate immunity in the common carp are strongly affected by seasonal changes. Moreover, we confirmed that the innate immune response is immuno-suppressed by 11-ketotestosterone in spring.

- by Esa-Matti Lilius
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- Zoology, Complement activation, Aquaculture, Innate immunity

The innate immune system employs a number of pattern recognition receptor families in response to DNAs and RNAs, either from invading microbes or within the hosts. These include the Tolllike receptors (TLRs), the retinoic acid inducible gene I (RIG-I) like receptors (RLRs), and the nucleotide-binding domain leucine-rich repeat/NOD-like receptor (NLRs), among other potential sensors in the cytoplasm. These receptors are composed of modular domain architecture, with ligand binding/sensing domains and signaling domains regulated either through dimerization/ oligomerization, or conformational changes directed by enzymatic activities. Signaling pathways from different families of receptors converge on their respective common adapter proteins and lead to activation of transcription factors or caspases. Many of these receptors induce orchestrated responses to similar ligands from different cell types, resulting in redundant and complementary immunity to infections. This highly efficient defense system is a double-edged sword: inappropriate reaction to host ligands leads to compromised innate tolerance and autoimmune diseases. Structural studies of innate immune receptors and their signaling pathways are essential in our understanding of pattern recognition mechanisms and design of more efficient vaccine adjuvants.

- by Sam Xiao
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- Immunology, Pattern Recognition, Biology, Innate immunity

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- by Bradly Bundrant
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- Epidemiology, Public Health, Medicine, Chronic Disease

Background: Infection by the pandemic influenza A (H1N1/09) virus resulted in significant pathology among specific ethnic groups worldwide. Natural Killer (NK) cells are important in early innate immune responses to viral infections. Activation of NK cells, in part, depend on killer-cell immunoglobulin-like receptors (KIR) and HLA class I ligand interactions. To study factors involved in NK cell dysfunction in overactive immune responses to H1N1 infection, KIR3DL1/S1 and KIR2DL2/L3 allotypes and cognate HLA ligands of H1N1/09 intensive-care unit (ICU) patients were determined. Methodology and Findings: KIR3DL1/S1, KIR2DL2/L3, and HLA-B and-C of 51 H1N1/09 ICU patients and 105 H1N1negative subjects (St. Theresa Point, Manitoba) were characterized. We detected an increase of 3DL1 ligand-negative pairs (3DL1/S1 + Bw6 + Bw4 2), and a lack of 2DL1 HLA-C2 ligands, among ICU patients. They were also significantly enriched for 2DL2/L3 ligand-positive pairs (P,0.001, Pc,0.001; Odds Ratio:6.3158, CI95%:2.481-16.078). Relative to St. Theresa aboriginals (STh) and Venezuelan Amerindians (VA), allotypes enriched among aboriginal ICU patients (Ab) were: 2DL3

- by Ma Luo
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- Immune response, Multidisciplinary, Probability, Natural Killer cells

The innate immune system provides critical protection during initial infections before the generation of an appropriate adaptive (antibody or T cell mediated) immune response. These early defense mechanisms may be particularly critical for neonates in whom the adaptive immune system is not fully operational. Pattern recognition molecules target potential pathogens for destruction by the innate immune system, and likely facilitate the initiation of a pathogen-specific immune response. Defense collagens, such as C1q, MBL and SPA, comprise a family of such proteins that, via specific interactions with phagocytic cells, play a role in this first line of defense. To begin to assess the importance of these innate defense mechanisms in neonates, cord blood plasma and leukocytes were isolated, and responses to these components of the innate defense system were assessed. C1q enhanced the phagocytosis of targets suboptimally opsonized with either IgG or complement components, and this enhancement of phagocytosis was blocked by anti-CD93/C1qR P MAb by 57% to 68%. Flow cytometric analysis demonstrated that neonatal monocytes and neutrophils expressed CD93/C1qR P similarly to adult cells, with several-fold greater expression on monocytes than on neutrophils and essentially no expression on lymphocytes. Superoxide production in response to multivalent C1q by neonatal neutrophils was also comparable to adult cells. We also confirm that C1q and MBL are present in neonate circulation. Thus, the data demonstrate that these recognition and effector mechanisms of the innate system are functional in the newborn and similar to that of adult cells. (Pediatr Res 54: 724-731, 2003) Abbreviations HBSS, Hank's balanced salt solution HSA, human serum albumin MBL, mannan binding lectin PBL, peripheral blood mononuclear leukocytes PMNL, polymorphonuclear leukocytes E, sheep erythrocytes EA IgG , E coated with IgG anti-E EA IgMC4b , E coated with IgM anti-E plus complement NHS, normal human serum PDBu, phorbol dibutyrate PI, phagocytic index SPA and SPD, surfactant protein A and D

- by Feizal Waffarn
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- Flow Cytometry, Innate immunity, Cell separation, Pregnancy

Background: The role of inflammation in the pathogenesis of ischemic and haemorrhagic stroke has been well established. We studied the prognostic value of peripheral markers of inflammation in determining the functional outcome 28 days following stroke. Method: Two hundred and five (205) cases of acute stroke confirmed by CT were evaluated for body temperature, TLC, blood glucose, platelet count, CRP and ESR on admission. Functional outcome was determined after a 28 day period by the modified Rankin scale. Results: A higher TLC (p 0.044), blood glucose(p 0.002) and CRP(p 0.003) was found in patients of ischemic stroke with a poor functional outcome. In patients of haemorrhagic stroke, higher blood glucose (0.001) and CRP (p 0.008) were associated with poor functional outcome after a 28 day period. Conclusion: Peripheral markers of inflammation can be used to assess the clinical severity following both ischemic and haemorrhagic stroke

- by Charles Raison
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- Immunology, Depression, Inflammation, Chronic Fatigue Syndrome

Although it has been demonstrated that mucosal immunization using vectors such as simian adenovirus (AdC) stimulates robust adaptive immune responses, there remains a paucity of information on the modulation of innate immune responses by such vectors. Using an established murine model of intravaginal immunization (Ivag), we have investigated whether mucosal gammadelta T cells participate in immune responses induced by AdC vectors. gammadelta T cell numbers were found to be increased in the vaginal tract. Moreover, gammadelta T cells isolated from the genital tract showed an activated phenotype and enhanced expression of cytokine gene. Altogether, our results demonstrate that AdC modulates gammadelta T cell responses and suggest that this cell population may influence immune responses following vaginal immunization.

- by Álvaro Menin
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- Immune response, Biological Sciences, Virus, Mice

Ehrlichia chaffeensis and Anaplasma phagocytophilum are obligatory intracellular bacteria that preferentially replicate inside leukocytes by utilizing biological compounds and processes of these primary host defensive cells. These bacteria incorporate cholesterol from the host for their survival. Upon interaction with host monocytes and granulocytes, respectively, these bacteria usurp the lipid raft domain containing GPI-anchored protein to induce a series of signaling events that result in internalization of the bacteria. Monocytes and neutrophils usually kill invading microorganisms by fusion of the phagosomes containing the bacteria with granules containing both antimicrobial peptides and lysosomal hydrolytic enzymes and/or through sequestering vital nutrients. However, E. chaffeensis and A. phagocytophilum alter vesicular traffic to create a unique intracellular membrane-bound compartment that allows their replication in seclusion from lysosomal killing. These bacteria are quite...

- by Yasuko Rikihisa
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- Microbiology, Signal Transduction, Veterinary Parasitology, Fisheries Sciences

Dendritic cells (DCs) are the most important antigen-presenting cells in the body. DCs are critical in the initiation of innate immune responses and the regulation of adaptive immune responses. Recent studies have indicated that the origins and subsets of DCs are extremely complicated. DCs actively participate in the induction of both immunity and tolerance. Functions of DCs are influenced by the activation status and surrounding environments. This review highlights some important progress reported in a recent DC conference. Topics in this review include immunophysiology of DCs, the role of DCs in innate, adaptive and infection immunity, and the role of DCs in immunopathology and therapeutics.

- by Ko-Jiunn Liu
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- Clinical research, Adaptive Immunity, Dendritic cell, innate immune response

Ž. Ž. Natural killer NK cells and nitric oxide NO are both important components of the natural or innate immune response. NK cells are large granular lymphocytes capable of destroying cells infected by virus or bacteria and susceptible tumor cells without prior sensitization and restriction by MHC antigens. They are abundant in blood, spleen, liver and lungs and are distinct from both T and B lymphocytes in their circulation patterns, profile of surface antigens, receptor repertoire and the way in which they discriminate between self and non-self. Uniquely, NK cells express receptors that can recognize and discriminate between normal and altered MHC class I determinants. NK cell cytotoxic activity is strongly induced by cytokines such as IL-2 and IL-12, and this activation is associated with synthesis of NO. Inhibitors of NO synthesis impair NK cell-mediated target cell killing, demonstrating a role for NO in NK cell function. Furthermore, NO itself can regulate NK cell activation. In this article, evidence that NO is a mediator of NK cell-mediated target cell killing, and that NO is a regulator of NK cell activation will be reviewed. Results of NO synthase gene deletion studies will be discussed, and rodent and human NK cells will be compared.

The production of gamma interferon (IFN-␥) is a key step in the protective innate immune response to Francisella tularensis. Natural killer cells and T cells in the liver are important sources of this cytokine during primary F. tularensis infections, and interleukin-12 (IL-12) appears to be an essential coactivating cytokine for hepatic IFN-␥ expression. The present study was undertaken to determine whether or not macrophages (M) or dendritic cells (DC) provide coactivating signals for the liver IFN-␥ response in vitro, whether IL-12 mediates these effects, and whether Toll-like receptor (TLR) signaling is essential to induce this costimulatory activity. Both bone marrow-derived M and DC significantly augmented the IFN-␥ response of F. tularensischallenged liver lymphocytes in vitro. While both cell types produced IL-12p40 in response to F. tularensis challenge, only DC secreted large quantities of IL-12p70. DC from both IL-12p35-deficient and TLR2-deficient mice failed to produce IL-12p70 and did not costimulate liver lymphocytes for IFN-␥ production in response to viable F. tularensis organisms. Conversely, liver lymphocytes from TLR2-deficient mice cocultured with wild-type accessory cells produced IFN-␥ at levels comparable to those for wild-type hepatic lymphocytes. These findings indicate that TLR2 controls hepatic lymphocyte IFN-␥ responses to F. tularensis by regulating DC IL-12 production. While M also coinduced hepatic IFN-␥ production in response to F. tularensis, they did so in a fashion less dependent on TLR2.

- by Hung-Wen Yeh
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- Macrophages, Dendritic Cells, Toll like receptor signaling, Biological Sciences

Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

- by Chi-Chao Chan
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- Immunology, Innate immunity, Gene expression, Neuroimmunology