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Results for “Immunity, Innate”

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PubMed2005

Variations in Helicobacter pylori lipopolysaccharide to evade the innate immune component surfactant protein D.

Helicobacter pylori is a common and persistent human pathogen of the gastric mucosa. Surfactant protein D (SP-D), a component of innate immunity, is expressed in the human gastric mucosa and is capable of aggregating H. pylori. Wide variation in the SP-D binding affinity to H. pylori has been observed in clinical isolates and laboratory-adapted strains. The aim of this study was to reveal potential mechanisms responsible for evading SP-D binding and establishing persistent infection. An escape variant, J178V, was generated in vitro, and the lipopolysaccharide (LPS) structure of the variant was compared to that of the parental strain, J178. The genetic basis for structural variation was explored by sequencing LPS biosynthesis genes. SP-D binding to clinical isolates was demonstrated by fluorescence-activated cell sorter analyses. Here, we show that H. pylori evades SP-D binding through phase variation in lipopolysaccharide. This phenomenon is linked to changes in the fucosylation of the O chain, which was concomitant with slipped-strand mispairing in a poly(C) tract of the fucosyltransferase A (fucT1) gene. SP-D binding organisms are predominant in mucus in vivo (P = 0.02), suggesting that SP-D facilitates physical elimination. Phase variation to evade SP-D contributes to the persistence of this common gastric pathogen.

Carbohydrate Sequence↗

PubMed2006

Susceptibility of prostate epithelial cells to Chlamydia muridarum infection and their role in innate immunity by recruitment of intracellular Toll-like receptors 4 and 2 and MyD88 to the inclusion.

Although Chlamydia infections are widespread throughout the world, data about immunopathogenesis of genitourinary tract infections in males are very limited. In the present work we present an in vitro model of male genital tract-derived epithelial cells, more precisely prostate epithelial cells (PEC), to analyze if they are susceptible and able to respond to Chlamydia muridarum infection. Our results demonstrate that rat PEC are susceptible to C. muridarum infection and respond to this pathogen by up-regulating different proinflammatory cytokine and chemokine genes that could participate in the recruitment and local activation of immune cells, therefore influencing innate and adaptive immune responses during Chlamydia infection. Moreover, we analyzed the expression of Toll-like receptor 4 (TLR4), TLR2, and related molecules on PEC and the effect of C. muridarum infection on their expression. Our results demonstrate that PEC express significant levels of TLR4, CD14, TLR2, and the adaptor molecule MyD88 and up-regulate these proteins in response to C. muridarum infection. Indeed, TLR4, CD14, TLR2, and the adaptor MyD88 are specifically recruited to the vicinity of the bacterial inclusion, suggesting that these TLRs are actively engaged in signaling from this intracellular location in these cells. This is, to our knowledge, the first time that an in vitro model of infection with Chlamydia of male tract-derived epithelial cells has been achieved, and it provides the opportunity to determine how these cells respond and participate in modulating innate and adaptive immune response during Chlamydia infections.

Active Transport, Cell Nucleus↗

PubMed2003

Growth hormone and mannan-binding lectin: emerging evidence for hormonal regulation of humoral innate immunity.

An increasing number of studies in animals and humans indicate that growth hormone (GH) and insulin-like growth factor-I (IGF-I) modulate immune function. It was recently reported that, surprisingly, GH therapy increased the mortality in critically ill patients. The excessive mortality was almost entirely due to septic shock or multi-organ failure, which could suggest that a GH-induced modulation of immune function was involved. Mannan-binding lectin (MBL) is a plasma protein that plays an important role in innate immunity through activation of the complement cascade and inflammation following binding to carbohydrate structures. The serum concentration of MBL is subject to large between-subjects differences, which primarily are caused by genetic factors. However, mounting evidence supports a significant influence from growth hormone on MBL levels. In the present review, we focus on the function of MBL, on the influence of growth hormone on MBL levels, and on the possible clinical consequences of this new link between the endocrine and the immune system.

Acute-Phase Reaction↗

PubMed2007

Changes in hepatic gene expression related to innate immunity, growth and iron metabolism in GH-transgenic amago salmon (Oncorhynchus masou) by cDNA subtraction and microarray analysis, and serum lysozyme activity.

Growth hormone (GH) transgenic amago salmon (Oncorhynchus masou) were generated with a construct containing the sockeye salmon GH1 gene fused to the metallothionein-B (MT-B) promoter from the same species. This transgene directed significant growth enhancement with transgenic fish reaching approximately four to five times greater weight than control salmon in F(2) and F(3) generations. This drastic growth enhancement by GH transgene is well known in fish species compared with mammals, however, such fish can show morphological abnormalities and physiological disorders like other GH transgenic animals. GH is known to have many acute effects, but currently there are no data describing the chronic effects of over-expression of GH on various hepatic genes in GH transgenic fish. Hepatic gene expression is anticipated to play very important roles in many physiological functions and growth performance of transgenic and control salmon. To examine these effects, we performed subtractive hybridization (using cDNA generated from liver RNA) in both directions to identify genes both increased and decreased in transgenic salmon relative to controls (576 clones were isolated and sequenced in total). Heme oxygenase, vitelline envelope protein, Acyl-coA binding protein, NADH dehydrogenase, mannose binding lectin-associated serine protease, hemopexin-like protein, leucyte-derived chemotaxin2 (LECT2), and many other genes were obtained in higher clone frequencies suggesting enhanced expression. In contrast, complement C3-1, lectin, rabin, alcohol dehydrogenase, Tc1-like transposase, Delta6-desaturase, and pentraxin genes were obtained in lower frequencies. Microarray analysis was also performed to obtain quantitative expression data for these subtracted cDNA clones. Analysis of fish across seasons was also conducted using both F(2) and F(3) salmon. Results of the microarray data essentially corresponded with those of the subtraction data when both F(2) and F(3) fish were completely immature, but the expression pattern was changed when fish approached maturation. Genes showing enhanced expression in GH transgenic fish in F(2) and F(3) by array analysis were vitelline envelope protein, hemopexin-like protein, heme-oxygenase, inter alpha-trypsin inhibitor, LECT2, GTP cyclohydrolase I feedback regulatory protein (GFRP), and bikunin. Reduced expression genes were lectin, Delta6-desaturase, apolipoprotein, and pentraxin. In particular, lectin was found to be highly suppressed in all F(2) and immature F(3) salmon. Further, serum lysozyme activity, one of innate immunity, was significantly (p<0.05) decreased in both F(2) and F(3) GH transgenic fish. These results indicate that the GH transgene fish had altered hepatic gene expression relating to iron-metabolism, innate immunity, reproduction, and growth.

Animals↗

PubMed2002

[Toll-like receptor and innate immunity in phylogenesis].

In protection against microbes, an organism recognizes the pathogen associated molecular pattern (PAMP) on microbes by pattern recognition receptor (PRR). Toll-like receptor is called innate immunity. A family of cell membrane receptor was found in recent years that can mediate innate immune responses through the activation of a series of immune-related genes. In phylogenesis, it is highly conservative. However, its functions are getting more diversified with the complication of the immune functions of organisms.

Animals↗

PubMedDate not supplied

Evolution of effectors and receptors of innate immunity.

The bony fishes are derived from one of the earliest divergent vertebrate lineages to have both innate and acquired immune systems. They are considered by some to be an ideal model to study the underpinnings of immune systems precisely because of their phylogenetic position and the fact that their adaptive immune systems have not been elaborated to the extent seen in mammals. By the same token, examination of innate immune systems in invertebrates and early chordates can provide insight into how homologous systems operate in fish and higher vertebrates. Herein, we provide an overview of the molecular evidence that we hope helps clarify the evolutionary relationships of innate immune molecules identified in bony fishes. The innate immune systems being considered include select chemokines (CC and CXC chemokines and their receptors), cytokines (IL-1, IL-8, interferons, TGF-beta, TNF-alpha), acute phase proteins (SAA, SAP, CRP, alpha2M, and the complement components--C3-C9, MASP, MBL, Bf), NK cell receptors, and molecules upstream and downstream of the Toll signaling pathways.

Acute-Phase Proteins↗

PubMed2006

Effect of heat-inactivated fish and non-fish derived probiotics on the innate immune parameters of a teleost fish (Sparus aurata L.).

The in vitro effects of four heat-inactivated bacterial species on the cellular innate immune responses of the gilthead seabream (Sparus aurata L.) were investigated. Head-kidney leucocytes were isolated and incubated for 30 min with two bacteria isolated from seabream skin (Pdp11 and 51M6; members of the Vibrionaceae and in the genus Shewanella) and two bacteria used as probiotics in humans and cattle (Lactobacillus delbrüeckii subsp. lactis and Bacillus subtilis) at 5 x 10(5), 5 x 10(6) or 5 x 10(7)CFU/ml. After incubation, different cellular innate immune parameters (leucocyte peroxidase content, phagocytosis, respiratory burst activity and cytotoxicity) were evaluated. The leucocyte peroxidase content was significantly higher after incubation with 51M6 at 5 x 10(7)CFU/ml. Head-kidney phagocytes were able to engulf the four bacterial species in all four cases, L. delbrüeckii subsp. lactis and B. subtilis being the most actively phagocytized. The incubation of seabream leucocytes with 51M6, L. delbrüeckii subsp. lactis and B. subtilis resulted in a great increase in respiratory burst activity. Cytotoxic activity was generally stimulated in a dose-dependent manner, the enhancement obtained with 5 x 10(7)CFU/ml being statistically significant. The usefulness of in vitro assays for screening and selecting candidate probiotic bacteria, as well as for optimising their effective dose, is discussed in relation with their immune-modulatory properties.

Bacillus subtilis↗

PubMed1999

Contribution of the innate immune system to autoimmune diabetes: a role for the CR1/CR2 complement receptors.

B lymphocytes are required for diabetogenesis in nonobese diabetic (NOD) mice. The complement component of the innate immune system regulates B cell activation and tolerance through complement receptors CR1/CR2. Thus, it is important to assess the contribution of complement receptors to autoimmune diabetes in NOD mice. Examination of the lymphoid compartments of NOD mice revealed striking expansion of a splenic B cell subset with high cell surface expression of CR1/CR2. This subset of B cells exhibited an enhanced C3 binding ability. Importantly, long-term in vivo blockade of C3 binding to CR1/CR2 prevented the emergence of the CR1/CR2(hi) B cells and afforded resistance to autoimmune diabetes in NOD mice. These findings implicate complement as an important regulatory element in controlling the T cell-mediated attack on islet beta cells of NOD mice.

Animals↗

PubMedDate not supplied

Role of lipopolysaccharide susceptibility in the innate immune response to Salmonella typhimurium infection: LPS, a primary target for recognition of Gram-negative bacteria.

Lipopolysaccharide is an important recognition marker by virtue of which the innate immune system senses and reacts against Gram-negative bacteria invading the LPS susceptible host. This review deals with the factors affecting LPS susceptibility and with the role of the latter in the course and outcome of Salmonella typhimurium infection.

Animals↗

PubMed2003

Polymorphisms of innate immunity genes and susceptibility to lymphatic filariasis.

We examined 906 residents of an area of Papua New Guinea where bancroftian filariasis is endemic for genetic polymorphisms in three innate immunity genes suspected of contributing to susceptibility to infection and lymphatic pathology. Active infection was confirmed by the presence of blood-borne microfilariae and circulating filarial antigen in plasma. Disease was ascertained by physical examination for the presence of overt lymphedema (severe swelling of an arm or leg) or hydrocele. There was no association of infection status, lymphedema of an extremity, or hydrocele with chitotriosidase genotype (CHIT1). Polymorphisms of toll-like receptor-2 and toll-like receptor-4 genes (TLR4 A896G; TLR2 T2178A, G2258A) were not detected (N=200-625 individuals genotyped) except for two individuals heterozygous for a TLR2 mutation (C2029 T). These results indicate that a CHIT1 genotype associated previously with susceptibility to filariasis in residents of southern India and TLR2 and TLR4 polymorphisms do not correlate with infection status or disease phenotype in this Melanesian population.

Animals↗

PubMed2006

Complex effect of adenovirus early region proteins on innate immune system.

Adenoviruses (Ads) cause acute and persistent infections. The genome of Ads has five early transcription units that are the first viral genes expressed during an active infection. The Early Region 1A (E1A) gene of the adenovirus genome is crucial for adenovirus transformation of the host cell. Ads E1A block some aspects of the innate immune system to enable viruses to invade the host cell. E1A suppresses nitric oxide (NO) production through transcriptional control of the inducible NO synthase (iNOS) gene. This inhibition of NO production may enable the virus to persist in human tissue because NO is an antiviral effector of the innate immune system. E1A also blocks secretory leukoprotease inhibitor (SLPI) and elafin/skin-derived antileukoproteinase (SKALP) secretion by alveolar epithelial cells. Recent scientific evidence suggests that SLPI and elafin/SKALP have broad-spectrum antibiotic activities that include bactericidal and antifungal properties. The inhibition of inflammation by Ad early region proteins is complex, as certain early region proteins can promote as well as inhibit inflammation depending on the genetic context of the virus. E1A DNA and protein are frequently detected in the lungs of chronic obstructive pulmonary disease (COPD) patients and it is associated with an increased inflammatory response. E1A enhances intercellular adhesion molecule-1 and interleukin-8 mRNA expression with lipopolysaccharide stimulation. Understanding the roles of the Ad gene products in the induction and inhibition of innate inflammatory functions will help us to clarify the pathogenesis of the chronic respiratory illness including COPD.

Adenoviridae Infections↗

PubMed2001

The athymic nude rat: an animal experimental model to reveal novel aspects of innate immune responses?

Athymic nude rats resemble nude mice in their lack of a normal thymus and functionally mature T cells. They have been useful in the study of mechanisms of tumor growth or graft rejection in immunocompromised hosts since they can accept major histocompatibility complex (MHC) mismatched organ allografts or xenografts for several months and because a number of tumor cell lines of human and rodent origin grow well in these rats. Injection of a few helper T (Th) cells from euthymic littermate rats partly restores the pool of mature T cells as well as full immunocompetence to reject organ allografts and has helped to reveal some of the cell interactions necessary for rejection to occur In contrast, immunologically naive athymic nude rats of certain strains, acutely reject allografts consisting of lymphocytes or bone marrow cells, which is due to the presence of alloreactive natural killer cells. These cells can recognize and kill MHC incompatible hematopoietic cells through the recognition of both mismatches within the classical (RT1.A) and nonclassical (RT1.C/E) MHC class I regions with a repertoire of inhibitory and activating killer lectin-like receptors (KLR) for MHC-I molecules, encoded by the Ly-49 portion of the rat natural killer cell gene complex (NKC). Some of these receptors have been identified and molecularly cloned and show similarities with NK receptors identified in the mouse. Other leukocytes in nude rats, such as dendritic cells, may also contribute to specific innate immune responses in the absence of mature T cells. Nude rats develop T-like cells expressing CD3 and T-cell receptor (TCR) with increasing age. Though their phenotype in peripheral lymphatic tissues resembles that of normal T cells, consisting mainly of CD4+ or CD8+ cells, they lack alloreactivity in vivo and their TCR repertoire is more of an oligoclonal nature. Their contribution to allograft rejection in T-cell-reconstituted rats is therefore questionable, and their role in innate immune response in these rats still enigmatic.

Animals↗

PubMed2004

Toll-like receptors and the host defense against microbial pathogens: bringing specificity to the innate-immune system.

Toll-like receptors (TLRs) have been identified as a major class of pattern-recognition receptors. Recognition of pathogen-associated molecular patterns (PAMPs) by TLRs, alone or in heterodimerization with other TLR or non-TLR receptors, induces signals responsible for the activation of genes important for an effective host defense, especially proinflammatory cytokines. Although a certain degree of redundancy exists between signals induced by the various TLRs, recent studies have identified intracellular pathways specific for individual TLRs. This leads to the release of cytokine profiles specific for particular PAMPs, and thus, TLRs confer a certain degree of specificity to the innate-immune response. In addition to the activation of the innate-immune response, TLR-mediated recognition represents a link between the innate- and acquired-immune systems, by inducing the maturation of dendritic cells and directing the T helper responses. Alternatively, recent data have also suggested TLR-mediated escape mechanisms used by certain pathogenic microorganisms, especially through TLR2 induction of anti-inflammatory cytokines. Finally, the crucial role of TLRs for the host defense against infections has been strengthened recently by the description of patients partially defective in the TLR-activation pathways.

Animals↗

PubMed2004

Evasive maneuvers by secreted bacterial proteins to avoid innate immune responses.

To cause disease, bacterial pathogens must first breach physical barriers, such as the mucous membrane that lines organs, and then successfully replicate and disseminate while avoiding destruction by the immune system. Many bacterial pathogens accomplish this by secreting proteins into their host environment, which act to subvert or dampen the expanding immune response. Here, we discuss how bacterial pathogens use an arsenal of secreted virulence proteins to modify the outcome of innate immune activation by altering how the immune system recognizes microbial invaders.

Bacteria↗

PubMed2004

He who laughs last laughs best--innate immunity and viral selection.

In this issue of Immunity, the Jonjic and Yokoyama teams provide evidence that beta-herpesvirus mutants can emerge under the selective pressure of innate immunity during primary infections. These rare mutants that escape natural killer cell recognition cause disease and death in mice that lack sterilizing T cell immunity.

Animals↗

PubMedDate not supplied

Nonspecific cytotoxic cells and innate immunity: regulation by programmed cell death.

Although programmed cell death (PCD) and the cellular pathology of apoptosis have been extensively studied in mammals and invertebrates, little is known regarding these important regulatory processes in cold blooded vertebrates, especially teleost fish. In the present review, select immunoregulatory properties of PCD/apoptosis in nonspecific cytotoxic cells (NCC) from catfish and tilapia were identified. The techniques used to define the characteristics of PCD in NCC were DNA ploidy, Annexin-V binding and cellular morphology. Using these procedures, we determined that the biochemical/genetic changes that NCC undergo during PCD are similar to those described in mammalian cells. We hypothesize that one immediate response of NCC to acute stress in teleost fish is the release of apoptosis regulatory factors (ARF) or stress activated serum factors (SASF) into the peripheral blood. These cytokine-like factors activate NCC by protecting them from initiation of: "activation induced cell death" (AICD); from "receptor induced apoptosis"; and from initiation of dexamethasone induced DNA hypoploidy. We predict that the mechanism of these actions is enhanced NCC recycling capacity and initiation of migration of NCC into sites of inflammation. In this review, studies were also summarized regarding the expression and release of "death and survival proteins" by NCC. Although the survey was not exhaustive, we showed that tilapia NCC that were activated in vitro with SASF contained increased levels of two adaptor proteins (i.e. CAS, FADD) and soluble FasL. At present the relevance of expression of the adaptor proteins by NCC is not known, however, additional evidence for the role of FasL in NCC innate immune responses was presented. Interestingly, NCC contained constitutive cytosolic FasL, and activation with tumor cells caused a significant decrease in the cytoplasmic levels of this "death protein". This indicated that FasL in NCC may function as a secretory cytokine-like molecule. Unlike mammalian NK cells and T-cells, activated NCC do not express membrane FasL. A level of phosphatase regulation of NCC apoptosis was indicated by demonstrating a reduced camptothecin induce DNA hypoploidy by pretreatment of NCC with the tyrosine phosphatase inhibitor sodium orthovanadate. This review emphasized the important regulatory functions of PCD/apoptosis for NCC in innate immune responses.

Animals↗

PubMed2003

Innate immune responses to LPS in mouse lung are suppressed and reversed by neutralization of GM-CSF via repression of TLR-4.

The innate immune inflammatory response to lipopolysaccharide (LPS, an endotoxin) is essential for lung host defense against infection by gram-negative bacteria but is also implicated in the pathogenesis of some lung diseases. Studies on genetically altered mice implicate granulocyte-macrophage colony-stimulating factor (GM-CSF) in lung responses to LPS; however, the physiological effects of GM-CSF neutralization are poorly characterized. We performed detailed kinetic and dose-response analyses of the lung inflammation response to LPS in the presence of the specific GM-CSF-neutralizing antibody 22E9. LPS instilled into the lungs of BALB/c mice induced a dose-dependent inflammation comprised of intense neutrophilia, macrophage infiltration and proliferation, TNF-alpha and matrix metalloproteinase release, and macrophage inflammatory protein-2 induction. The neutralization of anti-GM-CSF in a dose-dependent fashion suppressed these inflammatory indexes by 85% when given before or after LPS or after repeat LPS challenges. Here we report for the first time that the physiological expression of Toll-like receptor-4 in lung is reduced by anti-GM-CSF. We observed that lower Toll-like receptor-4 expression correlated with a similar decline in peak TNF- levels in response to endotoxin. Consequently, sustained expression of key inflammatory mediators over 24 h was reduced. These data expand the understanding of the contribution of GM-CSF to innate immune responses in lung and suggest that blocking GM-CSF might benefit some lung diseases where LPS has been implicated in etiology.

Animals↗

PubMed2005

Changes in the innate immune response of Atlantic salmon, Salmo salar L., exposed to experimental infection with Neoparamoeba sp.

An experiment was conducted to determine the effect of Neoparamoeba sp. infection on the innate immune responses of Atlantic salmon. Atlantic salmon were experimentally infected with Neoparamoeba sp. and serially sampled 0, 1, 4, 6, 8 and 11 days post-exposure (dpe). Histological analysis of infected fish gill arches identified the presence of characteristic amoebic gill disease lesions as early as 1 dpe with a steady increase in the number of affected gill filaments over time. Immune parameters investigated were anterior kidney phagocyte function (respiratory burst, chemotaxis and phagocytosis) and total plasma protein and lysozyme. In comparison with non-exposed control fish basal respiratory burst responses were suppressed at 8 and 11 dpe, while phorbol myristate acetate-stimulated activity was significantly suppressed at 11 dpe. Variable differences in phagocytic activity and phagocytic rate following infection were identified. There was an increase in the chemotactic response of anterior kidney macrophages isolated from exposed fish relative to control fish at 8 dpe. Total protein and lysozyme levels were not affected by Neoparamoeba sp. exposure.

Animals↗