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Results for “Immunity, Innate”

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PubMed2006

HIV-1 infection of mononuclear phagocytic cells: the case for bacterial innate immune deficiency in AIDS.

HIV-1 infection of mononuclear phagocytic cells, comprising monocytes, macrophages, and dendritic cells, has been the subject of extensive research over the past 20 years. The roles of mononuclear phagocytic cells in transmission of HIV-1 infection and as reservoirs of actively replicating virus have received particular attention. Experimental data have also accumulated about the effects of HIV-1 on the physiological function of mononuclear phagocytic cells, particularly their role in innate immunity to bacteria. The effects of HIV-1 on bacterial innate immune responses by mononuclear phagocytic cells are discussed here together with reports of direct interactions between HIV-encoded products and bacterial innate immune signalling pathways. These reports demonstrate mechanisms for HIV-mediated disruption of innate immune responses by mononuclear phagocytic cells that could provide novel therapeutic targets in HIV-infected patients. The clinical urgency is highlighted by greatly increased risk of invasive bacterial disease in this population, even in the era of highly active antiretroviral therapy. HIV-mediated injury to bacterial innate immunity provides an experimental paradigm that could broaden our overall understanding of innate immunity and be used to study responses to pathogens other than bacteria.

Acquired Immunodeficiency Syndrome↗

PubMed2007

Heat shock protein 60: regulatory role on innate immune cells.

Human heat shock protein 60 (Hsp60) exhibits immunoregulatory properties, primarily by inducing pro-inflammatory responses in innate immune cells. Extensive analyses identified specific receptor structures for the interaction of Hsp60 with these cells. The existence of distinct receptor structures responsible for Hsp60 binding and for Hsp60-induced release of pro-inflammatory mediators has been demonstrated, implying that the interaction of Hsp60 with innate immune cells is a multifaceted process. Distinct Hsp60 epitopes responsible for binding to innate immune cells and for the activation of these cells have been identified. Depending on the cell-type, the amino acid (aa) region 481-500 or the regions aa241-260, aa391-410 and aa461-480 are involved in Hsp60-binding to innate immune cells. An entirely different Hsp60-region, aa354-365 was found to bind lipopolysaccharide, thereby mediating the pro-inflammatory effects of Hsp60. Because of its immunoregulatory properties, Hsp60 has been proposed to act as intercellular danger signal, controlling innate and adaptive immune reactions.

Amino Acid Sequence↗

PubMed2004

Innate Immune System Gene Polymorphisms in Women with Vulvovaginal Infections.

The innate immune responses at mucosal surfaces of the lower female genital tract play a central role in preventing the establishment of infection. Variability in the genes regulating innate immune recognition or response to infectious microorganisms could explain interindividual differences in susceptibility to infection and severity of infectious disorders. Of the numerous genetic variations identified within immunoregulatory genes, only a few have so far been studied in relation to infectious disorders of the lower female genital tract. Although these studies broaden our understanding of the genetic influence on mucosal innate immunity and microbiologic outcome, they also highlight the complexity of links between genotypical and phenotypical features, ie, the influence of a single genetic marker on the phenotype is at best moderate and is not constant in every ethnic/racial group. Such inconsistency is primarily attributed to gene-to-gene interactions and demographic genetic variability. Large case-control studies evaluating multiple genetic markers simultaneously in well-defined subgroups will characterize patients more accurately and pave the way to personalized medicine.

Journal Article↗

PubMed2006

Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis.

Host genetic factors that regulate innate immunity determine susceptibility to sepsis. Disruption of nuclear factor-erythroid 2-related factor 2 (Nrf2), a basic leucine zipper transcription factor that regulates redox balance and stress response, dramatically increased the mortality of mice in response to endotoxin- and cecal ligation and puncture-induced septic shock. LPS as well as TNF-alpha stimulus resulted in greater lung inflammation in Nrf2-deficient mice. Temporal analysis of pulmonary global gene expression after LPS challenge revealed augmented expression of large numbers of proinflammatory genes associated with the innate immune response at as early as 30 minutes in lungs of Nrf2-deficient mice, indicating severe immune dysregulation. The expression profile indicated that Nrf2 has a global influence on both MyD88-dependent and -independent signaling. Nrf2-deficient mouse embryonic fibroblasts showed greater activation of NF-kappaB and interferon regulatory factor 3 in response to LPS and polyinosinic-polycytidylic acid [poly(I:C)] stimulus, corroborating the effect of Nrf2 on MyD88-dependent and -independent signaling. Nrf2's regulation of cellular glutathione and other antioxidants is critical for optimal NF-kappaB activation in response to LPS and TNF-alpha. Our study reveals Nrf2 as a novel modifier gene of sepsis that determines survival by mounting an appropriate innate immune response.

Animals↗

PubMed2006

Cytokine receptor-mediated trafficking of preformed IL-4 in eosinophils identifies an innate immune mechanism of cytokine secretion.

Although leukocytes of the innate immune system, including eosinophils, contain within their granules preformed stores of cytokines available for selective and rapid release, little is known about the mechanisms governing the mobilization and secretion of these cytokines. Here we show that a cytokine receptor, the IL-4 receptor alpha chain, mediates eotaxin-stimulated mobilization of preformed IL-4 from eosinophil granules into secretory vesicles. Eosinophils contain substantial intracellular quantities of several granule- and vesicle-associated cytokine receptors, including IL-4, IL-6, and IL-13 receptors as well as CCR3. Both IL-4 and IL-4 receptor alpha chain colocalized in eosinophil granules; and after eotaxin-stimulation, IL-4 receptor alpha chain, bearing bound IL-4, was mobilized into secretory vesicles. These findings indicate that intracellular cytokine receptors within secretory vesicles transport their cognate cytokines requisite for the secretion of cytokines preformed in innate immune leukocytes.

Cells, Cultured↗

PubMed2006

Innate immunity against vaccinia virus is mediated by TLR2 and requires TLR-independent production of IFN-beta.

Vaccinia virus (VV) has been used extensively as a vaccine vehicle in the clinical application for infectious diseases and cancer. Previous studies have suggested that the unique potency of VV-based vaccine lies in its effective activation of the innate immune system. However, how VV activates innate immune pathways remains largely unknown. In this study, we showed that VV elicited innate immune response through both Toll-like receptor (TLR)-dependent and -independent pathways. The TLR pathway was mediated by TLR2 and MyD88, leading to the production of proinflammatory cytokines, whereas activation of the TLR-independent pathway resulted in the secretion of IFN-beta. More importantly, both TLR-dependent and -independent pathways were required for activating innate and adaptive immunity to VV in vivo. These findings represent the first evidence that innate immune recognition of VV is mediated by TLR2, demonstrate that one pathogen can target both TLR and non-TLR innate immune pathways to work together in achieving efficient activation of host defense, and suggest potential new strategies for the design of effective vaccines.

Animals↗

PubMed2001

New therapeutic targets revealed through investigations of innate immunity.

OBJECTIVE: This review describes efforts to define new therapeutic targets by utilizing information derived from studies of the innate immune response to infection. These targets will provide new means to design novel therapeutics for the treatment of human disease caused by dysregulation of the innate immune response. DATA SOURCES AND ANALYSIS: The results were derived from model systems that reflect the cellular changes accompanying activation of the innate immune system. These model systems include the use of a rabbit model of endotoxin shock that requires multiple exposures to lipopolysaccharide to induce severe pathophysiological changes that result in death. The cellular systems range from primary explants of myeloid lineage cells to stably transfected lines bearing key receptors of the innate immune system, the latter of which includes the Toll-like receptors and CD14. Studies in animal models include blocking monoclonal antibodies to rabbit CD14 and rabbit tumor necrosis factor-alpha. Cellular studies use measurements of cell activation as defined by activation of nuclear factor-kappaB, MAP kinase, and gene expression. In some studies, direct measurements of secreted cytokine levels were performed. Standard approaches to data analysis have been used. CONCLUSIONS: Evidence demonstrates the utility of anti-CD14 monoclonal antibody therapy in septic shock and the potential value of targeting intracellular kinases to modulate harmful cellular responses during sepsis. The key element to each of these approaches is to blunt, but not eliminate, the dysregulated inflammatory response that may occur in sepsis.

Animals↗

PubMed2005

Role of xanthine oxidase, lactoperoxidase, and NO in the innate immune system of mammary secretion during active involution in dairy cows: manipulation with casein hydrolyzates.

The aims of this study were to test whether xanthine oxidase, lactoperoxidase, and NO are components of the innate immune system of mammary secretion during active involution in dairy cows, and whether the innate immune system is activated by casein hydrolysates. Our laboratory has shown recently that infusion of CNH into mammary glands induced involution and was associated with earlier increases in the concentrations of components of the innate immune system. Intact casein is inactive and served as control. Half of the glands of 8 Holstein cows scheduled for dry off (approximately 60 days before parturition) were injected for 3 days with a single dose of casein hydrolyzates and the contralateral glands with a single dose of intact casein with the same concentration. Involution elicited marked increases in xanthine oxidase and lactoperoxidase activities, and accumulation of urate and nitrate. NO and H(2)O(2) were constantly produced in the mammary gland secretion. Nitrite formed either by autooxidation of NO or by conversion of nitrate to nitrite by xanthine oxidase was converted into the powerful nitric dioxide radical by lactoperoxidase and H(2)O(2) that is derived from the metabolism of xanthine oxidase. Nitric dioxide is most likely responsible for the formation of nitrosothiols on thiol-bearing groups, which allows an extended NO presence in mammary secretion. Nitrite is effectively converted to nitrate, which accumulated in the range of approximately 25 microM -1 mM from the start of the experiment to the complete involution of glands. The mammary secretion in all glands was bactericidal and bacteriostatic during established involution, and this appeared sooner and more acutely in glands treated with casein hydrolyzates, within 8 to 24 h. It is concluded that xanthine oxidase, lactoperoxidase, and NO are components of the mammary innate immune system that form bactericidal and bacteriostatic activities in mammary secretions. The innate immune system play a major role in preventing intramammary infection during milk stasis and its activation may increase its effectiveness.

Animals↗

PubMed1997

Complement component 3 interactions with coxsackievirus B3 capsid proteins: innate immunity and the rapid formation of splenic antiviral germinal centers.

Innate immunity is central to the clearance of pathogens from hosts as well as to the definition of acquired immune responses (D. T. Fearon, and R. M. Locksley, Science 272:50-53, 1996). Coxsackievirus B3 (CVB3), a human cardiopathic virus, was evaluated for the ability to activate the alternative and classical pathway of complement. CVB3 proteins interact with complement component 3 (C3, a soluble protein effector of innate immunity) after either in vitro exposure to mouse serum or in vivo murine infection and activate the alternative pathway of complement. In addition, we demonstrate that viral antigen retention and localization in germinal centers is dependent on C3, while virus antigen retention in extrafollicular regions in the spleen is not. In vivo depletion of native C3 abolished the rapid formation of virus-specific germinal centers (by day 3 post-CVB3 infection) in the absence of serum anti-CVB3 antibodies. These studies demonstrate that innate immune mechanisms, such as C3 interaction with CVB3, are essential for splenic antiviral germinal center formation in naive (antigen nonsensitized) mice resistant (C57BL/6J strain) and susceptible (A/J strain) to CVB3-induced myocarditis.

Animals↗

PubMed2003

Nitric oxide contributes to induction of innate immune responses to gram-negative bacteria in Drosophila.

Studies in mammals uncovered important signaling roles of nitric oxide (NO), and contributions to innate immunity. Suggestions of conservation led us to explore the involvement of NO in Drosophila innate immunity. Inhibition of nitric oxide synthase (NOS) increased larval sensitivity to gram-negative bacterial infection, and abrogated induction of the antimicrobial peptide Diptericin. NOS was up-regulated after infection. Antimicrobial peptide reporters revealed that NO triggered an immune response in uninfected larvae. NO induction of Diptericin reporters in the fat body required immune deficiency (imd) and domino. These findings show that NOS activity is required for a robust innate immune response to gram-negative bacteria, NOS is induced by infection, and NO is sufficient to trigger response in the absence of infection. We propose that NO mediates an early step of the signal transduction pathway, inducing the innate immune response upon natural infection with gram-negative bacteria.

Amino Acid Sequence↗

PubMed2004

Functional dissection of an innate immune response by a genome-wide RNAi screen.

The innate immune system is ancient and highly conserved. It is the first line of defense and the only recognizable immune system in the vast majority of metazoans. Signaling events that convert pathogen detection into a defense response are central to innate immunity. Drosophila has emerged as an invaluable model organism for studying this regulation. Activation of the NF-kappaB family member Relish by the caspase-8 homolog Dredd is a central, but still poorly understood, signaling module in the response to gram-negative bacteria. To identify the genes contributing to this regulation, we produced double-stranded RNAs corresponding to the conserved genes in the Drosophila genome and used this resource in genome-wide RNA interference screens. We identified numerous inhibitors and activators of immune reporters in a cell culture model. Epistatic interactions and phenotypes defined a hierarchy of gene action and demonstrated that the conserved gene sickie is required for activation of Relish. We also showed that a second gene, defense repressor 1, encodes a product with characteristics of an inhibitor of apoptosis protein that inhibits the Dredd caspase to maintain quiescence of the signaling pathway. Molecular analysis revealed that Defense repressor 1 is upregulated by Dredd in a feedback loop. We propose that interruption of this feedback loop contributes to signal transduction.

Amino Acid Sequence↗

PubMed2004

Neutrophils in innate immunity.

Neutrophils are an important component of innate immunity in the lungs. During bacterial pneumonia, neutrophils are recruited from the capillaries of the pulmonary circulation in the gas-exchanging regions of the lungs. This process requires the coordinated activation of many cells within the lungs, including neutrophils and capillary endothelial cells. Cellular activation during innate immune responses is mediated in part by tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1-initiated signaling through their receptors, activation of nuclear factor kappa B (NF-kappaB) and downstream gene transcription, endothelial cell signaling initiated by neutrophil adherence to intercellular adhesion molecule (ICAM)-1, and binding of leukocyte adhesion molecules to cellular and matrix ligands. These events are essential to effective host defense during pneumonia.

Journal Article↗

PubMed2025

N6-methyladenosine modification of the subgroup J avian leukosis viral RNAs attenuates host innate immunity via MDA5 signaling.

Subgroup J avian leukosis virus (ALV-J), a retrovirus, elicits immunosuppression and persistent infections in chickens. Although it is widely acknowledged that ALV-J can evade the host's innate immune defenses, the mechanisms behind this immune evasion remain elusive. N6-methyladenosine (m6A), the most prevalent internal RNA modification, plays a role in innate immune evasion. Our research identified ALV-J as an inefficient stimulator of innate immunity in vitro and in vivo, with its genomic RNA featuring m6A modifications predominantly in the envelope protein (Env) region and 3' untranslated region (3'UTR). To elucidate the functional consequences of m6A modification, we subsequently generated m6A-deficient ALV-J through its culturing in the DF-1 overexpressing fat mass and obesity-associated protein (FTO) cells. The m6A-deficient ALV-J virus, or its RNAs significantly enhanced IFN-β production compared to the wild-type (wt) ALV-J, suggesting a pivotal regulatory function of m6A modifications in modulating innate immune response. Mechanistically, the m6A modification of the ALV-J genomic RNA directly impacted its recognition by MDA5, weakening its binding and ubiquitination and attenuating IFN-β activation. Moreover, m6A-deficient ALV-J, created by inducing mutations in m6A sites within Env and 3'UTR, exhibited reduced replication capacity and elevated IFN-β expression in host cells. Importantly, this phenomenon was abolished in MDA5-knockout DF-1 cells, further demonstrating the core role of MDA5. These data demonstrate that m6A modification of ALV-J genomic RNA dampens the host's innate immune response through MDA5 signaling pathway.

Animals↗

PubMed2001

Potent stimulation of the innate immune system by a Leishmania brasiliensis recombinant protein.

The interaction of the innate immune system with the microbial world involves primarily two sets of molecules generally known as microbial pattern recognition receptors and microbial pattern recognition molecules, respectively. Examples of the former are the Toll receptors present particularly in macrophages and dendritic cells. Conversely, the microbial pattern recognition molecules are conserved protist homopolymers, such as bacterial lipopolysaccharides, lipoteichoic acids, peptidoglycans, glucans, mannans, unmethylated bacterial DNA, and double-strand viral RNA. However, for protists that lack most of these molecules, such as protozoans, the innate immune system must have evolved receptors that recognize other groups of microbial molecules. Here we present evidence that a highly purified protein encoded by a Leishmania brasiliensis gene may be one such molecule. This recombinant leishmanial molecule, a homologue of eukaryotic ribosomal elongation and initiation factor 4a (LeIF), strongly stimulates spleen cells from severe combined immunodeficient (SCID) mice to produce interleukin-12 (IL-12), IL-18, and high levels of gamma interferon. In addition, LeIF potentiates the cytotoxic activity of the NK cells of these animals. Because LeIF is a conserved molecule and because SCID mice lack T and B lymphocytes but have a normal innate immune system (normal reticuloendothelial system and NK cells), these results suggest that proteins may also be included as microbial pattern recognition molecules. The nature of the receptor involved in this innate recognition is unknown. However, it is possible to exclude the Toll receptor Tlr4 as a putative LeIF receptor because the gene encoding this receptor is defective in C3H/HeJ mice, the mouse strain used in the present studies.

Animals↗

PubMed2002

Complement-induced impairment of innate immunity during sepsis.

This study defines the molecular basis for defects in innate immunity involving neutrophils during cecal ligation/puncture (CLP)-induced sepsis in rats. Blood neutrophils from CLP rats demonstrated defective phagocytosis and defective assembly of NADPH oxidase, the latter being due to the inability of p47(phox) to translocate from the cytosol to the cell membrane of neutrophils after cell stimulation by phorbol ester (PMA). The appearance of these defects was prevented by in vivo blockade of C5a in CLP rats. In vitro exposure of neutrophils to C5a led to reduced surface expression of C5aR and defective assembly of NADPH oxidase, as defined by failure in phosphorylation of p47(phox) and its translocation to the cell membrane, together with failure in phosphorylation of p42/p44 mitogen-activated protein kinases. These data identify a molecular basis for defective innate immunity involving neutrophils during sepsis.

Animals↗

PubMed2005

The innate immune system is activated by stimulation of vaginal epithelial cells with Staphylococcus aureus and toxic shock syndrome toxin 1.

Despite knowledge of the effects of toxic shock syndrome (TSS) toxin 1 (TSST-1) on the adaptive immune system, little is known about stimulation of the innate immune system, particularly epithelial cells. This study investigated the interactions of TSS Staphylococcus aureus and TSST-1 with human vaginal epithelial cells (HVECs) and porcine mucosal surfaces. When cocultured with HVECs for 6 h, TSS S. aureus MN8 proliferated, formed aggregates on the HVEC surfaces, and produced exotoxins. Receptor binding studies showed that 35S-TSST-1 bound to 5 x 10(4) receptors per HVEC, with saturation at 15 min. Affymetrix Human GeneChip U133A microarray analysis determined S. aureus MNSM (100 bacteria/HVEC) caused at least twofold up- or down-regulation of 410 HVEC genes by 6 h; these data were also confirmed with S. aureus MN8. TSST-1 (100 microg/ml) caused up- or down-regulation of 2,386 HVEC genes by 6 h. In response to S. aureus, the HVEC genes most up-regulated compared to those in controls were those coding for chemokines or cytokines--MIP-3alpha, 478-fold; GRO-alpha, 26-fold; GRO-beta, 14-fold; and GRO-gamma, 30-fold--suggesting activation of innate immunity. TSST-1 also caused up-regulation of chemokine/cytokine genes. Chemokine/cytokine gene up-regulation was confirmed by enzyme-linked immunosorbent assays measuring the corresponding proteins induced by S. aureus and TSST-1. S. aureus MN8, when incubated with porcine vaginal tissue, increased the flux of 35S-TSST-1 across the mucosal surface. This was accompanied by influx of lymphocytes into the upper layers of the tissue. These data suggest innate immune system activation through epithelial cells, reflected in chemokine/cytokine production and influx of lymphocytes, may cause changes in vaginal mucosa permeability, facilitating TSST-1 penetration.

Animals↗

PubMed2004

Innate immunity in plants and animals: striking similarities and obvious differences.

Innate immunity constitutes the first line of defense against attempted microbial invasion, and it is a well-described phenomenon in vertebrates and insects. Recent pioneering work has revealed striking similarities between the molecular organization of animal and plant systems for nonself recognition and anti-microbial defense. Like animals, plants have acquired the ability to recognize invariant pathogen-associated molecular patterns (PAMPs) that are characteristic of microbial organisms but which are not found in potential host plants. Such structures, also termed general elicitors of plant defense, are often indispensable for the microbial lifestyle and, upon receptor-mediated perception, inevitably betray the invader to the plant's surveillance system. Remarkable similarities have been uncovered in the molecular mode of PAMP perception in animals and plants, including the discovery of plant receptors resembling mammalian Toll-like receptors or cytoplasmic nucleotide-binding oligomerization domain leucine-rich repeat proteins. Moreover, molecular building blocks of PAMP-induced signaling cascades leading to the transcriptional activation of immune response genes are shared among the two kingdoms. In particular, nitric oxide as well as mitogen-activated protein kinase cascades have been implicated in triggering innate immune responses, part of which is the production of antimicrobial compounds. In addition to PAMP-mediated pathogen defense, disease resistance programs are often initiated upon plant-cultivar-specific recognition of microbial race-specific virulence factors, a recognition specificity that is not known from animals.

Animals↗

PubMed2006

[Innate immune recognition of viral infection].

Toll-like receptors (TLRs) are key molecules of the innate immune systems, which detect conserved structures found in a broad range of pathogens and triggers innate immune responses. A subset of TLRs recognize viral components and induce antiviral responses by producing type I interferons. Whereas TLR2 and TLR4 recognize viral components at the cell surface, TLR3, TLR7, TLR8 and TLR9 are exclusively expressed in endosomal compartments. After phagocytes internalize viruses or virus-infected apoptotic cells, viral nucleic acids are released in phagolysosomes and are recognized by these TLRs. Recent reports have shown that hosts also have a mechanism to detect replicating viruses in the cytoplasm in a TLR-independent manner. In this review, we focus on the viral recognition by innate immunity and the signaling pathways.

Animals↗