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Innate Immunity to H5N1 Influenza Viruses in Humans  [PDF]
Irene Ramos,Ana Fernandez-Sesma
Viruses , 2012, DOI: 10.3390/v4123363
Abstract: Avian influenza virus infections in the human population are rare due to their inefficient direct human-to-human transmission. However, when humans are infected, a strong inflammatory response is usually induced, characterized by elevated levels of cytokines and chemokines in serum, believed to be important in the severe pathogenesis that develops in a high proportion of these patients. Extensive research has been performed to understand the molecular viral mechanisms involved in the H5N1 pathogenesis in humans, providing interesting insights about the virus-host interaction and the regulation of the innate immune response by these highly pathogenic viruses. In this review we summarize and discuss the most important findings in this field, focusing mainly on H5N1 virulence factors and their impact on the modulation of the innate immunity in humans.
Curating the innate immunity interactome
David J Lynn, Calvin Chan, Misbah Naseer, Melissa Yau, Raymond Lo, Anastasia Sribnaia, Giselle Ring, Jaimmie Que, Kathleen Wee, Geoffrey L Winsor, Matthew R Laird, Karin Breuer, Amir K Foroushani, Fiona SL Brinkman, Robert EW Hancock
BMC Systems Biology , 2010, DOI: 10.1186/1752-0509-4-117
Abstract: Here, we describe the InnateDB curation project, which is manually annotating the human and mouse innate immunity interactome in rich contextual detail, and present our novel curation software system, which has been developed to ensure interactions are curated in a highly accurate and data-standards compliant manner. To date, over 13,000 interactions (protein, DNA and RNA) have been curated from the biomedical literature. Here, we present data, illustrating how InnateDB curation of the innate immunity interactome has greatly enhanced network and pathway annotation available for systems-level analysis and discuss the challenges that face such curation efforts. Significantly, we provide several lines of evidence that analysis of the innate immunity interactome has the potential to identify novel signalling, transcriptional and post-transcriptional regulators of innate immunity. Additionally, these analyses also provide insight into the cross-talk between innate immunity pathways and other biological processes, such as adaptive immunity, cancer and diabetes, and intriguingly, suggests links to other pathways, which as yet, have not been implicated in the innate immune response.In summary, curation of the InnateDB interactome provides a wealth of information to enable systems-level analysis of innate immunity.The immune system is traditionally divided into two different branches - the adaptive immune system, the arm of the immune system that mounts a specific response to foreign antigens, and the innate immune system. The importance of the innate immune response is now well recognised as the first, and perhaps even the most critical, line of defence against invading pathogens and there has been an explosion of interest in investigating it. Innate immunity is fast-acting by comparison to the adaptive response, which can take several days to respond, and furthermore, innate immunity instructs, regulates and shapes the subsequent adaptive response [1,2].Despite the lack of
Surface α-1,3-Glucan Facilitates Fungal Stealth Infection by Interfering with Innate Immunity in Plants  [PDF]
Takashi Fujikawa,Ayumu Sakaguchi equal contributor,Yoko Nishizawa equal contributor,Yusuke Kouzai,Eiichi Minami,Shigekazu Yano,Hironori Koga,Tetsuo Meshi,Marie Nishimura
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002882
Abstract: Plants evoke innate immunity against microbial challenges upon recognition of pathogen-associated molecular patterns (PAMPs), such as fungal cell wall chitin. Nevertheless, pathogens may circumvent the host PAMP-triggered immunity. We previously reported that the ascomycete Magnaporthe oryzae, a famine-causing rice pathogen, masks cell wall surfaces with α-1,3-glucan during invasion. Here, we show that the surface α-1,3-glucan is indispensable for the successful infection of the fungus by interfering with the plant's defense mechanisms. The α-1,3-glucan synthase gene MgAGS1 was not essential for infectious structure development but was required for infection in M. oryzae. Lack or degradation of surface α-1,3-glucan increased fungal susceptibility towards chitinase, suggesting the protective role of α-1,3-glucan against plants' antifungal enzymes during infection. Furthermore, rice plants secreting bacterial α-1,3-glucanase (AGL-rice) showed strong resistance not only to M. oryzae but also to the phylogenetically distant ascomycete Cochlioborus miyabeanus and the polyphagous basidiomycete Rhizoctonia solani; the histocytochemical analysis of the latter two revealed that α-1,3-glucan also concealed cell wall chitin in an infection-specific manner. Treatment with α-1,3-glucanase in vitro caused fragmentation of infectious hyphae in R. solani but not in M. oryzae or C. miyabeanus, indicating that α-1,3-glucan is also involved in maintaining infectious structures in some fungi. Importantly, rapid defense responses were evoked (a few hours after inoculation) in the AGL-rice inoculated with M. oryzae, C. miyabeanus and R. solani as well as in non-transgenic rice inoculated with the ags1 mutant. Taken together, our results suggest that α-1,3-glucan protected the fungal cell wall from degradative enzymes secreted by plants even from the pre-penetration stage and interfered with the release of PAMPs to delay innate immune defense responses. Because α-1,3-glucan is nondegradable in plants, it is reasonable that many fungal plant pathogens utilize α-1,3-glucan in the innate immune evasion mechanism and some in maintaining the structures.
Effect of Oral Administration of Enterococcus faecium Ef1 on Innate Immunity of Sucking Piglets  [PDF]
Wei-fen Li, Yi Huang§, Ya-li Li, Qin Huang, Zhi-wen Cui, Dong-you Yu, Imran R. Rajput and Cai-hong Hu*
Pakistan Veterinary Journal , 2013,
Abstract: The objective of this study was to evaluate the effect of orally administered Enterococcus faecium EF1 on innate immune responses of jejunal mucosa in newborn piglets. Twenty-four commercial crossbred healthy newborn piglets were randomly divided into two groups, control (T0) and treatment (T1) group. Each group consists of 12 piglets. T1 was administered sterilized skim milk 2 ml piglet-1 day-1 with addition of E. faecium EF1 (5~6×108 cfu/ml) by oral gavage on alternative odd days (1st, 3rd and 5th) after birth. T0 fed with the same volume of sterilized skim milk without probiotics. The merciful killing of piglets at the 25th day after birth was performed to collect the samples of jejunal mucosa to measure the innate cytokine responses and the Toll-like receptors gene expression by quantitative real time PCR. The results showed that TGF-β1 and TNF-α concentrations increased and mRNA expression levels also improved significantly in T1 as compared to T0. While, the production of IFN-γ and IL-8 decreased significantly in T1 and gene expression modification was not observed. In addition, TLR (Toll-like receptor) 2 and TLR 9 transcription levels were up-regulated in treatment (T1) group. These findings revealed that oral administration of E. faecium EF1 was effective to activate innate immunity and could modulate the TLRs expression in jejunal mucosa of piglets.
HMGB1 and Cord Blood: Its Role as Immuno-Adjuvant Factor in Innate Immunity  [PDF]
Alessandra Ciucci, Ida Gabriele, Zulema A. Percario, Elisabetta Affabris, Vittorio Colizzi, Giorgio Mancino
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023766
Abstract: In newborn the innate immune system provides essential protection during primary infections before the generation of an appropriate adaptive immune response that is initially not fully operative. Innate immune response is evoked and perpetuated by molecules derived from microorganisms or by the damage/death of host cells. These are collectively known as damage-associated molecular-pattern (DAMP) molecules. High-mobility group box 1 protein (HMGB1) or amphoterin, which previously was considered to be only a nuclear factor, has been recently identified as a DAMP molecule. When it is actively secreted by inflammatory cells or passively released from necrotic cells, HMGB1 mediates the response to infection, injury and inflammation, inducing dendritic cells maturation and T helper-1-cell responses. To characterize the role of HMGB1 in the innate and immature defense mechanisms in newborns, human cord blood (CB) mononuclear cells, in comparison to adult peripheral blood (PB) mononuclear cells, have been analyzed for its expression. By flow cytometry and western blot analysis, we observed that in CB and PB cells: i) HMGB1 is expressed on cell surface membranes of myeloid dendritic cell precursors, mostly, and lymphocytes (gamma/delta and CD4+ T cells) to a lesser extent; ii) different pro-inflammatory stimuli or molecules that mimic infection increased cell surface expression of HMGB1 as well as its secretion into extracellular environment; iii) the treatment with synthetic molecules such as aminobisphosphonates (ABs), identified to be γδ T cell antigens, triggered up-regulation of HMGB1 expression on mononuclear cells, as well γδ T lymphocytes, inducing its secretion. The modulation of its secretion and the HMGB1-mediated migration of monocytes indicated HMGB1 as regulator of immune response in an immature system, like CB, through engagement of γδ T lymphocytes and myeloid dendritic cell precursors, essential components of innate immunity. In addition, the increased HMGB1 expression/secretion triggered by ABs, previously characterized for their immuno-modulating and immune-adjuvant capabilities, indicated that immunomodulation might represent a new therapeutical approach for neonatal and adult pathologies.
Chronic Heat Stress Weakened the Innate Immunity and Increased the Virulence of Highly Pathogenic Avian Influenza Virus H5N1 in Mice
Yi Jin,Yanxin Hu,Deping Han,Ming Wang
Journal of Biomedicine and Biotechnology , 2011, DOI: 10.1155/2011/367846
Abstract: Chronic heat stress (CHS) can negatively affect immune response in animals. In this study we assessed the effects of CHS on host innate immunity and avian influenza virus H5N1 infection in mice. Mice were divided into two groups: CHS and thermally neutral (TN). The CHS treatment group exhibited reduced local immunity in the respiratory tract, including the number of pulmonary alveolar macrophages and lesions in the nasal mucosa, trachea, and lungs. Meanwhile, CHS retarded dendritic cells (DCs) maturation and reduced the mRNA levels of IL-6 and IFN- significantly (<.05). After the CHS treatment, mice were infected with H5N1 virus. The mortality rate and viral load in the lungs of CHS group were higher than those of TN group. The results suggest that the CHS treatment could suppress local immunity in the respiratory tract and innate host immunity in mice significantly and moderately increased the virulence in H5N1-infected mice.
A Shared Role for RBF1 and dCAP-D3 in the Regulation of Transcription with Consequences for Innate Immunity  [PDF]
Michelle S. Longworth ,James A. Walker,Endre Anderssen,Nam-Sung Moon,Andrew Gladden,Margarete M. S. Heck,Sridhar Ramaswamy,Nicholas J. Dyson
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002618
Abstract: Previously, we discovered a conserved interaction between RB proteins and the Condensin II protein CAP-D3 that is important for ensuring uniform chromatin condensation during mitotic prophase. The Drosophila melanogaster homologs RBF1 and dCAP-D3 co-localize on non-dividing polytene chromatin, suggesting the existence of a shared, non-mitotic role for these two proteins. Here, we show that the absence of RBF1 and dCAP-D3 alters the expression of many of the same genes in larvae and adult flies. Strikingly, most of the genes affected by the loss of RBF1 and dCAP-D3 are not classic cell cycle genes but are developmentally regulated genes with tissue-specific functions and these genes tend to be located in gene clusters. Our data reveal that RBF1 and dCAP-D3 are needed in fat body cells to activate transcription of clusters of antimicrobial peptide (AMP) genes. AMPs are important for innate immunity, and loss of either dCAP-D3 or RBF1 regulation results in a decrease in the ability to clear bacteria. Interestingly, in the adult fat body, RBF1 and dCAP-D3 bind to regions flanking an AMP gene cluster both prior to and following bacterial infection. These results describe a novel, non-mitotic role for the RBF1 and dCAP-D3 proteins in activation of the Drosophila immune system and suggest dCAP-D3 has an important role at specific subsets of RBF1-dependent genes.
Phosphorylation-Dependent Differential Regulation of Plant Growth, Cell Death, and Innate Immunity by the Regulatory Receptor-Like Kinase BAK1  [PDF]
Benjamin Schwessinger,Milena Roux,Yasuhiro Kadota,Vardis Ntoukakis,Jan Sklenar,Alexandra Jones,Cyril Zipfel
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002046
Abstract: Plants rely heavily on receptor-like kinases (RLKs) for perception and integration of external and internal stimuli. The Arabidopsis regulatory leucine-rich repeat RLK (LRR-RLK) BAK1 is involved in steroid hormone responses, innate immunity, and cell death control. Here, we describe the differential regulation of three different BAK1-dependent signaling pathways by a novel allele of BAK1, bak1-5. Innate immune signaling mediated by the BAK1-dependent RKs FLS2 and EFR is severely compromised in bak1-5 mutant plants. However, bak1-5 mutants are not impaired in BR signaling or cell death control. We also show that, in contrast to the RD kinase BRI1, the non-RD kinases FLS2 and EFR have very low kinase activity, and we show that neither was able to trans-phosphorylate BAK1 in vitro. Furthermore, kinase activity for all partners is completely dispensable for the ligand-induced heteromerization of FLS2 or EFR with BAK1 in planta, revealing another pathway specific mechanistic difference. The specific suppression of FLS2- and EFR-dependent signaling in bak1-5 is not due to a differential interaction of BAK1-5 with the respective ligand-binding RK but requires BAK1-5 kinase activity. Overall our results demonstrate a phosphorylation-dependent differential control of plant growth, innate immunity, and cell death by the regulatory RLK BAK1, which may reveal key differences in the molecular mechanisms underlying the regulation of ligand-binding RD and non-RD RKs.
Innate Immunity in multiple sclerosis white matter lesions: expression of natural cytotoxicity triggering receptor 1 (NCR1)
Pascal F Durrenberger, Anna Ettorre, Fatemah Kamel, Louise V Webb, Malcolm Sim, Richard S Nicholas, Omar Malik, Richard Reynolds, Rosemary J Boyton, Daniel M Altmann
Journal of Neuroinflammation , 2012, DOI: 10.1186/1742-2094-9-1
Abstract: We first investigated the expression of NCR1 on peripheral blood mononuclear cells and found no significant difference between healthy controls and MS patients. We then investigated mRNA levels in central nervous system (CNS) tissue from MS patients: NCR1 transcripts were increased more than 5 times in active disease lesions. However when we performed immunohistochemical staining of this tissue, few NCR1+ NK cells were identified. Rather, the major part of NCR1 expression was localised to astrocytes, and was considerably more pronounced in MS patients than controls. In order to further validate de novo expression of NCR1 in astrocytes, we used an in vitro staining of the human astrocytoma U251 cell line grown to model whether cell stress could be associated with expression of NCR1. We found up-regulation of NCR1 expression in U251 cells at both the mRNA and protein levels.The data presented here show very limited expression of NCR1+ NK cells in MS lesions, the majority of NCR1 expression being accounted for by expression on astrocytes. This is compatible with a role of this cell-type and NCR1 ligand/receptor interactions in the innate immune response in the CNS in MS patients. This is the first report of NCR1 expression on astrocytes in MS tissue: it will now be important to unravel the nature of cellular interactions and signalling mediated through innate receptor expression on astrocytes.NCR1 (natural cytotoxicity triggering receptor; NKp46; CD335) is a key receptor initiating NK cell mediated cytolysis [1]. It is expressed on all human NK cells irrespective of their state of maturation and activation and has been regarded as the prototypic, pan-NK cell marker [2]. The direct killing of a target by NK cells is orchestrated by activating receptors including CD16, CD80, NCR2 (NKp44 or CD336), NCR3 (NKp30 or CD337), NKG2D (CD314), 2B4 (CD244), the novel NKp80 (KLRF1) and the killer cell immunoglobulin-like receptors-KIRs [3].NCR1 was first identified in 1997 [4] and
The Interaction between Regulatory T Cells and NKT Cells in the Liver: A CD1d Bridge Links Innate and Adaptive Immunity  [PDF]
Jing Hua, Shuwen Liang, Xiong Ma, Tonya J. Webb, James P. Potter, Zhiping Li
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027038
Abstract: Background/Aims Regulatory T cells (Tregs) and natural killer T (NKT) cells are two distinct lymphocyte subsets that independently regulate hepatic adaptive and innate immunity, respectively. In the current study, we examine the interaction between Tregs and NKT cells to understand the mechanisms of cross immune regulation by these cells. Methods The frequency and function of Tregs were evaluated in wild type and NKT cell deficient (CD1dko) mice. In vitro lymphocyte proliferation and apoptosis assays were performed with NKT cells co-cultured with Tregs. The ability of Tregs to inhibit NKT cells in vivo was examined by adoptive transfer of Tregs in a model of NKT cell mediated hepatitis. Results CD1dko mice have a significant reduction in hepatic Tregs. Although, the Tregs from CD1dko mice remain functional and can suppress conventional T cells, their ability to suppress activation induced NKT cell proliferation and to promote NKT cell apoptosis is greatly diminished. These effects are CD1d dependent and require cell to cell contact. Adoptive transfer of Tregs inhibits NKT cell-mediated liver injury. Conclusions NKT cells promote Tregs, and Tregs inhibit NKT cells in a CD1d dependent manner requiring cell to cell contact. These cross-talk immune regulations provide a linkage between innate and adaptive immunity.
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