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Immunology
The Matrix Protein of Human Parainfluenza Virus Type 3 Induces Mitophagy that Suppresses Interferon Responses
Apr 13, 2017   Cell Host & Microbe
Ding B, Zhang L, Li Z, Zhong Y, Tang Q, Qin Y, Chen M
The Matrix Protein of Human Parainfluenza Virus Type 3 Induces Mitophagy that Suppresses Interferon Responses
Apr 13, 2017
Cell Host & Microbe
Mitophagy is a form of autophagy that selectively removes damaged mitochondria. Impaired mitochondria can be tagged by the kinase PINK1, which triggers recruitment of the E3-ubiquitin ligase Parkin and subsequent mitochondrial sequestration within autophagosomes. We previously found that human parainfluenza virus type 3 (HPIV3) infection induces autophagy, but the type and mechanisms of autophagy induction remain unknown. Here, we show that matrix protein (M) of HPIV3 translocates to mitochondria and interacts with Tu translation elongation factor mitochondrial (TUFM). M-mediated mitophagy does not require the Parkin-PINK1 pathway but rather an interaction between M and the LC3 protein that mediates autophagosome formation. These interactions with both TUFM and LC3 are required for the induction of mitophagy and lead to inhibition of the type I interferon response. These results reveal that a viral protein is sufficient to induce mitophagy by bridging autophagosomes and mitochondria. Copyright © 2017 Elsevier Inc. All rights reserved.
Modulation of innate immunity of patients with Alzheimer's disease by omega-3 fatty acids
Apr 19, 2017   FASEB Journal : Official Publication Of The Federation Of American Societies For Experimental Biology
Fiala M, Kooij G, Wagner K, Hammock B, Pellegrini M
Modulation of innate immunity of patients with Alzheimer's disease by omega-3 fatty acids
Apr 19, 2017
FASEB Journal : Official Publication Of The Federation Of American Societies For Experimental Biology
The innate immune system of patients with Alzheimer's disease and mild cognitive impairment (MCI) is deregulated with highly increased or decreased transcription of inflammatory genes and consistently depressed phagocytosis of amyloid-β1-42 (Aβ) by monocytes and macrophages. Current immune therapies target single mechanisms in the adaptive immune system but not innate immunity. Here, we summarize recent advances in therapy by ω-3, ω-6, and epoxy fatty acids; specialized proresolving mediators; and vitamin D3 that have proven immune effects and emerging cognitive effects in patients with MCI. The hypothesis of this approach is that macrophages of normal participants, but not those of patients with Alzheimer's disease and MCI, possess effective phagocytosis for Aβ and protect homeostasis of the brain and, furthermore, that defective MCI macrophages recover phagocytic function via ω-3. Recent studies of fish-derived ω-3 supplementation in patients with MCI have shown polarization of Apoε3/ε3 patients' macrophages to an intermediate M1-M2 phenotype that is optimal for Aβ phagocytosis and the stabilization of cognitive decline. Therefore, accumulating preclinical and preliminary clinical evidence indicates that ω-3 supplementation should be tested in a randomized controlled clinical trial and that the analysis should involve the apolipoprotein E genotype and intervening conditions during trial.-Fiala, M., Kooij, G., Wagner, K., Hammock, B., Pellegrini, M. Modulation of innate immunity of patients with Alzheimer's disease by omega-3 fatty acids. © FASEB.
Molecular cloning and functional characterization of duck nucleotide-binding oligomerization domain 1 (NOD1)
Apr 22, 2017   Developmental And Comparative Immunology
Li H, Jin H, Li Y, Liu D, Foda MF, Jiang Y, Luo R
Molecular cloning and functional characterization of duck nucleotide-binding oligomerization domain 1 (NOD1)
Apr 22, 2017
Developmental And Comparative Immunology
Nucleotide-binding oligomerization domain 1 (NOD1) is an imperative cytoplasmic pattern recognition receptor (PRR) and considered as a key member of the NOD-like receptor (NLR) family which plays a critical role in innate immunity through sensing microbial components derived from bacterial peptidoglycan. In the current study, the full-length of duck NOD1 (duNOD1) cDNA from duck embryo fibroblasts (DEFs) was cloned. Multiple sequence alignment and phylogenetic analysis demonstrated that duNOD1 exhibited a strong evolutionary relationship with chicken and rock pigeon NOD1. Tissue-specific expression analysis showed that duNOD1 was widely distributed in various organs, with the highest expression observed in the liver. Furthermore, duNOD1 overexpression induced NF-κB activation in DEFs and the CARD domain is crucial for duNOD1-mediated NF-κB activation. In addition, silencing the duNOD1 decreased the activity of NF-κB in DEFs stimulated by iE-DAP. Overexpression of duNOD1 significantly increased the expression of TNF-α, IL-6, and RANTES in DEFs. These findings highlight the crucial role of duNOD1 as an intracellular sensor in duck innate immune system. Copyright © 2017. Published by Elsevier Ltd.
Promising immunotherapy against fungal diseases
Apr 21, 2017   Expert Opinion On Biological Therapy
Posch W, Steger M, Wilflingseder D, Lass-Flörl C
Promising immunotherapy against fungal diseases
Apr 21, 2017
Expert Opinion On Biological Therapy
Despite the relatively high efficacy of antifungal drugs, invasive fungal infections (IFIs) are still associated with tremendous morbidity and mortality, since late diagnosis makes an antifungal drug therapy inefficient. Therefore, antifungal immunotherapies to specifically strengthen the host´s own immune mechanisms constitute an additional promising strategy in taking action against fungal pathogens. Areas covered: The authors summarize efforts in research and clinical trials to provide safe and efficient immunotherapeutic options against invasive fungal diseases. Treatment of IFIs is challenging as the number of available antifungals is limited and further complications include: toxicity, drug interactions and the emergence of drug resistance. Susceptibility is determined by the impaired immune status of the host. Hence, augmenting immunity by immunotherapeutic interventions may offer future directions to treat IFI. Expert opinion: A much better understanding of fungus and host cell interactions is essential for the development of safe and successful immunotherapeutic strategies. Indeed, there is encouraging preliminary data available that such approaches are possible; however, current data is too limited to allow solid conclusions on the risks and benefits in the clinical setting. Clinical trials focusing on the role of adjuvant immunotherapeutics with or without a combination of antifungals are highly needed for further evaluation.
Network-assisted analysis of GWAS data identifies a functionally-relevant gene module for childhood-onset asthma
Apr 21, 2017   Scientific Reports
Liu Y, Brossard M, Sarnowski C, Vaysse A, Moffatt M, Margaritte-Jeannin P, Llinares-López F, Dizier MH, Lathrop M, Cookson W, Bouzigon E, Demenais F
Network-assisted analysis of GWAS data identifies a functionally-relevant gene module for childhood-onset asthma
Apr 21, 2017
Scientific Reports
The number of genetic factors associated with asthma remains limited. To identify new genes with an undetected individual effect but collectively influencing asthma risk, we conducted a network-assisted analysis that integrates outcomes of genome-wide association studies (GWAS) and protein-protein interaction networks. We used two GWAS datasets, each consisting of the results of a meta-analysis of nine childhood-onset asthma GWASs (5,924 and 6,043 subjects, respectively). We developed a novel method to compute gene-level P-values (fastCGP), and proposed a parallel dense-module search and cross-selection strategy to identify an asthma-associated gene module. We identified a module of 91 genes with a significant joint effect on childhood-onset asthma (P 
Bacillus subtilis Improves Immunity and Disease Resistance in Rabbits
Apr 20, 2017   Frontiers In Immunology
Guo M, Wu F, Hao G, Qi Q, Li R, Li N, Wei L, Chai T
Bacillus subtilis Improves Immunity and Disease Resistance in Rabbits
Apr 20, 2017
Frontiers In Immunology
Probiotics such as Lactobacillus and Bifidobacterium have been successfully used to promote growth and prevent diseases. Previous reports have demonstrated that Bacillus subtilis (B. subtilis) was a potential probiotic for animals. In this research, 180 B. subtilis were isolated from the soil, identified, and investigated in vitro. Furthermore, five B. subtilis were selected and mixed to investigate their effect on growth performance, immune response, intestine microbiota, and disease resistance in rabbits. Rabbits with a diet of 106 CFU g-1 mixed B. subtilis exhibited the best growth performance and higher serum IgG and IgA than controls (P 
Germ-Cell-Specific Inflammasome Component NLRP14 Negatively Regulates Cytosolic Nucleic Acid Sensing to Promote Fertilization
Apr 19, 2017   Immunity
Abe T, Lee A, Sitharam R, Kesner J, Rabadan R, Shapira SD
Germ-Cell-Specific Inflammasome Component NLRP14 Negatively Regulates Cytosolic Nucleic Acid Sensing to Promote Fertilization
Apr 19, 2017
Immunity
Cytosolic sensing of nucleic acids initiates tightly regulated programs to limit infection. Oocyte fertilization represents a scenario wherein inappropriate responses to exogenous yet non-pathogen-derived nucleic acids would have negative consequences. We hypothesized that germ cells express negative regulators of nucleic acid sensing (NAS) in steady state and applied an integrated data-mining and functional genomics approach to identify a rheostat of DNA and RNA sensing-the inflammasome component NLRP14. We demonstrated that NLRP14 interacted physically with the nucleic acid sensing pathway and targeted TBK1 (TANK binding kinase 1) for ubiquitination and degradation. We further mapped domains in NLRP14 and TBK1 that mediated the inhibitory function. Finally, we identified a human nonsense germline variant associated with male sterility that results in loss of NLRP14 function and hyper-responsiveness to nucleic acids. The discovery points to a mechanism of nucleic acid sensing regulation that may be of particular importance in fertilization. Copyright © 2017 Elsevier Inc. All rights reserved.
An Amphibian Host Defense Peptide Is Virucidal for Human H1 Hemagglutinin-Bearing Influenza Viruses
Apr 19, 2017   Immunity
Holthausen DJ, Lee SH, Kumar VT, Bouvier NM, Krammer F, Ellebedy AH, Wrammert J, Lowen AC, George S, Pillai MR, Jacob J
An Amphibian Host Defense Peptide Is Virucidal for Human H1 Hemagglutinin-Bearing Influenza Viruses
Apr 19, 2017
Immunity
Although vaccines confer protection against influenza A viruses, antiviral treatment becomes the first line of defense during pandemics because there is insufficient time to produce vaccines. Current antiviral drugs are susceptible to drug resistance, and developing new antivirals is essential. We studied host defense peptides from the skin of the South Indian frog and demonstrated that one of these, which we named "urumin," is virucidal for H1 hemagglutinin-bearing human influenza A viruses. This peptide specifically targeted the conserved stalk region of H1 hemagglutinin and was effective against drug-resistant H1 influenza viruses. Using electron microscopy, we showed that this peptide physically destroyed influenza virions. It also protected naive mice from lethal influenza infection. Urumin represents a unique class of anti-influenza virucide that specifically targets the hemagglutinin stalk region, similar to targeting of antibodies induced by universal influenza vaccines. Urumin therefore has the potential to contribute to first-line anti-viral treatments during influenza outbreaks. Copyright © 2017 Elsevier Inc. All rights reserved.
The Birds, the Bees, and Innate Immunity
Apr 19, 2017   Immunity
Barber GN
The Birds, the Bees, and Innate Immunity
Apr 19, 2017
Immunity
The cytoplasm is usually a DNA-free zone, but during fertilization, sperm DNA enters oocyte cytoplasm and could potentially trigger a response. Abe et al. (2017) identify NLRP14 as a germ-cell-specific negative regulator of DNA sensing that may be of particular importance during fertilization. Copyright © 2017 Elsevier Inc. All rights reserved.
Hair and stress: A pilot study of hair and cytokine balance alteration in healthy young women under major exam stress
Apr 19, 2017   PloS One
Peters EMJ, Müller Y, Snaga W, Fliege H, Reißhauer A, Schmidt-Rose T, Max H, Schweiger D, Rose M, Kruse J
Hair and stress: A pilot study of hair and cytokine balance alteration in healthy young women under major exam stress
Apr 19, 2017
PloS One
Mouse models show that experimental stress mimicking prolonged life-stress exposure enhances neurogenic inflammation, induces adaptive immunity cytokine-imbalance characterized by a shift to Type 1 T-helper cell cytokines and increases apoptosis of epithelial cells. This affects hair growth in otherwise healthy animals. In this study, we investigate whether a prolonged naturalistic life-stress exposure affects cytokine balance and hair parameters in healthy humans. 33 (18 exam, 15 comparison) female medical students with comparable sociobiological status were analyzed during a stressful final examination period, at three points in time (T) 12 weeks apart. T1 was before start of the learning period, T2 between the three-day written exam and an oral examination, and T3 after a 12 week rest and recovery from the stress of the examination period. Assessments included: self-reported distress and coping strategies (Perceived Stress Questionnaire [PSQ], Trier Inventory for the Assessment of Chronic Stress [TICS]), COPE), cytokines in supernatants of stimulated peripheral blood mononucleocytes (PBMCs), and trichogram (hair cycle and pigmentation analysis). Comparison between students participating in the final medical exam at T2 and non-exam students, revealed significantly higher stress perception in exam students. Time-wise comparison revealed that stress level, TH1/TH2 cytokine balance and hair parameters changed significantly from T1 to T2 in the exam group, but not the control. However, no group differences were found for cytokine balance or hair parameters at T2. The study concludes that in humans, naturalistic stress, as perceived during participation in a major medical exam, has the potential to shift the immune response to TH1 and transiently hamper hair growth, but these changes stay within a physiological range. Findings are instructive for patients suffering from hair loss in times of high stress. Replication in larger and more diverse sample populations is required, to assess suitability of trichogram analysis as biological outcome for stress studies.
The gut microbiota as a modulator of innate immunity during melioidosis
Apr 19, 2017   PLoS Neglected Tropical Diseases
Lankelma JM, Birnie E, Weehuizen TAF, Scicluna BP, Belzer C, Houtkooper RH, Roelofs JJTH, de Vos AF, van der Poll T, Budding AE, Wiersinga WJ
The gut microbiota as a modulator of innate immunity during melioidosis
Apr 19, 2017
PLoS Neglected Tropical Diseases
Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is an emerging cause of pneumonia-derived sepsis in the tropics. The gut microbiota supports local mucosal immunity and is increasingly recognized as a protective mediator in host defenses against systemic infection. Here, we aimed to characterize the composition and function of the intestinal microbiota during experimental melioidosis. C57BL/6 mice were infected intranasally with B. pseudomallei and sacrificed at different time points to assess bacterial loads and inflammation. In selected experiments, the gut microbiota was disrupted with broad-spectrum antibiotics prior to inoculation. Fecal bacterial composition was analyzed by means of IS-pro, a 16S-23S interspacer region-based profiling method. A marked shift in fecal bacterial composition was seen in all mice during systemic B. pseudomallei infection with a strong increase in Proteobacteria and decrease in Actinobacteria, with an increase in bacterial diversity. We found enhanced early dissemination of B. pseudomallei and systemic inflammation during experimental melioidosis in microbiota-disrupted mice compared with controls. Whole-genome transcriptional profiling of the lung identified several genes that were differentially expressed between mice with a normal or disrupted intestinal microbiota. Genes involved in acute phase signaling, including macrophage-related signaling pathways were significantly elevated in microbiota disrupted mice. Compared with controls, alveolar macrophages derived from antibiotic pretreated mice showed a diminished capacity to phagocytose B. pseudomallei. This might in part explain the observed protective effect of the gut microbiota in the host defense against pneumonia-derived melioidosis. Taken together, these data identify the gut microbiota as a potential modulator of innate immunity during B. pseudomallei infection.
B Cell Functions Can Be Modulated by Antimicrobial Peptides in Rainbow Trout Oncorhynchus mykiss: Novel Insights into the Innate Nature of B Cells in Fish
Apr 19, 2017   Frontiers In Immunology
Zhang XJ, Wang P, Zhang N, Chen DD, Nie P, Li JL, Zhang YA
B Cell Functions Can Be Modulated by Antimicrobial Peptides in Rainbow Trout Oncorhynchus mykiss: Novel Insights into the Innate Nature of B Cells in Fish
Apr 19, 2017
Frontiers In Immunology
B cells in fish were recently proven to have potent innate immune activities like macrophages. This inspired us to further explore the innate nature of B cells in fish. Moreover, antimicrobial peptides (AMPs) are representative molecules of innate immunity, and they can modulate the functions of macrophages. These make fish an appropriate model to study the interactions between B cells and AMPs. Interestingly, the results in this study revealed that the IgM+ and IgT+ B cells of rainbow trout could express multiple AMP genes, including four cathelicidin genes and one β-defensin gene. The expression levels of the cathelicidin genes were obviously higher than that of the β-defensin gene. Further studies revealed that intracellular, extracellular, in vitro, and in vivo stimulations could significantly increase the expression of the cathelicidin genes in trout IgM+ and IgT+ B cells but not the expression of the β-defensin gene, indicating that cathelicidin peptides are the main innate immune effectors of trout B cells. More interestingly, we found that cathelicidin peptides could significantly enhance the phagocytic, intracellular bactericidal, and reactive oxygen species activities of trout IgM+ and IgT+ B cells, a phenomenon previously reported only in macrophages, and these activities might also be mediated by the P2X7 receptor. These results collectively suggest that B cells play multiple roles in the innate immunity of fish, and they provide new evidence for understanding the close relationship between B cells and macrophages in vertebrates.
Hepatic expression of oncogenes Bmi1 and Dkk1 is up-regulated in hepatitis B virus surface antigen-transgenic mice and can be induced by treatment with HBV particles or lipopolysaccharides in vitro
Apr 18, 2017   International Journal Of Cancer
Zhang R, Real CI, Liu C, Baba HA, Gerken G, Lu M, Broering R
Hepatic expression of oncogenes Bmi1 and Dkk1 is up-regulated in hepatitis B virus surface antigen-transgenic mice and can be induced by treatment with HBV particles or lipopolysaccharides in vitro
Apr 18, 2017
International Journal Of Cancer
Previous studies have shown that hepatocellular carcinoma (HCC) develops more frequently in hepatitis B virus surface antigen (HBsAg)-transgenic mice (Alb/HBs) than in wild-type (WT) mice. However, the mechanism of this HCC model has not been well documented. Toll-like receptor 4 (Tlr4) signaling probably links innate immunity and HCC progression. The current study was designed to investigate the role of innate immunity in hepatocarcinogenesis in Alb/HBs mice. Immunohistochemical analysis of liver specimens from Alb/HBs mice (16 per group) showed that the oncogenes Bmi1 (16/16, 100%) and Dkk1 (13/16, 81.25%) were highly expressed in Alb/HBs mice, whereas the other oncogenes evaluated were expressed in smaller percentages of mice (Afp, 9/16, 56.2%; Ctnnb1, 5/16, 31.3%; Epcam, 0/16; 0%). Comparable results were obtained by quantitative PCR analysis. Hepatic gene expression of Tlr2, Tlr4, Il6 and Tnf was additionally elevated in Alb/HBs mice. Stimulation of primary murine hepatocytes with cell culture-derived HBV particles or LPS increased the expression of oncogenes (Bmi1, Dkk1) and inflammatory factors (Tnf, Il6, Tlr4). Proliferation and colony formation of hepatoma cells were enhanced by treatment with HBV and LPS and were impaired by the suppression of Bmi1 and Dkk1 by small interfering RNAs. Ssubstantial induction of BMI1 and DKK1 was found in liver biopsy samples from patients with HBV-related HCC but not in HCC samples without HBV infection background. These findings suggest that innate immunity may link inflammation and tumor progression during chronic HBV infection, involving the oncogenes BMI1 and DKK1. This article is protected by copyright. All rights reserved. © 2017 UICC.
A dual positive and negative regulation of monocyte activation by leukocyte Ig-like receptor B4 depends on the position of the tyrosine residues in its ITIMs
Apr 14, 2017   Innate Immunity
Park M, Liu RW, An H, Geczy CL, Thomas PS, Tedla N
A dual positive and negative regulation of monocyte activation by leukocyte Ig-like receptor B4 depends on the position of the tyrosine residues in its ITIMs
Apr 14, 2017
Innate Immunity
The leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory cell surface receptor, primarily expressed on mono-myeloid cells. It contains 2 C-type Ig-like extracellular domains and a long cytoplasmic domain that contains three intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Data suggest that LILRB4 suppresses Fc receptor-dependent monocyte functions via its ITIMs, but relative contributions of the three ITIMs are not characterised. To address this, tyrosine (Tyr) residues at positions 337, 389 and 419 were single, double or triple mutated to phenylalanine and stably transfected into a human monocytic cell line, THP-1. Intact Tyr389 was sufficient to maximally inhibit FcγRI-mediated TNF-α production in THP-1 cells, but, paradoxically, Tyr337 significantly enhanced TNF-α production. In contrast, bactericidal activity was significantly enhanced in mutants containing Tyr419, while Tyr337 markedly inhibited bacteria killing. Taken together, these results indicate that LILRB4 might have dual inhibitory and activating functions, depending on the position of the functional tyrosine residues in its ITIMs and/or the nature of the stimuli.
The innate immunity of guinea pigs against highly pathogenic avian influenza virus infection
Apr 18, 2017   Oncotarget
Zhang K, Wei Xu W, Zhang Z, Liu J, Li J,   . . . . . .   , Liu W, Liao M, Chen H, Gao Y, Xia X
The innate immunity of guinea pigs against highly pathogenic avian influenza virus infection
Apr 18, 2017
Oncotarget
H5N1 avian influenza viruses are a major pandemic concern. In contrast to the highly virulent phenotype of H5N1 in humans and many animal models, guinea pigs do not typically display signs of severe disease in response to H5N1 virus infection. Here, proteomic and transcriptional profiling were applied to identify host factors that account for the observed attenuation of A/Tiger/Harbin/01/2002 (H5N1) virulence in guinea pigs. RIG-I and numerous interferon stimulated genes were among host proteins with altered expression in guinea pig lungs during H5N1 infection. Overexpression of RIG-I or the RIG-I adaptor protein MAVS in guinea pig cell lines inhibited H5N1 replication. Endogenous GBP-1 expression was required for RIG-I mediated inhibition of viral replication upstream of the activity of MAVS. Furthermore, we show that guinea pig complement is involved in viral clearance, the regulation of inflammation, and cellular apoptosis during influenza virus infection of guinea pigs. This work uncovers features of the guinea pig innate immune response to influenza that may render guinea pigs resistant to highly pathogenic influenza viruses.
Treatment of advanced melanoma with laser immunotherapy and ipilimumab
Apr 18, 2017   Journal Of Biophotonics
Naylor MF, Zhou F, Geister BV, Nordquist RE, Li X, Chen WR
Treatment of advanced melanoma with laser immunotherapy and ipilimumab
Apr 18, 2017
Journal Of Biophotonics
Immunotherapy has become a promising modality for melanoma, especially using checkpoint inhibitors, which revive suppressed T cells against the cancer. Such inhibitors should work better when combined with other treatments which could increase the number and quality of anti-tumor T cells. We treated one patient with advanced (stage IV) melanoma, using the combination of laser immunotherapy (LIT), a novel immunological approach for metastatic cancers that has been shown to stimulate adaptive immunity, and ipilimumab. The patient was treated with LIT, followed with one course of ipilimumab 3 months after the beginning of LIT. After LIT treatment, all treated cutaneous melanoma in head and neck cleared completely. After the application of ipilimumab, all the tumor nodules in the lungs decreased. The patient had remained tumor free for one year. While anecdotal, the responses seen in this patient support the hypothesis that laser immunotherapy increases the number and quality of anti-tumor T cells so that ipilimumab and other checkpoint inhibitors are more effective in enhancing the therapeutic effects. Picture: Schematic of treatment using laser immunotherapy and ipilimumab on a stage IV melanoma patient. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Essential Neuroscience in Immunology
Apr 18, 2017   Journal Of Immunology (Baltimore, Md. : 1950)
Chavan SS, Tracey KJ
Essential Neuroscience in Immunology
Apr 18, 2017
Journal Of Immunology (Baltimore, Md. : 1950)
The field of immunology is principally focused on the molecular mechanisms by which hematopoietic cells initiate and maintain innate and adaptive immunity. That cornerstone of attention has been expanded by recent discoveries that neuronal signals occupy a critical regulatory niche in immunity. The discovery is that neuronal circuits operating reflexively regulate innate and adaptive immunity. One particularly well-characterized circuit regulating innate immunity, the inflammatory reflex, is dependent upon action potentials transmitted to the reticuloendothelial system via the vagus and splenic nerves. This field has grown significantly with the identification of several other reflexes regulating discrete immune functions. As outlined in this review, the delineation of these mechanisms revealed a new understanding of immunity, enabled a first-in-class clinical trial using bioelectronic devices to inhibit cytokines and inflammation in rheumatoid arthritis patients, and provided a mosaic view of immunity as the integration of hematopoietic and neural responses to infection and injury. Copyright © 2017 by The American Association of Immunologists, Inc.
Molecular identification and immunological characteristics of goose suppressor of cytokine signaling 1 (SOCS-1) in vitro and vivo following DTMUV challenge
Apr 18, 2017   Cytokine
Zhang W, Chen S, Zhang J, Wu Z, Wang M, Jia R, Zhu D, Liu M, Sun K, Yang Q, Wu Y, Chen X, Cheng A
Molecular identification and immunological characteristics of goose suppressor of cytokine signaling 1 (SOCS-1) in vitro and vivo following DTMUV challenge
Apr 18, 2017
Cytokine
Purpose suppressor of cytokine signaling 1 (SOCS-1) is inducible feedback inhibitors of cytokine signaling and involved in viral infection through regulation of both innate and adaptive immunity. In this study, we firstly cloned SOCS-1 (goSOCS-1) from duck Tembusu virus (DTMUV) infected goose. The full-length sequence of goSOCS-1 ORF is 624bp and encoded 108 amino acids. Structurally, the mainly functional regions (KIR, SH2, SOCS-box) were conserved between avian and mammalian. The tissues distribution data showed SOCS-1 highly expressed in immune related tissues (SP, LU, HG) of both gosling and adult goose. Moreover, the goSOCS-1 transcripts were induced by goIFNs in GEFs and by TLR ligands in PBMCs. Notably, upon DTMUV infection, highly expression level of goSOCS-1 was detected in vitro and in vivo with high viral load. Our results indicated that goSOCS-1 might involve in both innate and adaptive antiviral immunity of waterfowl. Copyright © 2017 Elsevier Ltd. All rights reserved.
Dynamics of adaptive immunity against phage in bacterial populations
Apr 17, 2017   PLoS Computational Biology
Bradde S, Vucelja M, Teşileanu T, Balasubramanian V
Dynamics of adaptive immunity against phage in bacterial populations
Apr 17, 2017
PLoS Computational Biology
The CRISPR (clustered regularly interspaced short palindromic repeats) mechanism allows bacteria to adaptively defend against phages by acquiring short genomic sequences (spacers) that target specific sequences in the viral genome. We propose a population dynamical model where immunity can be both acquired and lost. The model predicts regimes where bacterial and phage populations can co-exist, others where the populations exhibit damped oscillations, and still others where one population is driven to extinction. Our model considers two key parameters: (1) ease of acquisition and (2) spacer effectiveness in conferring immunity. Analytical calculations and numerical simulations show that if spacers differ mainly in ease of acquisition, or if the probability of acquiring them is sufficiently high, bacteria develop a diverse population of spacers. On the other hand, if spacers differ mainly in their effectiveness, their final distribution will be highly peaked, akin to a "winner-take-all" scenario, leading to a specialized spacer distribution. Bacteria can interpolate between these limiting behaviors by actively tuning their overall acquisition probability.
Uncompromised NK cell activation is essential for virus-specific CTL activity during acute influenza virus infection
Apr 17, 2017   Cellular & Molecular Immunology
Liu Y, Zheng J, Liu Y, Wen L, Huang L, Xiang Z, Lam KT, Lv A, Mao H, Lau YL, Tu W
Uncompromised NK cell activation is essential for virus-specific CTL activity during acute influenza virus infection
Apr 17, 2017
Cellular & Molecular Immunology
Natural killer (NK) cells are indispensable components of both the innate and adaptive immune response. However, their precise roles in the cross-talk between innate and adaptive immunity during influenza virus infection remain controversial. By comparing NK cell dynamics and activity under a sub-lethal dose and high dose of influenza virus infection, we showed that influenza virus PR8 directly infected NK cells during natural infection, which was consistent with our previous findings obtained from an in vitro investigation of human NK cells. The impairments in cytotoxicity and IFN-γ production by spleen NK cells following high-dose infection were accompanied by decreased virus-specific killing mediated by cytotoxic T lymphocytes (CTLs). Importantly, the weakened CTL activity could be reversed by adoptive transfer of spleen NK cells harvested from low-dose-infected mice but not healthy donors. Taken together, our data provide direct evidence supporting the contribution of NK cells to antiviral T-cell responses. This study also indicates that a novel NK-targeted immune evasion strategy is used by influenza virus to shrink both innate and adaptive immune responses.Cellular & Molecular Immunology advance online publication, 17 April 2017; doi:10.1038/cmi.2017.10.
Interaction Between Familial Transmission and a Constitutively Active Immune System Shapes Gut Microbiota in Drosophila melanogaster
Apr 17, 2017   Genetics
Mistry R, Kounatidis I, Ligoxygakis P
Interaction Between Familial Transmission and a Constitutively Active Immune System Shapes Gut Microbiota in Drosophila melanogaster
Apr 17, 2017
Genetics
Resident gut bacteria are constantly influencing the immune system. Yet the role of the immune system in shaping microbiota composition during an organism's lifespan has remained unclear. Experiments in mice have been inconclusive due to differences in husbandry schemes that led to conflicting results. We used Drosophila as a genetically tractable system with simpler gut bacterial population structure and streamlined genetic backgrounds and established cross schemes to address this issue. We found that depending on their genetic background, young flies had microbiota of different diversities that converged with age to the same Acetobacteraceae-dominated pattern in healthy flies. This pattern was accelerated in immune-compromised flies with higher bacterial load and gut cell death. Nevertheless, immune compromised flies resembled their genetic background, indicating that familial transmission was the main force regulating gut microbiota. In contrast, flies with a constitutively active immune system had microbiota readily distinguishable from their genetic background with the introduction and establishment of previously undetectable bacterial families. This indicated the influence of immunity over familial transmission. Moreover, hyper active immunity and increased enterocyte death resulted in the highest bacterial load observed starting from early adulthood. Cohousing experiments showed that the microenvironment also played an important role in the structure of the microbiota where flies with constitutive immunity defined the gut microbiota of their co-habitants. Our data show that in Drosophila, constitutively active immunity shapes the structure and density of gut microbiota. Copyright © 2017, The Genetics Society of America.
Baseline β-catenin, programmed death-ligand 1 expression and tumour-infiltrating lymphocytes predict response and poor prognosis in BRAF inhibitor-treated melanoma patients
Apr 16, 2017   European Journal Of Cancer (Oxford, England : 1990)
Massi D, Romano E, Rulli E, Merelli B, Nassini R, De Logu F, Bieche I, Baroni G, Cattaneo L, Xue G, Mandalà M
Baseline β-catenin, programmed death-ligand 1 expression and tumour-infiltrating lymphocytes predict response and poor prognosis in BRAF inhibitor-treated melanoma patients
Apr 16, 2017
European Journal Of Cancer (Oxford, England : 1990)
The activation of oncogenic Wnt/β-catenin pathway in melanoma contributes to a lack of T-cell infiltration. Whether baseline β-catenin expression in the context of tumour-infiltrating lymphocytes (TILs) and programmed death ligand-1 (PD-L1) overexpression correlates with prognosis of metastatic melanoma patients (MMPs) treated with mitogen-activated protein kinase, MAPK inhibitor (MAPKi) monotherapy, however, has not been fully clarified. Sixty-four pre-treatment formalin-fixed and paraffin embedded melanoma samples from MMP treated with a BRAF inhibitor (n = 39) or BRAF and MEK inhibitors (n = 25) were assessed for presence of β-catenin, PD-L1, cluster of differentiation (CD)8, CD103 and forkhead box protein P3 (FOXP3) expression by immunohistochemistry, and results were correlated with clinical outcome. Quantitative assessment of mRNA transcripts associated with Wnt/β-catenin pathway and immune response was performed in 51 patients. We found an inverse correlation between tumoural β-catenin expression and the level of CD8, CD103 or forkhead box protein P3 (FOXP3) positivity in the tumour microenvironment (TME). By multivariate analysis, PD-L1
Differential effects of low-dose fludarabine or 5-fluorouracil on the tumor growth and myeloid derived immunosuppression status of tumor-bearing mice
Apr 15, 2017   International Immunopharmacology
Abedi-Valugerdi M, Zheng W, Benkessou F, Zhao Y, Hassan M
Differential effects of low-dose fludarabine or 5-fluorouracil on the tumor growth and myeloid derived immunosuppression status of tumor-bearing mice
Apr 15, 2017
International Immunopharmacology
Myeloid-derived suppressor cells (MDSCs) accumulate in tumor-bearing hosts and play a key role in the suppression of the innate and adaptive immunity. Chemotherapeutic strategies have been developed to deplete or deactivate MDSCs in different tumor models. The pyrimidine analog, 5-fluorouracil (5-FU) is found to reduce the tumor size by depleting MDSCs. Here, we asked whether the purine analog, fludarabine (Flu), could exert similar effects. Employing a lymphoma model, we demonstrated that in mice with advanced tumors (where MDSC-induced suppression was present), treatment with a single low-dose Flu (25, 50, 100mg/kg) elevated the numbers of splenic MDSCs and serum arginase activity, and simultaneously, increased the tumor growth (only the highest dose). On the other hand, in mice with palpable tumors (where the MDSC-induced suppression was in progress), treatment with Flu had no significant effects on the tumor growth or the number of splenic MDSCs. In contrast to Flu, treatment with low-dose 5-FU, irrespective of tumor stage, caused tumor regression which coincided with significant reductions in the numbers of splenic MDSCs and blood neutrophils, but increases in the ratios of splenic CD4+ T and CD8+ T cells to suppressive MDSCs. Finally, in healthy mice (where MDSC-induced immuosuppression did not exist), 5-FU, but not Flu induced significant decreases in the number of myeloid cells in the bone marrow, naturally occurring splenic MDSCs and thymocytes. In conclusion, Flu exacerbates MDSC-induced immunosuppression in a tumor stage-dependent manner, whereas 5-FU alleviates the suppressive effects of MDSC at all stages of tumor development. Copyright © 2017 Elsevier B.V. All rights reserved.
Batf3-dependent CD8α+ Dendritic Cells Aggravates Atherosclerosis via Th1 Cell Induction and Enhanced CCL5 Expression in Plaque Macrophages
Apr 15, 2017   EBioMedicine
Li Y, Liu X, Duan W, Tian H, Zhu G, He H, Yao S, Yi S, Song W, Tang H
Batf3-dependent CD8α+ Dendritic Cells Aggravates Atherosclerosis via Th1 Cell Induction and Enhanced CCL5 Expression in Plaque Macrophages
Apr 15, 2017
EBioMedicine
Dendritic cells (DCs) play an important role in controlling T cell-mediated adaptive immunity in atherogenesis. However, the role of the basic leucine zipper transcription factor, ATF-like 3 (Batf3)-dependent CD8α+ DC subset in atherogenesis remains unclear. Here we show that Batf3-/-Apoe-/- mice, lacking CD8α+ DCs, exhibited a significant reduction in atherogenesis and T help 1 (Th1) cells compared with Apoe-/- controls. Then, we found that CD8α+ DCs preferentially induce Th1 cells via secreting interleukin-12 (IL-12), and that the expression of interferon-gamma (IFN-γ)or chemokine (C-C motif) ligand 5 (CCL5) in aorta were significantly decreased in Batf3-/-Apoe-/- mice. We further demonstrated that macrophages were the major CCL5-expressing cells in the plaque, which was significantly reduced in Batf3-/-Apoe-/- mice. Furthermore, we found CCL5 expression in macrophages was promoted by IFN-γ. Finally, we showed that Batf3-/-Apoe-/- mice displayed decreased infiltration of leukocytes in the plaque. Thus, CD8α+ DCs aggravated atherosclerosis, likely by inducing Th1 cell response, which promoted CCL5 expression in macrophages and increased infiltration of leukocytes and lesion inflammation. Copyright © 2017. Published by Elsevier B.V.
Sequential Adaptive Changes in a c-Myc-Driven Model of Hepatocellular Carcinoma
Apr 22, 2017   The Journal Of Biological Chemistry
Dolezal JM, Wang H, Kulkarni S, Jackson L, Lu J, Ranganathan S, Goetzman ES, Bharathi S, Beezhold K, Byersdorfer CA, Prochownik EV
Sequential Adaptive Changes in a c-Myc-Driven Model of Hepatocellular Carcinoma
Apr 22, 2017
The Journal Of Biological Chemistry
Hepatocellular carcinoma (HCC) is a common cancer that frequently over-expresses the c-Myc (Myc) oncoprotein. Using a mouse model of Myc-induced HCC, we studied the metabolic, biochemical and molecular changes accompanying HCC progression, regression and recurrence. These involved altered rates of pyruvate and fatty acid β-oxidation and the likely re-directing of glutamine into biosynthetic rather than energy-generating pathways. Initial tumors also showed reduced mitochondrial mass and differential contributions of electron transport chain Complexes I and II to respiration. The uncoupling of Complex II's electron transport function from its succinate dehydrogenase activity also suggested a mechanism by which Myc generates reactive oxygen species. RNA-Seq studies revealed an orderly progression of transcriptional changes involving pathways pertinent to DNA damage repair, cell cycle progression, insulin-like growth factor signaling, innate immunity and further metabolic re-programming. Only a subset of functions deregulated in initial tumors were similarly deregulated in recurrent tumors thereby indicating that the latter can "normalize" some behaviors to suit their needs. An interactive and freely available software tool was developed to allow continued analyses of these and other transcriptional profiles. Collectively, these studies define the metabolic, biochemical and molecular events accompanying HCC evolution, regression and recurrence in the absence of any potentially confounding therapies. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.

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