Innate immune memory: implications for development of pediatric immunomodulatory agents and adjuvanted vaccines

Unique features of immunity early in life include a distinct immune system particularly reliant on innate immunity, with weak T helper (Th)1-polarizing immune responses, and impaired responses to certain vaccines leading to a heightened susceptibility to infection. To these important aspects, we now add an increasingly appreciated concept that the innate immune system displays epigenetic memory of an earlier infection or vaccination, a phenomenon that has been named “trained immunity”. Exposure of neonatal leukocytes in vitro or neonatal animals or humans in vivo to specific innate immune stimuli results in an altered innate immune set point. Given the particular importance of innate immunity early in life, trained immunity to early life infection and/or immunization may play an important role in modulating both acute and chronic diseases

Multivariate inference of pathway activity in host immunity and response to therapeutics

Developing a quantitative view of how biological pathways are regulated in response to environmental factors is central for understanding of disease phenotypes. We present a computational framework, named Multivariate Inference of Pathway Activity (MIPA), which quantifies degree of activity induced in a biological pathway by computing five distinct measures from transcriptomic profiles of its member genes. Statistical significance of inferred activity is examined using multiple independent self-contained tests followed by a competitive analysis. The method incorporates a new algorithm to identify a subset of genes that may regulate the extent of activity induced in a pathway. We present an in-depth evaluation of specificity, robustness, and reproducibility of our method. We benchmarked MIPA's false positive rate at less than 1%. Using transcriptomic profiles representing distinct physiological and disease states, we illustrate applicability of our method in (i) identifying gene–gene interactions in autophagy-dependent response to Salmonella infection, (ii) uncovering gene–environment interactions in host response to bacterial and viral pathogens and (iii) identifying driver genes and processes that contribute to wound healing and response to anti-TNFα therapy. We provide relevant experimental validation that corroborates the accuracy and advantage of our method

Candida albicans Yeast, Pseudohyphal, and Hyphal Morphogenesis Differentially Affects Immune Recognition

The authors thank Amy Whittington for preliminary experiments on in vitro induction of pseudohyphae and Mihai Netea for discussions. The authors also thank Michael Weig for the pga29 strains. Funding NG and AW were supported by the Wellcome Trust (086827, 075470, 097377, 101873, and 200208); the European Union ALLFUN (FP7/2007 2013, HEALTH-2010-260338), and the MRC Centre for Medical Mycology for funding (N006364/1). LM was supported by a SORSAS (Scottish Overseas Research Students Award Scheme) from the University of Aberdeen and Funding from the Rwandan Government.Peer reviewedPublisher PD

Fungal Chitin Dampens Inflammation through IL-10 Induction Mediated by NOD2 and TLR9 Activation

Funding: JW and NARG thank the Wellcome Trust (080088, 086827, 075470), The Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology (097377) and the European Union ALLFUN (FP7/2007 2013, HEALTH-2010-260338) for funding. MGN was supported by a Vici grant of the Netherlands Organisation for Scientific Research. AJPB and DMM were funded by STRIFE, ERC-2009-AdG-249793 and AJPB additionally by FINSysB, PITN-GA-2008-214004 and the BBSRC [BB/F00513X/1]. MDL was supported by the MRC (MR/J008230/1). GDB and SV were funded by the Wellcome Trust (086558) and TB and MK were funded by the Deutsche Forschungsgemeinschaft (Bi 696/3-1; Bi 696/5-2; Bi 696/10-1). MS was supported by the Deutsche Forschungsgemeinschaft (Sch 897/1-3) and the National Institute of Dental and Craniofacial Research (R01 DE017514-01). TDK and RKSM were funded by the National Institute of Health (AR056296, AI101935) and the American Lebanese Syrian Associated Charities (ALSAC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Andreev reflection at QGP/CFL interface

In this letter we address the question of the phenomena of Andreev reflection between the cold quark-gluon plasma phase and CFL color superconductor. We show that there are two different types of reflections connected to the structure of the CFL phase. We also calculate the probability current at the interface and we show that it vanishes for energy of scattering quarks below the superconducting gap.Comment: 6 pages, 1 figure. Minor changes in the "Conclusions

Change of bilateral difference in radial artery pulse morphology with one-side arm movement

Previous studies have demonstrated that the compliance of peripheral artery changes with arm movement. This study aimed to quantify the bilateral difference in radial artery pulse morphology with one-side arm movement. Twenty-four healthy subjects were recruited. Radial artery pulses were synchronously recorded from both arms, with one arm (left or right) at five different positions (90°, 45°, 0°, −45° and −90°) and the other arm at horizontal level (0°) as reference. Two types of indices of arterial pulse morphology were derived from the normalized arterial pulse signals: the waveform width corresponding to the 50%, 60% and 70% pulse amplitude (W50, W60, W70) and the total area of normalized pulse waveform (Apulse). No matter whether the moving arm was left or right arm, when compared with the other side reference arm, all the waveform widths decreased with arm moving from 90°, 45°, 0°, −45°, and −90°. The bilateral difference of W50, W60 and W70 with the moving arm (either left or right) at 90°, 45° were significantly positive (both p < 0.01) and significantly negative at −90° (both p < 0.05). Meanwhile, no matter whether the moving arm is left or right, Apulse decreased with arm moving from 90°, 45°, 0°, −45°, and −90°. The bilateral difference of Apulse with the left moving arm were significantly positive at 45°, 90° (both p < 0.05). Meanwhile, the bilateral difference of Apulse from the moving right arm was significantly positive at 90° and significantly negative at −45° and −90° (all p < 0.05). In summary, this study quantified the bilateral arterial pulse morphology between arteries with different compliances induced by a simple arm positioning procedure

Lactate signalling regulates fungal β-glucan masking and immune evasion

AJPB: This work was supported by the European Research Council (STRIFE, ERC- 2009-AdG-249793), The UK Medical Research Council (MR/M026663/1), the UK Biotechnology and Biological Research Council (BB/K017365/1), the Wellcome Trust (080088; 097377). ERB: This work was supported by the UK Biotechnology and Biological Research Council (BB/M014525/1). GMA: Supported by the CNPq-Brazil (Science without Borders fellowship 202976/2014-9). GDB: Wellcome Trust (102705). CAM: This work was supported by the UK Medical Research Council (G0400284). DMM: This work was supported by UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/K000306/1). NARG/JW: Wellcome Trust (086827, 075470,101873) and Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology (097377). ALL: This work was supported by the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1).Peer reviewedPostprin

Trained immunity or tolerance : opposing functional programs induced in human monocytes after engagement of various pattern recognition receptors

Article Accepted Date: 29 January 2014. ACKNOWLEDGMENTS D.C.I. received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement HEALTH-2010-260338 (“Fungi in the setting of inflammation, allergy and autoimmune diseases: translating basic science into clinical practices” [ALLFUN]) (awarded to M.G.N.). M.G.N. and J.Q. were supported by a Vici grant of the Netherlands Organization of Scientific Research (awarded to M.G.N.). This work was supported, in part, by National Institutes of Health grant GM53522 to D.L.W. N.A.R.G. was supported by the Wellcome Trust.Peer reviewedPublisher PD

The dipeptidylpeptidase-IV inhibitors sitagliptin, vildagliptin and saxagliptin do not impair innate and adaptive immune responses

Inhibitors of dipeptidylpeptidase IV (DPP-IV) represent a novel class of frequently used anti-diabetic drugs. In addition to its function in metabolic regulation, DPP-IV also plays a role in the immune system. Whether the DPP-IV inhibitors sitagliptin, vildagliptin or saxagliptin impair immune responses is, however, currently unknown. Here, we investigated the effect of these agents on both innate and adaptive immunity. We found that the DPP-IV inhibitors did not affect the innate immune response induced by Toll-like receptor (TLR) ligands, as cytokine secretion and induction of co-stimulatory molecules by human blood mononuclear cells was not impaired. Furthermore, proliferation of T cells and suppressive function of regulatory T cells was preserved. Mice treated with vildagliptin showed normal cytokine production, immune cell activation and lymphocyte trafficking upon TLR activation. Thus, crucial immunological parameters remain unaffected upon treatment with DPP-IV inhibitors, a fact that is reassuring with respect to safety of these drugs

Dectin-1 plays a redundant role in the immunomodulatory activities of β-glucan-rich ligands in vivo

Copyright © 2013 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.Peer reviewedPublisher PD