http://hdl.handle.net/10993/104 Search this channel search https://orbilu.uni.lu/simple-search http://hdl.handle.net/10993/40897 Title: Investigation of the immune functions of DJ-1 <br/> <br/>Author, co-author: Zeng, Ni http://hdl.handle.net/10993/33066 Title: Proinflammatory T Cell Status Associated with Early Life Adversity <br/> <br/>Author, co-author: Elwenspoek, M.M.C.; Hemgesch, X.; Leenen, F.A.D; Schritz, A.; Sias, K.; Schaan, Violetta; Mériaux, S.B.; Schmitz, S.; Bonnemberger, F.; Schächinger, H.; Vögele, Claus; Turner, J.D.; Muller, C.P. <br/> <br/>Abstract: Early life adversity (ELA) has been associated with an increased risk for diseases in which the immune system plays a critical role. The ELA immune phenotype is characterized by inflammation, impaired cellular immunity, and immunosenescence. However, data on cell-specific immune effects are largely absent. Additionally, stress systems and health behaviors are altered in ELA, which may contribute to the generation of the ELA immune phenotype. The present investigation tested cell-specific immune differences in relationship to the ELA immune phenotype, altered stress parameters, and health behaviors in individuals with ELA (n = 42) and those without a history of ELA (control, n = 73). Relative number and activation status (CD25, CD69, HLA-DR, CD11a, CD11b) of monocytes, NK cells, B cells, T cells, and their main subsets were assessed by flow cytometry. ELA was associated with significantly reduced numbers of CD69+CD8+ T cells (p = 0.022), increased numbers of HLA-DR+ CD4 and HLA-DR+ CD8 T cells (p < 0.001), as well as increased numbers of CD25+CD8+ T cells (p = 0.036). ELA also showed a trend toward higher numbers of CCR4+CXCR3−CCR6+ CD4 T cells. Taken together, our data suggest an elevated state of immune activation in ELA, in which particularly T cells are affected. Although several aspects of the ELA immune phenotype were related to increased activation markers, neither stress nor health-risk behaviors explained the observed group differences. Thus, the state of immune activation in ELA does not seem to be secondary to alterations in the stress system or health-risk behaviors, but rather a primary effect of early life programming on immune cells. http://hdl.handle.net/10993/28347 Title: Chemometric analysis of attenuated total reflectance infrared spectra of Proteus mirabilis strains with defined structures of LPS. <br/> <br/>Author, co-author: Zarnowiec, Paulina; Mizera, Andrzej; Chrapek, Magdalena; Urbaniak, Mariusz; Kaca, Wieslaw http://hdl.handle.net/10993/27299 Title: Broad RNA interference-mediated antiviral immunity and virus-specific inducible responses in Drosophila <br/> <br/>Author, co-author: Kemp, Cordula; Mueller, Stefanie; Goto, Akira; Barbier, Vincent; Paro, Simona; Bonnay, François; Dostert, Catherine; Troxler, Laurent; Hetru, Charles; Meignin, Carine; Pfeffer, Sébastien; Hoffmann, Jules A.; Imler, Jean-Luc <br/> <br/>Abstract: The fruit fly Drosophila melanogaster is a good model to unravel the molecular mechanisms of innate immunity and has led to some important discoveries about the sensing and signaling of microbial infections. The response of Drosophila to virus infections remains poorly characterized and appears to involve two facets. On the one hand, RNA interference involves the recognition and processing of dsRNA into small interfering RNAs by the host RNase Dicer-2 (Dcr-2), whereas, on the other hand, an inducible response controlled by the evolutionarily conserved JAK-STAT pathway contributes to the antiviral host defense. To clarify the contribution of the small interfering RNA and JAK-STAT pathways to the control of viral infections, we have compared the resistance of flies wild-type and mutant for Dcr-2 or the JAK kinase Hopscotch to infections by seven RNA or DNA viruses belonging to different families. Our results reveal a unique susceptibility of hop mutant flies to infection by Drosophila C virus and cricket paralysis virus, two members of the Dicistroviridae family, which contrasts with the susceptibility of Dcr-2 mutant flies to many viruses, including the DNA virus invertebrate iridescent virus 6. Genome-wide microarray analysis confirmed that different sets of genes were induced following infection by Drosophila C virus or by two unrelated RNA viruses, Flock House virus and Sindbis virus. Overall, our data reveal that RNA interference is an efficient antiviral mechanism, operating against a large range of viruses, including a DNA virus. By contrast, the antiviral contribution of the JAK-STAT pathway appears to be virus specific. Copyright © 2013 by The American Association of Immunologists, Inc. http://hdl.handle.net/10993/27283 Title: Modulation of Pleurodeles waltl DNA Polymerase mu Expression by Extreme Conditions Encountered during Spaceflight <br/> <br/>Author, co-author: Schenten, Véronique; Gueguinou, Nathan; Baatout, Sarah; Frippiat, Jean-Pol <br/> <br/>Abstract: DNA polymerase μ is involved in DNA repair, V(D)J recombination and likely somatic hypermutation of immunoglobulin genes. Our previous studies demonstrated that spaceflight conditions affect immunoglobulin gene expression and somatic hypermutation frequency. Consequently, we questioned whether Polμ expression could also be affected. To address this question, we characterized Polμ of the Iberian ribbed newt Pleurodeles waltl and exposed embryos of that species to spaceflight conditions or to environmental modifications corresponding to those encountered in the International Space Station. We noted a robust expression of Polμ mRNA during early ontogenesis and in the testis, suggesting that Polμ is involved in genomic stability. Full-length Polμ transcripts are 8-9 times more abundant in P. waltl than in humans and mice, thereby providing an explanation for the somatic hypermutation predilection of G and C bases in amphibians. Polμ transcription decreases after 10 days of development in space and radiation seem primarily involved in this down-regulation. However, space radiation, alone or in combination with a perturbation of the circadian rhythm, did not affect Polμ protein levels and did not induce protein oxidation, showing the limited impact of radiation encountered during a 10-day stay in the International Space Station. © 2013 Schenten et al. http://hdl.handle.net/10993/27282 Title: Molecular cloning and expression analysis of Pleurodeles waltl complement component C3 under normal physiological conditions and environmental stresses <br/> <br/>Author, co-author: Gueguinou, Nathan; Huin-Schohn, Cécile; Ouzren-Zarhloul, Nassima; Ghislin, Stéphanie; Frippiat, Jean-Pol <br/> <br/>Abstract: C3 is a component of the complement system that plays a central role in immunity, development and tissue regeneration. In this study, we isolated the C3 cDNA of the Iberian ribbed newt Pleurodeles waltl. This cDNA encodes a 1637 amino acid protein with an estimated molecular mass of 212.5. kDa. The deduced amino acid sequence showed that P. waltl C3 contains all the conserved domains known to be critical for C3 function. Quantitative real-time PCR (qRT-PCR) demonstrated that under normal physiological conditions, P. waltl C3 mRNA is expressed early during development because it is likely required for neurulation. Then, its expression increased as the immune system developed. In adults. the liver is the richest source of C3, though other tissues can also contribute. Further analysis of C3 expression demonstrated that C3 transcription increased when P. waltl larvae were exposed to pH or temperature stress, suggesting that environmental modifications might affect this animal's defenses against pathogens. © 2014 Elsevier Ltd. http://hdl.handle.net/10993/27279 Title: The chemokine receptor CXCR3 limits injury after acute toxic liver damage <br/> <br/>Author, co-author: Moreno Zaldivar, Mirko; Berres, Marie-Luise; Sahin, Hacer; Nellen, Andreas; Heinrichs, Daniel; Schmitz, Petra; Gassler, Nicolaus; Streetz, Konrad; Trautwein, Christian; Wasmuth, Hermann <br/> <br/>Abstract: Although acute liver failure is a rare disease, its presence is associated with high morbidity and mortality in affected patients. While a contribution of the immune system to the outcome of toxic liver failure is anticipated, functionally relevant immune cell receptors for liver cell damage need to be better defined. We here investigate the relevance of the chemokine receptor CXCR3, which is important for hepatic immune cell infiltration, in a model of experimental acute liver failure. Liver injury was induced by a single intraperitoneal injection of carbon tetrachloride (CCl 4) in CXCR3 -/-, CCR1 -/-, CCR5 -/- and wild-type mice. In this model, CXCR3 -/- mice displayed augmented liver damage compared with all other mouse strains as assessed by liver histology and serum transaminases 24 and 72 h after injury. Phenotypically, CXCR3 -/- mice had significantly reduced intrahepatic NK and NKT cells after injury at all investigated time points (all P≤0.05), but strongly elevated expression levels of IL1-Β, TNF-α and IFN-γ. In line with a functional role of innate immune cells, wild-type mice depleted for NK cells with an anti-ASIALO GM1 antibody before liver injury also displayed increased liver injury after CCl 4 challenge. CXCR3 -/- and NK cell-depleted mice show reduced apoptotic liver cells (TUNEL assay), but more necrotic hepatocytes. Functionally, the augmented liver cell necrosis in CXCR3 -/- and NK cell-depleted mice was associated with increased expression of high mobility group 1 (HMGB1) protein and a consecutive enhanced infiltration of neutrophils into the liver. In conclusion, the results demonstrate a primarily unexpected beneficial role of CXCR3 in acute toxic liver injury. These findings should be taken into account when planning trials with CXCR3 antagonists. © 2012 USCAP, Inc All rights reserved. http://hdl.handle.net/10993/27263 Title: Pharmacological countermeasures to spaceflight-induced alterations of the immune system <br/> <br/>Author, co-author: Gueguinou, Nathan; Bascove, Matthieu; Frippiat, Jean-Pol <br/> <br/>Abstract: Opportunities for microbes to establish infections are enhanced under spaceflight conditions because space travel stimulates their growth (Chap. 15) and has a negative impact on immune functions. Indeed, it has been shown that spaceflight affects lymphoid organs (Gridley et al. 2003; Baqai et al. 2009) and induces variations in peripheral blood leukocyte subsets (Chap. 9). Neutrophil, monocyte, and NK cell functions are affected by spaceflight (Chaps. 10-12). The activation of T lymphocytes is also severely depressed under low gravity conditions (Cogoli et al. 1984) because interleukin-2 (IL-2) and IL-2receptor gene expression are modified, the delivery of the costimulatory signal to activate the B7/CD28 pathway and the protein kinase A (PKA) signaling pathway, which is a key early regulator in T cell activation, are hindered. Furthermore, a TH2 cytokine shift is associated with spaceflight. If this TH2 shift persists during long missions, it could represent a significant clinical risk for TH2-related autoimmune diseases, allergies, hypersensitivities, and disease susceptibility related to diminished cell-mediated immunity. Studies on plasma antibody levels did not reveal significant changes after short spaceflights (Rykova et al. 2008), but contradictory results were reported after long missions. Indeed, several studies (Konstantinova et al. 1993; Bascove et al. 2008, 2009; Guéguinou et al. 2009, 2010) reported increased levels of immunoglobulin while Rykova et al. (2008) reported normal amounts of antibodies after prolonged space missions. Lastly, a differential sensitivity of cellular and humoral immunity to spaceflight conditions seems to exist because it was shown that the cellular, but not the humoral, systems are affected by short periods of flight. © 2012 Springer-Verlag Berlin Heidelberg. All rights are reserved. <br/> <br/>Commentary: 9783642222726; 3642222714; 9783642222719 http://hdl.handle.net/10993/27259 Title: Innate and adaptive effects of inflammasomes on T cell responses <br/> <br/>Author, co-author: Dostert, Catherine; Ludigs, Kristina; Guarda, Greta <br/> <br/>Abstract: Inflammasomes are protein complexes that form in response to pathogen-derived or host-derived stress signals. Their activation leads to the production of inflammatory cytokines and promotes a pyrogenic cell death process. The massive release of inflammatory mediators that follows inflammasome activation is a key event in alarming innate immune cells. Growing evidence also highlights the role of inflammasome-dependent cytokines in shaping the adaptive immune response, as exemplified by the capacity of IL-1β to support Th17 responses, or by the finding that IL-18 evokes antigen-independent IFN-γ secretion by memory CD8+ T cells. A deeper understanding of these mechanisms and on how to manipulate this powerful inflammatory system therefore represents an important step forward in the development of improved vaccine strategies. © 2013 Elsevier Ltd. http://hdl.handle.net/10993/26351 Title: Near Full-Length Characterization and Population Dynamics of the Human Immunodeficiency Virus Type I Circulating Recombinant Form 42 (CRF42_BF) in Luxembourg <br/> <br/>Author, co-author: De Landtsheer, Sébastien http://hdl.handle.net/10993/22027 Title: Inflammation Promotes a Conversion of Astrocytes into Neural Progenitor Cells via NF-κB Activation <br/> <br/>Author, co-author: Gabel, Sebastien; Koncina, Eric; Dorban, Gauthier; Heurtaux, Tony; Birck, Cindy; Glaab, Enrico; Michelucci, Alessandro; Heuschling, Paul; Grandbarbe, Luc <br/> <br/>Abstract: Brain inflammation, a common feature in neurodegenerative diseases, is a complex series of events, which can be detrimental and even lead to neuronal death. Nonetheless, several studies suggest that inflammatory signals are also positively influencing neural cell proliferation, survival, migration, and differentiation. Recently, correlative studies suggested that astrocytes are able to dedifferentiate upon injury and may thereby re-acquire neural stem cell (NSC) potential. However, the mechanism underlying this dedifferentiation process upon injury remains unclear. Here, we report that during the early response of reactive gliosis, inflammation induces a conversion of mature astrocytes into neural progenitors. A TNF treatment induces the decrease of specific astrocyte markers, such as glial fibrillary acidic protein (GFAP) or genes related to glycogen metabolism, while a subset of these cells re-expresses immaturity markers, such as CD44, Musashi-1, and Oct4. Thus, TNF treatment results in the appearance of cells that exhibit a neural progenitor phenotype and are able to proliferate and differentiate into neurons and/or astrocytes. This dedifferentiation process is maintained as long as TNF is present in the culture medium. In addition, we highlight a role for Oct4 in this process, since the TNF-induced dedifferentiation can be prevented by inhibiting Oct4 expression. Our results show that activation of the NF-κB pathway through TNF plays an important role in the dedifferentiation of astrocytes via the re-expression of Oct4. These findings indicate that the first step of reactive gliosis is in fact a dedifferentiation process of resident astrocytes mediated by the NF-κB pathway. http://hdl.handle.net/10993/16443 Title: Inference of surface membrane factors of HIV-1 infection through functional interaction networks. <br/> <br/>Author, co-author: Ertaylan, Gökhan; Jaeger, S.; van Dijk, D.; Leser, U.; Sloot, P. <br/> <br/>Abstract: Background: HIV infection affects the populations of T helper cells, dendritic cells and macrophages. Moreover, it has a serious impact on the central nervous system. It is yet not clear whether this list is complete and why specifically those cell types are affected. To address this question, we have developed a method to identify cellular surface proteins that permit, mediate or enhance HIV infection in different cell/tissue types in HIV-infected individuals. Receptors associated with HIV infection share common functions and domains and are involved in similar cellular processes. These properties are exploited by bioinformatics techniques to predict novel cell surface proteins that potentially interact with HIV. METHODOLOGY/PRINCIPAL FINDINGS: We compiled a set of surface membrane proteins (SMP) that are known to interact with HIV. This set is extended by proteins that have direct interaction and share functional similarity. This resulted in a comprehensive network around the initial SMP set. Using network centrality analysis we predict novel surface membrane factors from the annotated network. We identify 21 surface membrane factors, among which three have confirmed functions in HIV infection, seven have been identified by at least two other studies, and eleven are novel predictions and thus excellent targets for experimental investigation. CONCLUSIONS: Determining to what extent HIV can interact with human SMPs is an important step towards understanding patient specific disease progression. Using various bioinformatics techniques, we generate a set of surface membrane factors that constitutes a well-founded starting point for experimental testing of cell/tissue susceptibility of different HIV strains as well as for cohort studies evaluating patient specific disease progression. http://hdl.handle.net/10993/16442 Title: Identifying potential survival strategies of HIV-1 through virus-host protein interaction networks <br/> <br/>Author, co-author: Ertaylan, Gökhan; van Dijk, D.; Boucher, C. A.; Sloot, P. M. <br/> <br/>Abstract: Background: The National Institute of Allergy and Infectious Diseases has launched the HIV-1 Human Protein Interaction Database in an effort to catalogue all published interactions between HIV-1 and human proteins. In order to systematically investigate these interactions functionally and dynamically, we have constructed an HIV-1 human protein interaction network. This network was analyzed for important proteins and processes that are specific for the HIV life-cycle. In order to expose viral strategies, network motif analysis was carried out showing reoccurring patterns in virus-host dynamics. RESULTS: Our analyses show that human proteins interacting with HIV form a densely connected and central sub-network within the total human protein interaction network. The evaluation of this sub-network for connectivity and centrality resulted in a set of proteins essential for the HIV life-cycle. Remarkably, we were able to associate proteins involved in RNA polymerase II transcription with hubs and proteasome formation with bottlenecks. Inferred network motifs show significant over-representation of positive and negative feedback patterns between virus and host. Strikingly, such patterns have never been reported in combined virus-host systems. CONCLUSIONS: HIV infection results in a reprioritization of cellular processes reflected by an increase in the relative importance of transcriptional machinery and proteasome formation. We conclude that during the evolution of HIV, some patterns of interaction have been selected for resulting in a system where virus proteins preferably interact with central human proteins for direct control and with proteasomal proteins for indirect control over the cellular processes. Finally, the patterns described by network motifs illustrate how virus and host interact with one another. http://hdl.handle.net/10993/1464 Title: HIV-1 Vpu's lipid raft association is dispensable for counteraction of the particle release restriction imposed by CD317/Tetherin. <br/> <br/>Author, co-author: Fritz, Joëlle; Tibroni, Nadine; Keppler, Oliver T.; Fackler, Oliver T. <br/> <br/>Abstract: HIV-1 Vpu antagonizes the block to particle release mediated by CD317 (BST-2/HM1.24/Tetherin) via incompletely understood mechanisms. Vpu and CD317 partially reside in cholesterol-rich lipid rafts where HIV-1 budding preferentially occurs. Here we find that lipid raft association of ectopically expressed or endogenous CD317 was unaltered upon co-expression with Vpu or following HIV-1 infection. Similarly, Vpu's lipid raft association remained unchanged upon expression of CD317. We identify amino acids V25 and Y29 of Vpu as crucial for microdomain partitioning and single substitution of these amino acids resulted in Vpu variants with markedly reduced or undetectable lipid raft association. These mutations did not affect Vpu's subcellular distribution and binding capacity to CD317, nor its ability to downmodulate cell surface CD317 and promote HIV-1 release from CD317-positive cells. We conclude that (i) lipid raft incorporation is dispensable for Vpu-mediated CD317 antagonism and (ii) Vpu does not antagonize CD317 by extraction from lipid rafts. <br/> <br/>Commentary: Copyright (c) 2011 Elsevier Inc. All rights reserved. http://hdl.handle.net/10993/8184 Title: Distinct antimicrobial peptide expression determines host species-specific bacterial associations <br/> <br/>Author, co-author: Franzenburg, Sören; Walter, Jonas; Künzel, Sven; Wang, Jun; Baines, John F; Bosch, Thomas C G; Fraune, Sebastian <br/> <br/>Abstract: Animals are colonized by coevolved bacterial communities, which contribute to the host’s health. This commensal microbiota is often highly specific to its host-species, inferring strong selective pressures on the associated microbes. Several factors, including diet, mucus composition, and the immune system have been proposed as putative determinants of host-associated bacterial communities. Here we report that species-specific antimicrobial peptides account for different bacterial communities associated with closely related species of the cnidarian Hydra. Gene family extensions for potent antimicrobial peptides, the arminins, were detected in four Hydra species, with each species possessing a unique composition and expression profile of arminins. For functional analysis, we inoculated arminin-deficient and control polyps with bacterial consortia characteristic for different Hydra species and compared their selective preferences by 454 pyrosequencing of the bacterial microbiota. In contrast to control polyps, arminin-deficient polyps displayed decreased potential to select for bacterial communities resembling their native microbiota. This finding indicates that species-specific antimicrobial peptides shape species-specific bacterial associations. http://hdl.handle.net/10993/5645 Title: Nuclear receptors in human immune cells: expressions and correlations <br/> <br/>Author, co-author: Muller, Claude P.; Schiltz, Jang; Turner, Jonathan D.; Schote, Andrea B. <br/> <br/>Abstract: Nuclear receptors (NR) are key modulators of gene transcription. Their activity is ligand induced and modulates a large variety of tissue-specific cellular functions. However, for many NR little is known about their role in cells of the immune system. In this study, expression patterns and distribution of 24 NR were investigated in human peripheral blood mononuclear cells.We provide the first evidence of the expression of the 12 receptors CAR, CoupTF , CoupTF , FXR, GCNF, HNF4 , PPAR / , PXR, RevErb , TR2, TR4 and TLX in highly purified CD4, CD8, CD19, CD14 cells. The expression profile of RevErb and LXR previously observed in B cell and macrophages, respectively, has been extended to CD4, CD8 and CD14 cells. Except for RAR , which was absence in any of the cells tested, our results suggest an almost ubiquitous expression of the NR in the different cell lineages of the immune system. The expression of CAR, CoupTF , FXR was also confirmed at a protein level and despite conspicuous mRNA levels of HNF4 , only low levels of this receptor were detectable in the nuclear fraction of PBMCs. Expression of the latter receptors was mostly only a fraction (4–20%) of their expression in the thyroid gland, the adrenal gland, the lung or subcutaneous adipose tissue. The Spearman rank order correlation test was performed to examine the correlation in expression between individual nuclear receptor pairs in the four cell types for several donors. Distinct correlation patterns were observed between receptor pairs in the individual cell types. In CD4 T cells four NR, GCNF, PPAR , PPAR 7 and RevErb are perfectly correlated with each other (P≥0.0167). In the other cell types correlations betweenNRpairs were more diverse, but also statistically highly significant. Interestingly, the relative expression level of a number of receptor pairs ranked identical or similar in at least three (CoupTF and PPAR / , CoupTF andHNF4 as well asROR and PXR) or four cell types (CoupTF and CoupTF , PPAR and RevErb ). Despite the variability of NR expression in immune cells, these results suggest that some of the NR may be co-regulated in human immune cells. http://hdl.handle.net/10993/2840 Title: From meta-omics to causality: experimental models for human microbiome research <br/> <br/>Author, co-author: Fritz, Joëlle; Desai, Mahesh; Shah, Pranjul; Schneider, Jochen; Wilmes, Paul <br/> <br/>Abstract: Large-scale ‘meta-omic’ projects are greatly advancing our knowledge of the human microbiome and its specific role in governing health and disease states. A myriad of ongoing studies aim at identifying links between microbial community disequilibria (dysbiosis) and human diseases. However, due to the inherent complexity and heterogeneity of the human microbiome, cross-sectional, case–control and longitudinal studies may not have enough statistical power to allow causation to be deduced from patterns of association between variables in high-resolution omic datasets. Therefore, to move beyond reliance on the empirical method, experiments are critical. For these, robust experimental models are required that allow the systematic manipulation of variables to test the multitude of hypotheses, which arise from high-throughput molecular studies. Particularly promising in this respect are microfluidics-based in vitro co-culture systems, which allow high-throughput first-pass experiments aimed at proving cause-and-effect relationships prior to testing of hypotheses in animal models. This review focuses on widely used in vivo, in vitro, ex vivo and in silico approaches to study host-microbial community interactions. Such systems, either used in isolation or in a combinatory experimental approach, will allow systematic investigations of the impact of microbes on the health and disease of the human host. All the currently available models present pros and cons, which are described and discussed. Moreover, suggestions are made on how to develop future experimental models that not only allow the study of host-microbiota interactions but are also amenable to high-throughput experimentation.