Metabolic control of dendritic cell activation and function: Recent advances and clinical implications

Dendritic cells (DCs) are key regulators of both immunity and tolerance by controlling activation and polarization of effector T helper cell and regulatory T cell responses. Therefore, there is a major focus on developing approaches to manipulate DC function for immunotherapy. It is well known that changes in cellular activation are coupled to profound changes in cellular metabolism. Over the past decade there is a growing appreciation that these metabolic changes also underlie the capacity of immune cells to perform particular functions. This has led to the concept that the manipulation of cellular metabolism can be used to shape innate and adaptive immune responses. While most of our understanding in this area has been gained from studies with T cells and macrophages, evidence is emerging that the activation and function of DCs are also dictated by the type of metabolism these cells commit to. We here discuss these new insights and explore whether targeting of metabolic pathways in DCs could hold promise as a novel approach to manipulate the functional properties of DCs for clinical purposes

Conserved role for 14-3-3ϵ downstream of type I TGFβ receptors

AbstractSchistosoma mansoni receptor kinase-1 (SmRK1) is a divergent type I transforming growth factor β (TGFβ) receptor on the surface of adult parasites. Using the intracellular domain of SmRK1 as bait in a yeast two-hybrid screen we identified an interaction with S. mansoni 14-3-3ϵ. The interaction which is phosphorylation-dependent is not specific to schistosomes since 14-3-3ϵ also binds to TβRI, the human type I TGFβ receptor. 14-3-3ϵ enhances TGFβ-mediated signaling by TβRI and is the first TβRI-interacting non-Smad protein identified that positively regulates this receptor. The interaction of 14-3-3ϵ with schistosome and human TβRI suggests a conserved, but previously unappreciated, role for this protein in TGFβ signaling pathways

Phylogenetic relationships of the Wolbachia of nematodes and arthropods

Wolbachia are well known as bacterial symbionts of arthropods, where they are reproductive parasites, but have also been described from nematode hosts, where the symbiotic interaction has features of mutualism. The majority of arthropod Wolbachia belong to clades A and B, while nematode Wolbachia mostly belong to clades C and D, but these relationships have been based on analysis of a small number of genes. To investigate the evolution and relationships of Wolbachia symbionts we have sequenced over 70 kb of the genome of wOvo, a Wolbachia from the human-parasitic nematode Onchocerca volvulus, and compared the genes identified to orthologues in other sequenced Wolbachia genomes. In comparisons of conserved local synteny, we find that wBm, from the nematode Brugia malayi, and wMel, from Drosophila melanogaster, are more similar to each other than either is to wOvo. Phylogenetic analysis of the protein-coding and ribosomal RNA genes on the sequenced fragments supports reciprocal monophyly of nematode and arthropod Wolbachia. The nematode Wolbachia did not arise from within the A clade of arthropod Wolbachia, and the root of the Wolbachia clade lies between the nematode and arthropod symbionts. Using the wOvo sequence, we identified a lateral transfer event whereby segments of the Wolbachia genome were inserted into the Onchocerca nuclear genome. This event predated the separation of the human parasite O. volvulus from its cattle-parasitic sister species, O. ochengi. The long association between filarial nematodes and Wolbachia symbionts may permit more frequent genetic exchange between their genomes

Cell Death and Reproductive Regression in Female Schistosoma mansoni

The vitellarium is a highly proliferative organ, producing cells which are incorporated along with a fertilized ovum into the schistosome egg. Vitellarial growth fails to occur in virgin female schistosomes in single sex (female-only) infections, and involution of this tissue, which is accompanied by physical shrinkage of the entire worm, occurs when mature females sexually regress upon removal from their male partners. We have found that upon removal from their hosts into tissue culture, female parasites regress whether they are mated or not, but that cessation of egg production and a decline in expression of the vitelline gene p14 is delayed by mating. We used BrdU labeling to investigate whether there was a loss of proliferation in the vittelarium that might account for regression and found that the proliferation rate declined equally in paired and singled females once placed into culture. However, TUNEL staining and Caspase 3 activity measurements indicate that the loss of vitrellarial cellularity associated with regression is associated with profound apoptotic vitelline cell death, which is not apparent in the vitellaria of paired females immediately ex vivo, and which develops in vitro regardless of whether males are present or not. Furthermore, primordial vitellaria in virgin females have a high frequency of apoptotic cells but are characterized by a proliferation rate that is indistinguishable from that in fully developed vitellaria in mature paired females. Taken together, our data suggest that the vitelline proliferation rate is independent of pairing status. In contrast, the survival of vitelline cells, and therefore the development of the vitellarium, is highly male-dependent. Both processes are negatively affected by removal from the host regardless of whether male worms are present or not, and are unsustainable using standard tissue culture approaches

TGF-β Signaling Controls Embryo Development in the Parasitic Flatworm Schistosoma mansoni

Over 200 million people have, and another 600 million are at risk of contracting, schistosomiasis, one of the major neglected tropical diseases. Transmission of this infection, which is caused by helminth parasites of the genus Schistosoma, depends upon the release of parasite eggs from the human host. However, approximately 50% of eggs produced by schistosomes fail to reach the external environment, but instead become trapped in host tissues where pathological changes caused by the immune responses to secreted egg antigens precipitate disease. Despite the central importance of egg production in transmission and disease, relatively little is understood of the molecular processes underlying the development of this key life stage in schistosomes. Here, we describe a novel parasite-encoded TGF-β superfamily member, Schistosoma mansoni Inhibin/Activin (SmInAct), which is key to this process. In situ hybridization localizes SmInAct expression to the reproductive tissues of the adult female, and real-time RT-PCR analyses indicate that SmInAct is abundantly expressed in ovipositing females and the eggs they produce. Based on real-time RT-PCR analyses, SmInAct transcription continues, albeit at a reduced level, both in adult worms isolated from single-sex infections, where reproduction is absent, and in parasites from IL-7R(−/−) mice, in which viable egg production is severely compromised. Nevertheless, Western analyses demonstrate that SmInAct protein is undetectable in parasites from single-sex infections and from infections of IL-7R(−/−) mice, suggesting that SmInAct expression is tightly linked to the reproductive potential of the worms. A crucial role for SmInAct in successful embryogenesis is indicated by the finding that RNA interference–mediated knockdown of SmInAct expression in eggs aborts their development. Our results demonstrate that TGF-β signaling plays a major role in the embryogenesis of a metazoan parasite, and have implications for the development of new strategies for the treatment and prevention of an important and neglected human disease

Fatty acid oxidation is essential for egg production by the parasitic flatworm Schistosoma mansoni

Schistosomes, parasitic flatworms that cause the neglected tropical disease schistosomiasis, have been considered to have an entirely carbohydrate based metabolism, with glycolysis playing a dominant role in the adult parasites. However, we have discovered a close link between mitochondrial oxygen consumption by female schistosomes and their ability to produce eggs. We show that oxygen consumption rates (OCR) and egg production are significantly diminished by pharmacologic inhibition of carnitine palmitoyl transferase 1 (CPT1), which catalyzes a rate limiting step in fatty acid β-oxidation (FAO) and by genetic loss of function of acyl CoA synthetase, which complexes with CPT1 and activates long chain FA for use in FAO, and of acyl CoA dehydrogenase, which catalyzes the first step in FAO within mitochondria. Declines in OCR and egg production correlate with changes in a network of lipid droplets within cells in a specialized reproductive organ, the vitellarium. Our data point to the importance of regulated lipid stores and FAO for the compartmentalized process of egg production in schistosomes

The glacial geomorphology of upper Godthåbsfjord (Nuup Kangerlua) in south-west Greenland

© 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of Journal of Maps. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The Greenland Ice Sheet (GrIS) is known to have experienced widespread retreat over the last century. Information on outlet glacier dynamics, prior to this, are limited due to both a lack of observations and a paucity of mapped or mappable deglacial evidence which restricts our understanding of centennial to millennial timescale dynamics of the GrIS. Here we present glacial geomorphological mapping, for upper Godthåbsfjord, covering 5800 km 2 at a scale of 1:92,000, using a combination of ASTER GDEM V2, a medium-resolution DEM (error < 10 m horizontal and < 6 m vertical accuracy), panchromatic orthophotographs and ground truthing. This work provides a detailed geomorphological assessment for the area, compiled as a single map, comprising of moraines, meltwater channels, streamlined bedrock, sediment lineations, ice-dammed lakes, trimlines, terraces, gullied sediment and marine limits. Whilst some of the landforms have been previously identified, the new information presented here improves our understanding of ice margin behaviour and can be used for future numerical modelling and landform dating programmes. Data also form the basis for palaeoglaciological reconstructions and contribute towards understanding of the centennial to millennial timescale record of this sector of the GrIS.Peer reviewedFinal Published versio

Schistosoma mansoni in IL-4-deficient mice

Immunopathology and Immune responses to Schistosoma mansoni were examined in IL-4 -/- mice. IL-5 and IL-10 production by lymphoid cells stimulated with soluble egg antigen (SEA), peripheral eosinophilla and serum levels of soluble IL-4 receptor but not IgE were all significantly elevated over background normal levels in IL-4 -/- mice as a result of infection. Additionally, IL-10 and IL-5 in addition to IL-2 and IFN-γ transcripts were equally evident in diseased liver tissue from infected IL-4 -/- and wild-type mice. Nevertheless, analysis of antigen-stimulated IL-2, IL-4, IL-5, IL-10 and IFN-γ production by lymphoid organ cells from infected or egg-injected IL-4 / mice revealed a more Th1 -like pattern of cytokine production (IFN-γ > IL-5) than In (wild-type) mice in which a stronger type 2 response to SEA was detectable (IL-4, IL-5 > IFN-γ). Despite this, at 8 and 16 weeks after infection, liver pathology, as indicated by the size, ceilularity, cellular composition and collagen content of granulomas, was similar in IL-4 / and wild-type animals. As in wild-type animals, granuloma size at week 16 was smaller than at week 8, Indicating that modulation had occurred in the absence of IL-4. Differences in pathology were seen only when eggs were experimentally embolized to the lungs, in which case IL-4 / mice made smaller granulomatous responses than did wild-type animals. These data clearly show that IL-4 Is not necessary for the hepatic granuloma formation which occurs during experimental schistosomiasi