34 results found
Sharrock J, Estacio Gomez A, Jacobson J, et al., 2019, fs(1)h controls metabolic and immune function and enhances survival via AKT and FOXO in Drosophila, Disease Models & Mechanisms, Vol: 12, ISSN: 1754-8403
The Drosophila fat body is the primary organ of energy storage as well as being responsible for the humoral response to infection. Its physiological function is of critical importance to the survival of the organism; however, many molecular regulators of its function remain ill-defined. Here, we show that the Drosophila melanogaster bromodomain-containing protein FS(1)H is required in the fat body for normal lifespan as well as metabolic and immune homeostasis. Flies lacking fat body fs(1)h exhibit short lifespan, increased expression of immune target genes, an inability to metabolize triglyceride, and low basal AKT activity, mostly resulting from systemic defects in insulin signalling. Removal of a single copy of the AKT-responsive transcription factor foxo normalises lifespan, metabolic function, uninduced immune gene expression and AKT activity. We suggest that the promotion of systemic insulin signalling activity is a key in vivo function of fat body fs(1)h.
Gordon O, Henry CM, Srinivasan N, et al., 2018, alpha-actinin accounts for the bioactivity of actin preparations in inducing STAT target genes in Drosophila melanogaster, eLife, Vol: 7, ISSN: 2050-084X
Damage-associated molecular patterns (DAMPs) are molecules exposed or released bydead cells that trigger or modulate immunity and tissue repair. In vertebrates, the cytoskeletalcomponent F-actin is a DAMP specifically recognised by DNGR-1, an innate immune receptor.Previously we suggested that actin is also a DAMP in Drosophila melanogaster by inducing STATdependent genes (Srinivasan et al., 2016). Here, we revise that conclusion and report that aactinin is far more potent than actin at inducing the same STAT response and can be found in traceamounts in actin preparations. Recombinant expression of actin or a-actinin in bacteriademonstrated that only a-actinin could drive the expression of STAT target genes in Drosophila.The response to injected a-actinin required the same signalling cascade that we had identified inour previous work using actin preparations. Taken together, these data indicate that a-actininrather than actin drives STAT activation when injected into Drosophila.
Pean CB, Schiebler M, Tan S, et al., 2017, Regulation of phagocyte triglyceride by a STAT-ATG2 pathway controls mycobacterial infection, Nature Communications, Vol: 8, ISSN: 2041-1723
Mycobacterium tuberculosis remains a global threat to human health yet the molecular mechanisms regulating immunity remain poorly understood. Cytokines can promote or inhibit mycobacterial survivalinside macrophages, andthe underlying mechanisms represent potential targets for host-directed therapies. Here we show that cytokine-STAT signaling promotesmycobacterial survivalwithin macrophages by deregulating lipid droplets via ATG2 repression. In Drosophilainfected withMycobacterium marinum,mycobacterium-induced STAT activitytriggered by unpaired-familycytokinesreduces Atg2 expression, permittingderegulation of lipid droplets. Increased Atg2expression, or reduced macrophage triglyceride biosynthesis,normalizes lipid deposition in infected phagocytes and reduces numbersof viable intracellular mycobacteria. In human macrophages,addition ofIL-6promotes mycobacterial survival and BCG-induced lipid accumulation by a similar, but probably not identical, mechanism. Our results reveal Atg2regulation as amechanism by which cytokines can control lipid droplet homeostasis and consequently resistance to mycobacterial infectionin Drosophila.
Srinivasan N, Gordon O, Ahrens S, et al., 2016, Actin is an evolutionarily-conserved damage-associated molecular pattern that signals tissue injury in Drosophila melanogaster, eLife, Vol: 5, ISSN: 2050-084X
Damage-associated molecular patterns (DAMPs) are molecules released by dead cells that trigger sterile inflammation and, in vertebrates, adaptive immunity. Actin is a DAMP detected in mammals by the receptor, DNGR-1, expressed by dendritic cells (DCs). DNGR-1 is phosphorylated by Src-family kinases and recruits the tyrosine kinase Syk to promote DC cross-presentation of dead cell-associated antigens. Here we report that actin is also a DAMP in invertebrates that lack DCs and adaptive immunity. Administration of actin to Drosophila melanogaster triggers a response characterised by selective induction of STAT target genes in the fat body through the cytokine Upd3 and its JAK/STAT-coupled receptor, Domeless. Notably, this response requires signalling via Shark, the Drosophila orthologue of Syk, and Src42A, a Drosophila Src-family kinase, and is dependent on Nox activity. Thus, extracellular actin detection via a Src-family kinase-dependent cascade is an ancient means of detecting cell injury that precedes the evolution of adaptive immunity.
Kierdorf K, Dionne MS, 2016, The software and hardware of macrophages: a diversity of options, Developmental Cell, Vol: 38, Pages: 122-125, ISSN: 1878-1551
Macrophages play important immune and homeostatic roles that depend on the ability to receive and interpret specific signals from environmental stimuli. Here we describe the different activation states these cells can exhibit in response to signals and how these states affect and can be affected by bacterial pathogens.
Cagin U, Duncan OF, Gatt AP, et al., 2015, Erratum: Mitochondrial retrograde signaling regulates neuronal function (Proceedings of the National Academy of Sciences of the United States of America (2015) 112 (E6000-E6009) DOI 10.1073/pnas.1505036112), Proceedings of the National Academy of Sciences of the United States of America, Vol: 112, ISSN: 0027-8424
Cagin U, Duncan OF, Gatt AP, et al., 2015, Mitochondrial retrograde signaling regulates neuronal function, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 112, Pages: E6000-E6009, ISSN: 0027-8424
Woodcock KJ, Kierdorf K, Pouchelon CA, et al., 2015, Macrophage-Derived upd3 Cytokine Causes Impaired Glucose Homeostasis and Reduced Lifespan in Drosophila Fed a Lipid-Rich Diet, Immunity, Vol: 42, Pages: 133-144, ISSN: 1097-4180
Long-term consumption of fatty foods is associated with obesity, macrophage activation and inflammation, metabolic imbalance, and a reduced lifespan. We took advantage of Drosophila genetics to investigate the role of macrophages and the pathway(s) that govern their response to dietary stress. Flies fed a lipid-rich diet presented with increased fat storage, systemic activation of JAK-STAT signaling, reduced insulin sensitivity, hyperglycemia, and a shorter lifespan. Drosophila macrophages produced the JAK-STAT-activating cytokine upd3, in a scavenger-receptor (crq) and JNK-dependent manner. Genetic depletion of macrophages or macrophage-specific silencing of upd3 decreased JAK-STAT activation and rescued insulin sensitivity and the lifespan of Drosophila, but did not decrease fat storage. NF-κB signaling made no contribution to the phenotype observed. These results identify an evolutionarily conserved “scavenger receptor-JNK-type 1 cytokine” cassette in macrophages, which controls glucose metabolism and reduces lifespan in Drosophila maintained on a lipid-rich diet via activation of the JAK-STAT pathway.
Colas C, Menezes S, Gutierrez-Martinez E, et al., 2014, An improved flow cytometry assay to monitor phagosome acidification, JOURNAL OF IMMUNOLOGICAL METHODS, Vol: 412, Pages: 1-13, ISSN: 0022-1759
Stramer BM, Dionne MS, 2014, Unraveling tissue repair immune responses in flies, SEMINARS IN IMMUNOLOGY, Vol: 26, Pages: 310-314, ISSN: 1044-5323
Dionne MS, 2014, Immune-metabolic interaction in Drosophila, FLY, Vol: 8, Pages: 75-79, ISSN: 1933-6934
Pean CB, Dionne MS, 2014, Intracellular infections in Drosophila melanogaster: Host defense and mechanisms of pathogenesis, DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY, Vol: 42, Pages: 57-66, ISSN: 0145-305X
Clark RI, Walker DW, Dionne MS, 2014, Metabolic and immune integration in aging and age-related disease, AGING-US, Vol: 6, Pages: 3-4, ISSN: 1945-4589
Dionne MS, 2013, Comparative immunology: allorecognition and variable surface receptors outside the jawed vertebrates, CURRENT OPINION IN IMMUNOLOGY, Vol: 25, Pages: 608-612, ISSN: 0952-7915
Pilatova M, Dionne MS, 2012, Burkholderia thailandensis Is Virulent in Drosophila melanogaster, PLOS ONE, Vol: 7, ISSN: 1932-6203
Clark RI, Woodcock KJ, Geissmann F, et al., 2011, Multiple TGF-beta Superfamily Signals Modulate the Adult Drosophila Immune Response, CURRENT BIOLOGY, Vol: 21, Pages: 1672-1677, ISSN: 0960-9822
Dionne MS, Schneider DS, 2008, Models of infectious diseases in the fruit fly Drosophila melanogaster, DISEASE MODELS & MECHANISMS, Vol: 1, Pages: 43-49, ISSN: 1754-8403
Dionne MS, Schneider DS, 2008, Host-pathogen interactions in Drosophila, DISEASE MODELS & MECHANISMS, Vol: 1, Pages: 67-68, ISSN: 1754-8403
Shirasu-Hiza MM, Dionne MS, Pham LN, et al., 2007, Interactions between circadian rhythm and immunity in Drosophila melanlogaster, CURRENT BIOLOGY, Vol: 17, Pages: R353-R355, ISSN: 0960-9822
Schneider DS, Ayres JS, Brandt SM, et al., 2007, Drosophila eiger mutants are sensitive to extracellular pathogens, PLOS PATHOGENS, Vol: 3, ISSN: 1553-7366
Pham LN, Dionne MS, Shirasu-Hiza M, et al., 2007, A specific primed immune response in Drosophila is dependent on phagocytes, PLOS PATHOGENS, Vol: 3, ISSN: 1553-7366
Dionne MS, Pham LN, Shirasu-Hiza M, et al., 2006, Akt and foxo dysregulation contribute to infection-induced wasting in Drosophila, CURRENT BIOLOGY, Vol: 16, Pages: 1977-1985, ISSN: 0960-9822
Gordon MD, Dionne MS, Schneider DS, et al., 2005, WntD is a feedback inhibitor of Dorsal/NF-kappa B in Drosophila development and immunity, NATURE, Vol: 437, Pages: 746-749, ISSN: 0028-0836
Brandt SM, Dionne MS, Khush RS, et al., 2004, Secreted bacterial effectors and host-produced eiger/TNF drive death in a Salmonella-infected fruit fly, PLOS BIOLOGY, Vol: 2, Pages: 2067-2075, ISSN: 1544-9173
Mansfield BE, Dionne MS, Schneider DS, et al., 2003, Exploration of host-pathogen interactions using Listeria monocytogenes and Drosophila melanogaster, CELLULAR MICROBIOLOGY, Vol: 5, Pages: 901-911, ISSN: 1462-5814
Khokha MK, Hsu D, Brunet LJ, et al., 2003, Gremlin is the BMP antagonist required for maintenance of Shh and Fgf signals during limb patterning, NATURE GENETICS, Vol: 34, Pages: 303-307, ISSN: 1061-4036
Dionne MS, Ghori N, Schneider DS, 2003, Drosophila melanogaster is a genetically tractable model host for Mycobacterium marinum, INFECTION AND IMMUNITY, Vol: 71, Pages: 3540-3550, ISSN: 0019-9567
Dionne MS, Brunet LJ, Eimon PM, et al., 2002, Noggin is required for correct guidance of dorsal root ganglion axons, DEVELOPMENTAL BIOLOGY, Vol: 251, Pages: 283-293, ISSN: 0012-1606
Dionne MS, Schneider DS, 2002, Screening the fruitfly immune system., Genome Biol, Vol: 3
The anti-microbial defense system of Drosophila shows functional similarities with the vertebrate innate immune system. Two recent gene-expression profiling studies of fruitflies challenged with infectious agents have identified key molecular players in the fruitfly's response to bacterial and fungal infection, as well as a large number of immune-regulated genes with unknown immunological function.
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