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      Polydnaviral Ankyrin Proteins Aid Parasitic Wasp Survival by Coordinate and Selective Inhibition of Hematopoietic and Immune NF-kappa B Signaling in Insect Hosts

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          Abstract

          Polydnaviruses are mutualists of their parasitoid wasps and express genes in immune cells of their Lepidopteran hosts. Polydnaviral genomes carry multiple copies of viral ankyrins or vankyrins. Vankyrin proteins are homologous to IκB proteins, but lack sequences for regulated degradation. We tested if Ichnoviral Vankyrins differentially impede Toll-NF-κB-dependent hematopoietic and immune signaling in a heterologous in vivo Drosophila, system. We first show that hematopoiesis and the cellular encapsulation response against parasitoid wasps are tightly-linked via NF-κB signaling. The niche, which neighbors the larval hematopoietic progenitors, responds to parasite infection. Drosophila NF-κB proteins are expressed in the niche, and non cell-autonomously influence fate choice in basal and parasite-activated hematopoiesis. These effects are blocked by the Vankyrin I 2-vank-3, but not by P-vank-1, as is the expression of a NF-κB target transgene. I 2-vank-3 and P-vank-1 differentially obstruct cellular and humoral inflammation. Additionally, their maternal expression weakens ventral embryonic patterning. We propose that selective perturbation of NF-κB-IκB interactions in natural hosts of parasitic wasps negatively impacts the outcome of hematopoietic and immune signaling and this immune deficit contributes to parasite survival and species success in nature.

          Author Summary

          Parasitoid wasps are insects whose development takes place within the body of other insects. To survive, wasp larvae must overcome the immune defenses of their hosts. How parasitic wasps overcome host immunity is not fully understood even though we know that different strategies using venoms, virus-like particles, or viruses are involved. A unique class of viruses, called polydnaviruses is found in two families of wasps that comprise more than 20,000 wasp species. The genomes of polydnaviruses encode proteins with ankyrin repeats. Ankyrin repeats are also found in Cactus, the inhibitor protein of NF-κB signaling in Drosophila. Viral ankyrin proteins, or Vankyrins, however, lack the amino acid sequences necessary for turnover found in Cactus and mammalian IκB family members. We show that Vankyrins produced by polydnaviruses of a parasitic wasp that attacks caterpillars of many common agricultural pests can block NF-κB signaling in fruit fly larvae. This inhibition supports parasite success. Our work highlights the crucial role of NF-κB signaling across insect taxa in insect-insect and insect-virus interactions. Studies of polydnaviral ankyrin proteins in Drosophila reveal that immune-suppressive viruses may block both cellular and humoral immunity in insects to win the biological ‘arms race’.

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          Most cited references 48

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          Targeted gene expression as a means of altering cell fates and generating dominant phenotypes.

           N Perrimon,  H. Brand (1993)
          We have designed a system for targeted gene expression that allows the selective activation of any cloned gene in a wide variety of tissue- and cell-specific patterns. The gene encoding the yeast transcriptional activator GAL4 is inserted randomly into the Drosophila genome to drive GAL4 expression from one of a diverse array of genomic enhancers. It is then possible to introduce a gene containing GAL4 binding sites within its promoter, to activate it in those cells where GAL4 is expressed, and to observe the effect of this directed misexpression on development. We have used GAL4-directed transcription to expand the domain of embryonic expression of the homeobox protein even-skipped. We show that even-skipped represses wingless and transforms cells that would normally secrete naked cuticle into denticle secreting cells. The GAL4 system can thus be used to study regulatory interactions during embryonic development. In adults, targeted expression can be used to generate dominant phenotypes for use in genetic screens. We have directed expression of an activated form of the Dras2 protein, resulting in dominant eye and wing defects that can be used in screens to identify other members of the Dras2 signal transduction pathway.
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            NF-kappaB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis.

            The family of nuclear factor-kappaB (NF-kappaB) transcription factors is intimately involved in the regulation of expression of numerous genes in the setting of the inflammatory response. Since inflammatory processes play a fundamental role in the damage of articular tissues, many in vitro and in vivo studies have examined the contribution of components of the NF-kappaB signaling pathways to the pathogenesis of various rheumatic diseases, in particular, of osteoarthritis (OA) and rheumatoid arthritis (RA). Inflammation, cartilage degradation, cell proliferation, angiogenesis and pannus formation are processes in which the role of NF-kappaB is prominent. Consequently, large efforts have been devoted to the study of the pharmacologic modulation of the NF-kappaB pathways. These studies have employed currently available therapeutic agents including non-steroidal anti-inflammatory drugs, corticosteroids, nutraceuticals and disease-modifying anti-rheumatic drugs, as well as novel small molecule inhibitors targeted to specific proteins of the NF-kappaB pathways. In addition, promising strategies such as improved antisense DNA therapy and RNA interference have been examined with encouraging results. However, since NF-kappaB also plays a crucial beneficial role in normal physiology and technical problems for effective gene therapy still remain, further research will be needed before NF-kappaB-aimed strategies become an effective therapy for joint diseases, such as OA and RA.
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              Postembryonic hematopoiesis in Drosophila.

              We have investigated the blood cell types present in Drosophila at postembryonic stages and have analysed their modifications during development and under immune conditions. The anterior lobes of the larval hematopoietic organ or lymph gland contain numerous active secretory cells, plasmatocytes, few crystal cells, and a number of undifferentiated prohemocytes. The posterior lobes contain essentially prohemocytes. The blood cell population in larval hemolymph differs and consists mainly of plasmatocytes which are phagocytes, and of a low percentage of crystal cells which reportedly play a role in humoral melanisation. We show that the cells in the lymph gland can differentiate into a given blood cell lineage when solicited. Under normal nonimmune conditions, we observe a massive differentiation into active macrophages at the onset of metamorphosis in all lobes. Simultaneously, circulating plasmatocytes modify their adhesion and phagocytic properties to become pupal macrophages. All phagocytic cells participate in metamorphosis by ingesting doomed larval tissues. The most dramatic effect on larval hematopoiesis was observed following infestation by a parasitoid wasp. Cells within all lymph gland lobes, including prohemocytes from posterior lobes, massively differentiate into a new cell type specifically devoted to encapsulation, the lamellocyte. Copyright 2001 Academic Press.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                August 2013
                August 2013
                29 August 2013
                : 9
                : 8
                Affiliations
                [1 ]Biology Department, The City College of the City University of New York, New York, New York, United States of America
                [2 ]The Graduate Center of the City University of New York, New York, New York, United States of America
                Stanford University, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: GG MEK JR JU SG. Performed the experiments: GG MEK JR JU SG. Analyzed the data: GG MEK JR JU SG. Contributed reagents/materials/analysis tools: SG. Wrote the paper: GG MEK JR JU SG.

                Article
                PPATHOGENS-D-13-00039
                10.1371/journal.ppat.1003580
                3757122
                24009508

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 14
                Funding
                This publication was made possible by grants from NSF (1121817), USDA (NRI/USDA CSREES 2006-03817 and 2009-35302-05277), and the National Center for Research Resources(2G12RR03060-26A1) from NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Immunology
                Immunity
                Humoral Immunity
                Immune Defense
                Immune Suppression
                Inflammation
                Innate Immunity
                Immune Response
                Model Organisms
                Animal Models
                Drosophila Melanogaster
                Molecular Cell Biology
                Signal Transduction

                Infectious disease & Microbiology

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