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      A novel mode of induction of the humoral innate immune response in Drosophila larvae

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          ABSTRACT

          Drosophila adults have been utilized as a genetically tractable model organism to decipher the molecular mechanisms of humoral innate immune responses. In an effort to promote the utility of Drosophila larvae as an additional model system, in this study, we describe a novel aspect of an induction mechanism for innate immunity in these larvae. By using a fine tungsten needle created for manipulating semi-conductor devices, larvae were subjected to septic injury. However, although Toll pathway mutants were susceptible to infection with Gram-positive bacteria as had been shown for Drosophila adults, microbe clearance was not affected in the mutants. In addition, Drosophila larvae were found to be sensitive to mechanical stimuli with respect to the activation of a sterile humoral response. In particular, pinching with forceps to a degree that might cause minor damage to larval tissues could induce the expression of the antifungal peptide gene Drosomycin; notably, this induction was partially independent of the Toll and immune deficiency pathways. We therefore propose that Drosophila larvae might serve as a useful model to analyze the infectious and non-infectious inflammation that underlies various inflammatory diseases such as ischemia, atherosclerosis and cancer.

          Abstract

          Editors' choice: Drosophila larvae represent a useful model of infectious inflammation and sterilely induced humoral innate response, which are relevant for disorders associated with chronic inflammation.

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          Most cited references72

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          The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults.

          The cytokine-induced activation cascade of NF-kappaB in mammals and the activation of the morphogen dorsal in Drosophila embryos show striking structural and functional similarities (Toll/IL-1, Cactus/I-kappaB, and dorsal/NF-kappaB). Here we demonstrate that these parallels extend to the immune response of Drosophila. In particular, the intracellular components of the dorsoventral signaling pathway (except for dorsal) and the extracellular Toll ligand, spätzle, control expression of the antifungal peptide gene drosomycin in adults. We also show that mutations in the Toll signaling pathway dramatically reduce survival after fungal infection. Antibacterial genes are induced either by a distinct pathway involving the immune deficiency gene (imd) or by combined activation of both imd and dorsoventral pathways.
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            Immunity in Drosophila melanogaster--from microbial recognition to whole-organism physiology.

            Since the discovery of antimicrobial peptide responses 40 years ago, the fruit fly Drosophila melanogaster has proven to be a powerful model for the study of innate immunity. Early work focused on innate immune mechanisms of microbial recognition and subsequent nuclear factor-κB signal transduction. More recently, D. melanogaster has been used to understand how the immune response is regulated and coordinated at the level of the whole organism. For example, researchers have used this model in studies investigating interactions between the microbiota and the immune system at barrier epithelial surfaces that ensure proper nutritional and immune homeostasis both locally and systemically. In addition, studies in D. melanogaster have been pivotal in uncovering how the immune response is regulated by both endocrine and metabolic signalling systems, and how the immune response modifies these systems as part of a homeostatic circuit. In this Review, we briefly summarize microbial recognition and antiviral immunity in D. melanogaster, and we highlight recent studies that have explored the effects of organism-wide regulation of the immune response and, conversely, the effects of the immune response on organism physiology.
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              Drosophila intestinal response to bacterial infection: activation of host defense and stem cell proliferation.

              Although Drosophila systemic immunity is extensively studied, little is known about the fly's intestine-specific responses to bacterial infection. Global gene expression analysis of Drosophila intestinal tissue to oral infection with the Gram-negative bacterium Erwinia carotovora revealed that immune responses in the gut are regulated by the Imd and JAK-STAT pathways, but not the Toll pathway. Ingestion of bacteria had a dramatic impact on the physiology of the gut that included modulation of stress response and increased stem cell proliferation and epithelial renewal. Our data suggest that gut homeostasis is maintained through a balance between cell damage due to the collateral effects of bacteria killing and epithelial repair by stem cell division. The Drosophila gut provides a powerful model to study the integration of stress and immunity with pathways associated with stem cell control, and this study should prove to be a useful resource for such further studies.
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                Author and article information

                Journal
                Dis Model Mech
                Dis Model Mech
                DMM
                dmm
                Disease Models & Mechanisms
                The Company of Biologists Ltd
                1754-8403
                1754-8411
                1 March 2017
                1 March 2017
                : 10
                : 3
                : 271-281
                Affiliations
                [1 ]Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University , Sendai 980-8578, Japan
                [2 ]Graduate School of Medical Sciences, Kanazawa University , Ishikawa 920-1192, Japan
                [3 ]Department of Microbiology and Immunology, Keio University School of Medicine , Tokyo 160-8582, Japan
                [4 ]Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University , Ishikawa 920-1192, Japan
                [5 ]PRESTO, Japan Science and Technology Agency , Tokyo 102-0076, Japan
                Author notes
                [*]

                These authors contributed equally to this work

                [§]

                Senior author

                Author information
                http://orcid.org/0000-0001-5375-6678
                http://orcid.org/0000-0002-9493-6082
                http://orcid.org/0000-0002-0301-872X
                Article
                DMM027102
                10.1242/dmm.027102
                5374318
                28250052
                71cc99fc-0c80-4a2d-9ee5-3f85b8a8dfdb
                © 2017. Published by The Company of Biologists Ltd

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                History
                : 12 July 2016
                : 20 January 2017
                Funding
                Funded by: Japan Science and Technology Agency, http://dx.doi.org/10.13039/501100002241;
                Funded by: Ministry of Education, Culture, Sports, Science, and Technology, http://dx.doi.org/10.13039/501100001700;
                Categories
                Dros
                Research Article

                Molecular medicine
                innate immunity,drosophila,larvae
                Molecular medicine
                innate immunity, drosophila, larvae

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