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      Inhibition of melanization by serpin-5 and serpin-9 promotes baculovirus infection in cotton bollworm Helicoverpa armigera

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          Abstract

          Melanization, an important insect defense mechanism, is mediated by clip-domain serine protease (cSP) cascades and is regulated by serpins. Here we show that proteolytic activation of prophenoloxidase (PPO) and PO-catalyzed melanization kill the baculovirus in vitro. Our quantitative proteomics and biochemical experiments revealed that baculovirus infection of the cotton bollworm, Helicoverpa armigera, reduced levels of most cascade members in the host hemolymph and PO activity. By contrast, serpin-9 and serpin-5 were sequentially upregulated after the viral infection. The H. armigera serpin-5 and serpin-9 regulate melanization by directly inhibiting their target proteases cSP4 and cSP6, respectively and cSP6 activates PPO purified from hemolymph. Furthermore, serpin-5/9-depleted insects exhibited high PO activities and showed resistance to baculovirus infection. Together, our results characterize a part of the melanization cascade in H. armigera, and suggest that natural insect virus baculovirus has evolved a distinct strategy to suppress the host immune system.

          Author summary

          Melanization is one of important modules in insect defense system. It consists of a cascade of clip-domain serine proteases (cSPs) that converts the zymogen prophenoloxidase (PPO) to active phenoloxidase (PO), which is negatively regulated by serpins. PO then catalyses the formation of melanin that physically encapsulates certain pathogens. Parasites and bacteria have evolved to produce specific proteins or antibiotic to suppress the melanization response of host insects for survival. However, the mechanisms by which virus persists in the face of the insect melanization are poorly understood. In this study, we show that a DNA virus baculovirus infection of the cotton bollworm, Helicoverpa armigera, reduced the levels of most cascade members in the host hemolymph and PO activity. By contrast, serpin-9 and serpin-5 were sequentially upregulated after the viral infection. Our results also reveal that melanization kills baculovirus in vitro. Serpin-5 and serpin-9 regulate melanization by directly inhibiting their target proteases cSP4 and cSP6, respectively and cSP6 activates PPO purified from hemolymph. Moreover, serpin-5/9-depleted insects show resistance to baculovirus infection. Our findings have enriched the understanding of molecular mechanisms by which pathogens suppress the melanization response of host insect for survival.

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          Most cited references51

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          RNA-based antiviral immunity.

          In eukaryotic RNA-based antiviral immunity, viral double-stranded RNA is recognized as a pathogen-associated molecular pattern and processed into small interfering RNAs (siRNAs) by the host ribonuclease Dicer. After amplification by host RNA-dependent RNA polymerases in some cases, these virus-derived siRNAs guide specific antiviral immunity through RNA interference and related RNA silencing effector mechanisms. Here, I review recent studies on the features of viral siRNAs and other virus-derived small RNAs from virus-infected fungi, plants, insects, nematodes and vertebrates and discuss the innate and adaptive properties of RNA-based antiviral immunity.
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            Evolutionary dynamics of immune-related genes and pathways in disease-vector mosquitoes.

            Mosquitoes are vectors of parasitic and viral diseases of immense importance for public health. The acquisition of the genome sequence of the yellow fever and Dengue vector, Aedes aegypti (Aa), has enabled a comparative phylogenomic analysis of the insect immune repertoire: in Aa, the malaria vector Anopheles gambiae (Ag), and the fruit fly Drosophila melanogaster (Dm). Analysis of immune signaling pathways and response modules reveals both conservative and rapidly evolving features associated with different functional gene categories and particular aspects of immune reactions. These dynamics reflect in part continuous readjustment between accommodation and rejection of pathogens and suggest how innate immunity may have evolved.
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              The proPO-system: pros and cons for its role in invertebrate immunity.

              Melanisation is an important immune response in many invertebrates. Recent evidence also strongly implies that the melanisation (prophenoloxidase activating) cascade is intimately associated with the appearance of factors stimulating cellular defence by aiding phagocytosis and encapsulation reactions. However, some controversy exists in the field, and at least in flies and mosquitoes, the successful combat of some pathogens does not seem to be dependent on phenoloxidase activity. This may be because of redundancy among separate immune mechanisms, inappropriate testing, species differences or a combination thereof. Recently, by using RNA interference against phenoloxidase or in specific host-pathogen interactions where the pathogen prevents melanin production by the host, convincing data have confirmed the importance of this cascade in invertebrate innate immunity.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: ValidationRole: Visualization
                Role: InvestigationRole: MethodologyRole: ValidationRole: Visualization
                Role: InvestigationRole: MethodologyRole: ValidationRole: Visualization
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                27 September 2017
                September 2017
                : 13
                : 9
                : e1006645
                Affiliations
                [1 ] State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
                [2 ] University of Chinese Academy of Sciences, Beijing, China
                [3 ] State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
                Iowa State University, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-3550-7656
                Article
                PPATHOGENS-D-17-00918
                10.1371/journal.ppat.1006645
                5633200
                28953952
                503748e9-ab8a-46e8-933e-25b28feb1363
                © 2017 Yuan et al

                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.

                History
                : 27 April 2017
                : 12 September 2017
                Page count
                Figures: 8, Tables: 0, Pages: 28
                Funding
                Funded by: Strategic Priority Research Program of the Chinese Academy of Sciences
                Award ID: XDB11030400
                Award Recipient :
                Funded by: Strategic Priority Research Program of the Chinese Academy of Sciences
                Award ID: XDB11030600
                Funded by: National Key Plan for Scientific Research and Development of China
                Award ID: No. 2017YFC1201004, 2017ZY060055,No. 2016YFD0500300, 2016YFC1200604
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31621061
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: No. 31672291, L1524009
                Funded by: Open research Fund Program of State Key Laboratory of Integrated Pest Management
                Award ID: IPM1714
                This work was supported by grants from Strategic Priority Research Program of the Chinese Academy of Science (No. XDB11030400, XDB11030600), National Key Plan for Scientific Research and Development of China (No. 2017YFC1201004, 2017YFD0200400, 2016YFD0500300, 2016YFC1200604), National Natural Science Foundation of China (No. 31621061, 31672291, L1524009), Key research project of frontier science of Chinese Academy of Sciences (QYZDJ-SSW-SMC021), Open Research Fund Program of State Key Laboratory of Integrated Pest Management (IPM1714). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Developmental Biology
                Life Cycles
                Larvae
                Biology and Life Sciences
                Microbiology
                Virology
                Viral Transmission and Infection
                Biology and Life Sciences
                Immunology
                Immune System Proteins
                Medicine and Health Sciences
                Immunology
                Immune System Proteins
                Biology and Life Sciences
                Biochemistry
                Proteins
                Immune System Proteins
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Invertebrates
                Arthropoda
                Insects
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Molecular Probe Techniques
                Immunoblot Analysis
                Research and Analysis Methods
                Molecular Biology Techniques
                Molecular Probe Techniques
                Immunoblot Analysis
                Biology and Life Sciences
                Biochemistry
                Proteomics
                Biology and Life Sciences
                Biochemistry
                Enzymology
                Enzymes
                Proteases
                Biology and Life Sciences
                Biochemistry
                Proteins
                Enzymes
                Proteases
                Biology and Life Sciences
                Biochemistry
                Proteins
                Recombinant Proteins
                Custom metadata
                vor-update-to-uncorrected-proof
                2017-10-09
                The mass spectrometry data (PXD006126) have been deposited in the PRIDE repository ( http://www.ebi.ac.uk/pride). All sequence data that support the findings of this study are available in GenBank with the following accession numbers: serpin-5 (KY680238), serpin-9 (KY680239), cSP4 (KY680240), cSP6 (KY680241), cSP8 (KY680243), cSP29 (KY680244), PPO1 (KY744277), PPO2 (KY744278).

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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