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      The Aedes aegypti Toll Pathway Controls Dengue Virus Infection

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      PLoS Pathogens

      Public Library of Science

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          Aedes aegypti, the mosquito vector of dengue viruses, utilizes its innate immune system to ward off a variety of pathogens, some of which can cause disease in humans. To date, the features of insects' innate immune defenses against viruses have mainly been studied in the fruit fly Drosophila melanogaster, which appears to utilize different immune pathways against different types of viruses, in addition to an RNA interference–based defense system. We have used the recently released whole-genome sequence of the Ae. aegypti mosquito, in combination with high-throughput gene expression and RNA interference (RNAi)-based reverse genetic analyses, to characterize its response to dengue virus infection in different body compartments. We have further addressed the impact of the mosquito's endogenous microbial flora on virus infection. Our findings indicate a significant role for the Toll pathway in regulating resistance to dengue virus, as indicated by an infection-responsive regulation and functional assessment of several Toll pathway–associated genes. We have also shown that the mosquito's natural microbiota play a role in modulating the dengue virus infection, possibly through basal-level stimulation of the Toll immune pathway.

          Author Summary

          The Aedes aegypti mosquito is largely responsible for the transmission of dengue viruses that cause disease in humans. The virus is taken up with an infected blood meal from which it will first infect the mosquito gut tissue. From the gut it will migrate to other parts of the mosquito, including the salivary glands, from where it can be transmitted to another human upon a second blood meal. In this study we show that the mosquito utilizes its innate immune system to control dengue virus infection. Infection with the virus will result in the activation of mosquito immune responses that are mainly controlled by the Toll pathway. These responses entail antiviral activities that limit infection with the virus. We also show that the mosquito's natural microbial flora play a role in modulating the dengue virus infection, possibly through the stimulation of the mosquito's immune system.

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          Most cited references 35

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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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            GenMAPP, a new tool for viewing and analyzing microarray data on biological pathways.

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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.

                Author and article information

                Role: Editor
                PLoS Pathog
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                July 2008
                July 2008
                4 July 2008
                : 4
                : 7
                W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
                Stanford University, United States of America
                Author notes

                Current address: Department of Entomology, Michigan State University, East Lansing, Michigan, United States of America

                Conceived and designed the experiments: ZX JR GD. Performed the experiments: ZX JR. Analyzed the data: ZX JR GD. Contributed reagents/materials/analysis tools: ZX JR. Wrote the paper: ZX JR GD.

                Xi 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.
                Page count
                Pages: 12
                Research Article
                Immunology/Innate Immunity
                Infectious Diseases/Neglected Tropical Diseases
                Infectious Diseases/Viral Infections
                Microbiology/Immunity to Infections
                Microbiology/Innate Immunity
                Virology/Host Antiviral Responses

                Infectious disease & Microbiology


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