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      Dengue vascular leakage is augmented by mast cell degranulation mediated by immunoglobulin Fcγ receptors

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          Abstract

          Dengue virus (DENV) is the most significant human arboviral pathogen and causes ∼400 million infections in humans each year. In previous work, we observed that mast cells (MC) mediate vascular leakage during DENV infection in mice and that levels of MC activation are correlated with disease severity in human DENV patients ( St John et al., 2013b). A major risk factor for developing severe dengue is secondary infection with a heterologous serotype. The dominant theory explaining increased severity during secondary DENV infection is that cross-reactive but non-neutralizing antibodies promote uptake of virus and allow enhanced replication. Here, we define another mechanism, dependent on FcγR-mediated enhanced degranulation responses by MCs. Antibody-dependent mast cell activation constitutes a novel mechanism to explain enhanced vascular leakage during secondary DENV infection.

          DOI: http://dx.doi.org/10.7554/eLife.05291.001

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          Pathogenesis of dengue: challenges to molecular biology.

          Scott B Halstead (1988)
          Dengue viruses occur as four antigenically related but distinct serotypes transmitted to humans by Aedes aegypti mosquitoes. These viruses generally cause a benign syndrome, dengue fever, in the American and African tropics, and a severe syndrome, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), in Southeast Asian children. This severe syndrome, which recently has also been identified in children infected with the virus in Puerto Rico, is characterized by increased vascular permeability and abnormal hemostasis. It occurs in infants less than 1 year of age born to dengue-immune mothers and in children 1 year and older who are immune to one serotype of dengue virus and are experiencing infection with a second serotype. Dengue viruses replicate in cells of mononuclear phagocyte lineage, and subneutralizing concentrations of dengue antibody enhance dengue virus infection in these cells. This antibody-dependent enhancement of infection regulates dengue disease in human beings, although disease severity may also be controlled genetically, possibly by permitting and restricting the growth of virus in monocytes. Monoclonal antibodies show heterogeneous distribution of antigenic epitopes on dengue viruses. These epitopes serve to regulate disease: when antibodies to shared antigens partially neutralize heterotypic virus, infection and disease are dampened; enhancing antibodies alone result in heightened disease response. Further knowledge of the structure of dengue genomes should permit rapid advances in understanding the pathogenetic mechanisms of dengue.
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            Research on dengue during World War II.

            A SABIN (1952)
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              Antibody-enhanced dengue virus infection in primate leukocytes.

              S B Halstead, E. O'Rourke (1977)
              Article 0 comments Cited 167 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Ruslan Medzhitov: Role: Reviewing editor
                Journal
                Journal ID (nlm-ta): eLife
                Journal ID (hwp): eLife
                Journal ID (publisher-id): eLife
                Title: eLife
                Publisher: eLife Sciences Publications, Ltd
                ISSN (Print): 2050-084X
                ISSN (Electronic): 2050-084X
                Publication date (Electronic, pub): 18 March 2015
                Publication date Collection: 2015
                Volume: 4
                Electronic Location Identifier: e05291
                Affiliations
                [1 ]deptProgram in Emerging Infectious Diseases , Duke-National University of Singapore , Singapore, Singapore
                [2 ]deptDepartment of Pathology , Duke University Medical Center , Durham, United States
                Howard Hughes Medical Institute, Yale University School of Medicine , United States
                Howard Hughes Medical Institute, Yale University School of Medicine , United States
                Author notes
                [†]

                These authors contributed equally to this work.

                Article
                Publisher ID: 05291
                DOI: 10.7554/eLife.05291
                PMC ID: 4362203
                PubMed ID: 25783751
                SO-VID: 1368d23c-a55b-4384-af23-da1e37a7ab45
                Copyright © © 2015, Syenina et al
                License:

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                Date received : 24 October 2014
                Date accepted : 23 February 2015
                Related
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001349, National Medical Research Council (NMRC);
                Award ID: 1054/2011
                Award Recipient :
                Funded by: Duke-NUS Graduate Medical School;
                Award ID: Start-up Funding
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Subject: Research Advance
                Subject: Immunology
                Subject: Microbiology and Infectious Disease
                Custom metadata
                elife-xml-version 2.0
                Author impact statement Building on previous work (St John et al., 2013), we explain why secondary infection by dengue virus is associated with more severe vascular disease than primary infection.

                ScienceOpen disciplines: Life sciences
                Keywords: dengue virus,vascular leakage,antibodies,mast cell,fc receptor,mouse
                Data availability:
                ScienceOpen disciplines: Life sciences
                Keywords: dengue virus, vascular leakage, antibodies, mast cell, fc receptor, mouse

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