IgG antibodies to dengue enhanced for Fc gamma RIIIA binding determine disease severity

• Type of Material: Article
• Authors: Taia T. Wang, Rockefeller University; Jaturong Sewatanon, Emory University; Matthew J. Memoli, National Institutes of Health; Jens Wrammert, Emory University; Stylianos Bournazos, Rockefeller University; Siddhartha Kumar Bhaumik, Emory University; Benjamin A. Pinsky, Stanford University; Kulkanya Chokephaibulkit, Mahidol University; Nattawat Onlamoon, Mahidol University; Kovit Pattanapanyasat, Mahidol University; Jeffery K. Taubenberger, National Institutes of Health; Rafi Ahmed, Emory University; Jeffrey V. Ravetch, The Rockefeller University
• Language: English
• Date: 2017-01-27
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017, Copyright © 2017, American Association for the Advancement of Science
• Final Published Version (URL): http://dx.doi.org/10.1126/science.aai8128
• Title of Journal or Parent Work: Science
• ISSN: 0036-8075
• Volume: 355
• Issue: 6323
• Start Page: 395
• End Page: +
• Grant/Funding Information: K.P. was funded by HHS National Institutes of Health (NIH) (IRO1AI099385).; Analysis of clinical samples in this work was approved by the Institutional Review Board of Rockefeller University (protocol #TWA-0804 (T.T.W.)).; The influenza A virus challenge study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), as well as the NIAID Extramural Clinical Research Acceleration Program.; Research reported in this publication was supported by the National Institute of Allergy And Infectious Diseases of the NIH under Award Numbers U19AI111825 (J.V.R.), U19AI057266 (R.A., J.W.), and U01AI115651 (R.A.).; S.B. was supported by an amfAR Mathilde Krim Fellowship in Basic Biomedical Research (109519-60-RKVA).; Support and infrastructure were also provided by The Rockefeller University and by Stanford University School of Medicine.; T.T.W. was supported, in part, by grant #UL1TR001866 from the National Center for Advancing Translational Sciences, NIH and the Clinical and Translational Science Award program.
• Keywords: CORRELATE; MACROPHAGES; RECEPTOR; Science & Technology - Other Topics; Science & Technology; VIRUS-INFECTION; DEPENDENT ENHANCEMENT; SEROTYPE; PATHOGENESIS; IN-VITRO; Multidisciplinary Sciences; HEMORRHAGIC-FEVER; POLYMORPHISM
• Research Categories: Health Sciences, Public Health; Health Sciences, Immunology

Abstract

Dengue virus (DENV) infection in the presence of reactive, non-neutralizing immunoglobulin G (IgG) (RNNIg) is the greatest risk factor for dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Progression to DHF/DSS is attributed to antibody-dependent enhancement (ADE); however, because only a fraction of infections occurring in the presence of RNNIg advance to DHF/DSS, the presence of RNNIg alone cannot account for disease severity. We discovered that DHF/DSS patients respond to infection by producing IgGs with enhanced affinity for the activating Fc receptor FcγRIIIA due to afucosylated Fc glycans and IgG1 subclass. RNNIg enriched for afucosylated IgG1 triggered platelet reduction in vivo and was a significant risk factor for thrombocytopenia. Thus, therapeutics and vaccines restricting production of afucosylated, IgG1 RNNIg during infection may prevent ADE of DENV disease.