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Author Notes:

Corresponding author, ravetch@rockefeller.edu

We thank Sheng Zhang and Robert Sherwood at the Cornell Proteomics and Mass Spectrometry Facility for helpful discussions and excellent technical support.

The authors also thank the staff of the Stanford Clinical Virology Laboratory for their assistance with dengue virus serologic testing.

T.T.W. thanks Barry Coller, Sarah J Schlesinger and the Rockefeller University KL2 Clinical Scholars Program for training and support.

J.S. would like to thank Shiyu Wang and Sivaram Gunisetty for helping with preparation of sera from patient samples.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

The data presented in this manuscript are tabulated in the main paper and in the supplementary materials.

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Research Funding:

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.

K.P. was funded by HHS National Institutes of Health (NIH) (IRO1AI099385).

S.B. was supported by an amfAR Mathilde Krim Fellowship in Basic Biomedical Research (109519-60-RKVA).

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.).

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.

Support and infrastructure were also provided by The Rockefeller University and by Stanford University School of Medicine.

Analysis of clinical samples in this work was approved by the Institutional Review Board of Rockefeller University (protocol #TWA-0804 (T.T.W.)).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • VIRUS-INFECTION
  • HEMORRHAGIC-FEVER
  • DEPENDENT ENHANCEMENT
  • IN-VITRO
  • CORRELATE
  • RECEPTOR
  • SEROTYPE
  • PATHOGENESIS
  • POLYMORPHISM
  • MACROPHAGES

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

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Journal Title:

Science

Volume:

Volume 355, Number 6323

Publisher:

, Pages 395-+

Type of Work:

Article | Post-print: After Peer Review

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.

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© 2017, Copyright © 2017, American Association for the Advancement of Science

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