High titers and low fucosylation of early human anti-SARS-CoV-2 IgG promote inflammation by alveolar macrophages.

Abstract

Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early-phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific immunoglobulin G (IgG) in serum of critically ill COVID-19 patients induces excessive inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more proinflammatory because of different glycosylation, particularly low fucosylation, of the antibody Fc tail. Low fucosylation of anti-spike IgG was normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fcγ receptor (FcγR) IIa and FcγRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated human macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Last, we demonstrate that the inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small-molecule inhibitor of Syk kinase.

• Authors: Willianne Hoepel, Hung-Jen Chen, Chiara E Geyer, Sona Allahverdiyeva, Xue D Manz, Steven W de Taeye, Jurjan Aman, Lynn Mes, Maurice Steenhuis, Guillermo R Griffith, Peter I Bonta, Philip J M Brouwer, Tom G Caniels, Karlijn van der Straten, Korneliusz Golebski, René E Jonkers, Mads D Larsen, Federica Linty, Jan Nouta, Cindy P A A van Roomen, Frank E H P van Baarle, Cornelis M van Drunen, Gertjan Wolbink, Alexander P J Vlaar, Godelieve J de Bree, Rogier W Sanders, Lisa Willemsen, Annette E Neele, Diederik van de Beek, Theo Rispens, Manfred Wuhrer, Harm Jan Bogaard, Marit J van Gils, Gestur Vidarsson, Menno de Winther, Jeroen den Dunnen
• Journal: Science translational medicine (Sci Transl Med) Vol. 13 Issue 596 (06 02 2021) ISSN: 1946-6242 [Electronic] United States
• PMID: 33979301 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

Chemical References

• Antibodies, Viral
• Immunoglobulin G
• Spike Glycoprotein, Coronavirus

Topics

• Antibodies, Viral (chemistry)
• COVID-19 (immunology)
• Glycosylation
• Humans
• Immunoglobulin G (chemistry)
• Inflammation
• Macrophages, Alveolar (immunology)
• SARS-CoV-2
• Spike Glycoprotein, Coronavirus (immunology)