Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses
clinical immunology/immunity inflammation therapeutics
Authors: Hoepel et al.
Tags: Clinical, Immunology/Immunity, Inflammation, Therapeutics
Co-stimulation with polyIC and serum of severely ill COVID patients complexed with the SARS-CoV-2 Spike protein induces a pro-inflammatory cytokine release in human macrophages in vitro. The levels of cytokines secreted correlate with Ab titers.
Co-stimulation of macrophages with Spike protein and serum of severe COVID-19 induced long-lasting endothelial barrier disruption and enhanced platelet binding in an in vitro model for endothelial barrier integrity.
An aberrant glycosylation pattern from anti-spike IgGs from severe COVID-19 contributes to the anti-spike cytokine induction, that can be abrogated by a Syk inhibitor in vitro.
Hoepel et al. provide evidence that anti-spike IgG antibodies may correlate with disease severity in COVID-19 patients. In vitro M2-polarised macrophages stimulated with serum of severely ill patients complexed with SARS-CoV-2 Spike protein, together with the viral RNA-mimic PolyIC, induce the release of pro-inflammatory cytokines. Levels of cytokines secreted by macrophages correlate with the antibody titers. The co-stimulation of macrophages with Spike protein and serum of severe COVID-19 also induces long-lasting endothelial barrier disruption in an in vitro model for endothelial barrier integrity. Increased platelet adhesion and an active pro-coagulant state of the endothelium were also observed. An aberrant glycosylation pattern, decreased fucosylation and increased galactosylation, may be responsible for the induction of pro-inflammatory cytokines, as shown by artificially glycosylated anti-spike antibodies. FDA-approved drug that blocks Syk signalling downstream of FcgRs completely blocked pro-inflammatory cytokine production. Altogether, these results suggest that ADE (antibody-dependent enhancement) cannot be discarded as a mechanism for disease severity in COVID-19 and that vaccines against spike protein should be developed with caution.
Impact for SARS-CoV2/COVID19 research efforts
Understand the immune response to SARS-CoV2/COVID19
Clinical symptoms and pathogenesis of SARS-Cov2/COVID19
Treat of SARS-CoV2/COVID19 positive individuals
In vitro study
Strengths and limitations of the paper
Novelty: Evidence that anti-Spike antibodies from severely ill COVID-19 patients can exacerbate the disease. Possible explanation of the increased severity of COVID 19 post adaptive immune response due to cytokine storm.
Standing in the field: The study supports a possible ADE effect for severe COVID-19. Importantly, as most of the vaccine candidates are based on the Spike protein, a correct antibody response against that should be evaluated.
Appropriate statistics: Yes
Viral model used:Clinical samples and spike protein.
Translatability:The block of Syk by R406 (the active component of the small molecule inhibitor fostamatinib, an FDA- and EMA-approved drug) for treatment of immune thrombocytopenia resulted in a decrease of macrophage activation and could be incorporated in a clinical trial. This study should encourage further research in ADE in COVID 19
In figure 1A we couldn’t find how many replicates there are.
The study does not evaluate the type of antibodies or the specific epitopes they bind in the spike protein. The stimulation in the study are done with “crude” sample serum selected based on binding to the virus spike protein. When artificial antibodies are used the reaction is not as strong (might be due to galactose residues)
The Syk inhibitor is only tried on monocyte derived macrophages, no lung macrophages
The study only addresses “M2” macrophages responses, no other cells are taken into consideration