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. 2024 Oct 16;11(11):ofae626.
doi: 10.1093/ofid/ofae626. eCollection 2024 Nov.

Altered Spike Immunoglobulin G Fc N-Linked Glycans Are Associated With Hyperinflammatory State in Adult Coronavirus Disease 2019 and Multisystem Inflammatory Syndrome in Children

Jacob D Sherman  1 , Vinit Karmali  1 , Bhoj Kumar  2 , Trevor W Simon  1 , Sarah Bechnak  1 , Anusha Panjwani  1 , Caroline R Ciric  3 , Dongli Wang  1 , Christopher Huerta  1 , Brandi Johnson  1 , Evan J Anderson  1   3 , Nadine Rouphael  1 , Matthew H Collins  1 , Christina A Rostad  3 , Parastoo Azadi  2 , Erin M Scherer  1
Affiliations

Altered Spike Immunoglobulin G Fc N-Linked Glycans Are Associated With Hyperinflammatory State in Adult Coronavirus Disease 2019 and Multisystem Inflammatory Syndrome in Children

Jacob D Sherman et al. Open Forum Infect Dis. .

Abstract

Background: Severe coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome (MIS-C) are characterized by excessive inflammatory cytokines/chemokines. In adults, disease severity is associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulin G (IgG) Fc afucosylation, which induces proinflammatory cytokine secretion from innate immune cells. This study aimed to define spike IgG Fc glycosylation following SARS-CoV-2 infection in adults and children and following SARS-CoV-2 vaccination in adults and the relationships between glycan modifications and cytokines/chemokines.

Methods: We analyzed longitudinal (n = 146) and cross-sectional (n = 49) serum/plasma samples from adult and pediatric COVID-19 patients, MIS-C patients, adult vaccinees, and adult and pediatric controls. We developed methods for characterizing bulk and spike IgG Fc glycosylation by capillary electrophoresis and measured levels of 10 inflammatory cytokines/chemokines by multiplexed enzyme-linked immunosorbent assay.

Results: Spike IgG was more afucosylated than bulk IgG during acute adult COVID-19 and MIS-C. We observed an opposite trend following vaccination, but it was not significant. Spike IgG was more galactosylated and sialylated and less bisected than bulk IgG during adult COVID-19, with similar trends observed during pediatric COVID-19/MIS-C and following SARS-CoV-2 vaccination. Spike IgG glycosylation changed with time following adult COVID-19 or vaccination. Afucosylated spike IgG exhibited inverse and positive correlations with inflammatory markers in MIS-C and following vaccination, respectively; galactosylated and sialylated spike IgG inversely correlated with proinflammatory cytokines in adult COVID-19 and MIS-C; and bisected spike IgG positively correlated with inflammatory cytokines/chemokines in multiple groups.

Conclusions: We identified previously undescribed relationships between spike IgG glycan modifications and inflammatory cytokines/chemokines that expand our understanding of IgG glycosylation changes that may impact COVID-19 and MIS-C immunopathology.

Keywords: COVID-19; Fc; MIS-C; antibody glycosylation; inflammation.

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Conflict of interest statement

Potential conflicts of interest. E. J. A. is currently employed by Moderna and owns stock or stock options in Moderna. C. A. R. has received grants or contracts to Emory from BioFire Inc, GSK, MedImmune, Micron, Merck, Novavax, PaxVax, Regeneron, Pfizer, Sanofi-Pasteur, Janssen, Moderna, NIH, and CDC; is a co-inventor of patented respiratory syncytial virus (RSV) vaccine technology that has been licensed to Meissa Vaccines Inc and has received royalties from Meissa Vaccines Inc; and has patents pending or issued: “Chimeric RSV, Immunogenic Compositions, and Methods of Use,” International PCT Application No. PCT/US2016/058976, filed 28 December 2016 by Emory University and “RSV Live-Attenuated Vaccine Candidates with Deleted G-Protein Mucin Domains,” US Patent Application No. 63/411,251, filed 29 September 2022 by Emory University. N. R. has received grants or contracts to Emory from NIH, Merck, Sanofi, Pfizer, Vaccine Company, Immorna, Quidel, and Lilly; has received consulting fees from Krog; has received payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Virology Education; has received support for attending meetings and/or travel from Sanofi and Moderna; has participated in data safety monitoring boards for Emmes, ICON, Biomedical Advanced Research and Development Authority, CyanVac, and Micron and advisory boards for Moderna, Sanofi, Seqirus, and Pfizer; has held advisory roles for the Antibacterial Resistance Leadership Group, TMRC, and CDC-Pertussis challenge; is Associate Editor of Clinical Infectious Diseases; and has received equipment, materials, drugs, medical writing, gifts, or other services to Emory from Georgia Research Alliance. E. M. S. has received grants from NIH, JC Kennedy Foundation, and Georgia Clinical & Translational Science Alliance; has received materials from Merck; has received honoraria for lectures/presentations from Merck; and has patents pending or issued: “Anti-ALPP/ALPP2 Antibodies,” US Patent Provisional Application Nos. 63/162,635, 63/301,574, and 18/282,232 filed 18 March 2021, 21 January 2022, and 15 September 2023 by Seagen, “Anti-ALPP/ALPP2 Antibodies,” International PCT Application No. PCT/US2022/020697 filed 17 March 2022 by Seagen, “Antibodies that Bind CD228,” US Patent Provisional Application No. 63/408,605, filed 21 September 2022 by Seagen, “Novel Fusion Protein Specific for CD137 and CD228,” US Patent Provisional Application Nos. 63/408,634, 63/413,174, and 63/496,463 filed 21 September 2022, 4 October 2022, and 17 April 2023 by Seagen. All other authors report no potential conflicts.

Figures

Figure 1.
Figure 1.
Schematic of immunoglobulin G (IgG) structure with conserved N-linked complex glycan at residue 297. IgG is composed of the antigen-binding domains, F(ab)2, and constant domain, Fc. The Fc has a highly conserved complex N-glycan at Asn297, which is composed of a core with 7 GlcNAc and mannose sugars and additional, variable modifying sugars.
Figure 2.
Figure 2.
Proinflammatory cytokines and chemokines are significantly elevated in adult coronavirus disease 2019 (COVID-19) patients and multisystem inflammatory syndrome (MIS-C) patients compared to healthy controls. Differences in interleukin (IL) 10, interferon gamma induced protein 10 (IP-10), IL-8, interferon gamma (IFN-γ), IL-6, and macrophage-inflammatory protein 1 alpha (MIP-1α) levels between adult healthy controls, which includes vaccinees at baseline, patients enrolled in the Adaptive COVID-19 Treatment Trial (ACTT-1) with different COVID-19 severities by ordinal scale (OS) at enrollment (V1), or vaccinees (7 d post–second dose [7d psd]); as well as between pediatric healthy controls or pediatric patients with severe acute respiratory syndrome coronavirus 2 or MIS-C. Kruskal-Wallis with Dunn test (*P < .05, **P < .01, ***P < .001, ****P < .0001).
Figure 3.
Figure 3.
Spike-coated beads capture anti-spike immunoglobulin G (IgG) from purified bulk IgG of a seropositive participant. A, After treatment 3 times with His Dynabeads coated with 0 μg (red circles) or 12 μg (blue squares) severe acute respiratory syndrome coronavirus 2 spike protein, depleted bulk IgG was analyzed for spike binding by enzyme-linked immunosorbent assay alongside the purified bulk IgG (green triangles). B, Measurement of spike binding by postenrichment IgG eluates from His Dynabeads coated with 0 μg (red circles) or 12 μg (blue squares) spike.
Figure 4.
Figure 4.
Afucosylated anti-spike immunoglobulin G (IgG) is significantly increased in severe coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome (MIS-C) over bulk and healthy controls, while anti-spike IgG is globally more sialylated and less bisected than bulk or healthy control IgG. Kruskal-Wallis with Dunn test (*P < .05, **P < .01, ***P < .001, ****P < .0001).
Figure 5.
Figure 5.
Changes in immunoglobulin G (IgG) Fc glycans between acute infection and convalescence in patients with severe coronavirus disease 2019 (COVID-19). Differences in afucosylated, sialylated, galactosylated, or bisected bulk (black symbols, first and third columns) or anti-spike (red symbols, second and fourth columns) IgG Fc glycan abundances between acute infection and convalescence in paired serum samples of adults with severe COVID-19 (ordinal scale 5 and 7), who received either remdesivir or placebo. Wilcoxon matched-pairs signed-rank test (*P < .05, **P < .01).
Figure 6.
Figure 6.
Inverse correlations observed between afucosylated, sialylated, or galactosylated glycan abundances and proinflammatory cytokine levels in adult coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome (MIS-C) patients are not observed in vaccinees. Spearman correlation coefficients were estimated between serum cytokine/chemokine levels and spike immunoglobulin G (IgG) glycan abundances in moderate (ordinal scale [OS] 4) and severe (OS5/7) COVID-19 at enrollment (V1), mRNA vaccine recipients at 7 d after the second vaccine dose (7d psd), and MIS-C patients. Gradient from blue to red indicates strength of positive or inverse correlation, respectively. Significant relationships are indicated by asterisks (*P < .05, **P < .01, ***P < .001). Cytokine abbreviations: IFN-γ, interferon gamma; IL, interleukin; IP-10, interferon gamma induced protein 10; MCP-1, monocyte chemoattractant protein 1; MCP-3, monocyte chemoattractant protein 3; MIP-1α, macrophage-inflammatory protein 1 alpha; TNF-α, tumor necrosis factor alpha.
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