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Glycosylated IgG antibodies contribute to the recovery of haemorrhagic fever with renal syndrome patients
Key Laboratory of Emerging Infectious Diseases in Universities of Shandong, Shandong First Medical University and Shandong Academy of Medical Sciences, China
The Second Affiliated Hospital of Shandong First Medical University, China
School of Public Health, Shandong First Medical University and Shandong Academy of Medical Sciences, China
Medical Records and Statistics Management Office, Tengzhou Central People’s Hospital, China
Department of Neurobiology and Physiology, School of Clinical and Basic Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, China
School of Life Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, China
National Virus Reference Laboratory, School of Medicine, University College Dublin, Ireland
International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Japan
Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China
Shanghai Institute of Virology, Shanghai Jiao Tong University School of Medicine, China
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Glycosylated IgG antibodies contribute to the recovery of haemorrhagic fever with renal syndrome patients
The authors investigated the potential role of IgG N-glycosylation in Haemorrhagic Fever with Renal Syndrome (HFRS), which may offer significant insights for understanding molecular mechanisms and for the development of therapeutic strategies for this infectious disease. The findings are
to the field and the strength of evidence to support the findings is
https://doi.org/10.7554/eLife.106989.4.sa0
: Findings that have theoretical or practical implications for a subfield
: Methods, data and analyses broadly support the claims with only minor weaknesses
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Haemorrhagic fever with renal syndrome (HFRS) is a fatal disease caused by Hantaan virus (HTNV) infection. Humoral immunity is essential for effective viral clearance; however, the glycosylation characteristics of immunoglobulin G (IgG) in HFRS patients are not well known. Peripheral blood mononuclear cells from HFRS patients were obtained for B subset analysis using scRNA-seq and flow cytometry. HTNV-specific IgG antibody titers were detected by enzyme-linked immunosorbent assay, and IgG glycosylation was analyzed by ultra-performance liquid chromatography. The proportions of the antibody-secreting memory (ASM) B cells and plasmablasts (PB) were significantly expanded among acute HFRS patients. We discovered significantly increased fucosylated IgG and decreased bisecting N-acetylglucosamine during the convalescent phase of HTNV infection. Meanwhile, positive correlations were observed between ASM subsets and galactosylation/sialylation in the IgG Fc region, and between PB subsets and sialylation. Notably, the glycosylation-related genes, such as
, were primarily expressed differentially in the ASM and PB subclusters, which were enriched in the N-glycosylation modifications of proteins through asparagine. Our findings indicated that IgG N-glycosylation may play a crucial role in combating HTNV infection and contributing to clinical recovery, which provided new insights for optimizing glycoengineered therapeutic antibodies.
The causative agent of haemorrhagic fever with renal syndrome (HFRS) is Hantaan virus, which belongs to the family
and is primarily transmitted by rodents (
). China is the most heavily affected country by HFRS, accounting for >90% of global cases, and a total of 32,462 cases of HFRS were reported in China during 2019–2022, with a fatality rate ranging from 0.1 to 15% (
Hantaviruses are tri-segmented, single-stranded, negative-sense RNA viruses, whose genomes consist of three regions: large (L), medium (M), and small (S). The glycoproteins Gn and Gc, encoded by the M segment, can infect target cells - primarily vascular endothelial cells - via β3 integrin receptors (
). Simultaneously, they could also infect other cell types, such as mononuclear macrophages and dendritic cells, leading to systemic viral infection. Although hantavirus replication is thought to occur primarily in the vascular endothelium without direct cytopathic effects, a plethora of innate immune cells mediate host antiviral defenses. These include natural killer cells, neutrophils, monocytes, and macrophages, together with pattern recognition receptors (PRRs), interferons (IFNs), antiviral proteins, and complement activation, e.g., via the pentraxin 3 (PTX3) pathway, which can exacerbate HFRS disease progression leading to immunopathological damage through cytokine/chemokine production, cytoskeletal rearrangements in endothelial cells, ultimately amplifying vascular dysfunction (
). Rapid and effective humoral immune responses, however, such as neutralizing antibody responses targeting the glycoproteins Gn/Gc, contribute to rapid recovery from HFRS and are critical for protection from severe disease (
Immunoglobulin G (IgG) N-linked glycosylation mediates critical functions modulating antiviral immunity during viral infection. Changes in the conserved N-linked glycan Asn297 in the Fc region of IgG, typically by fucosylation, galactosylation, or sialylation, can alter antibody effector function. A reduction in core fucosylation decreases IgG binding to NK cell FcγRIIIa promotes antibody-dependent cellular cytotoxicity (ADCC) necessary for clearance of viruses, including SARS-CoV-2, dengue, and HIV-1, whereas sialylation can attenuate immune responses, resulting in immune evasion (
). Changes in IgG and other protein N-linked glycosylation profiles, therefore, shape virus-host interactions and disease progression.
Importantly, there have not been prior studies specifically examining plasma IgG N-glycome profiles derived from chromatographic peak data in HFRS patients, particularly in relation to seroconversion status. This gap in our knowledge motivated our systematic investigation of both total and virus-specific IgG glycosylation dynamics during acute infection. In the present study, we combined scRNA-seq and flow cytometry to reveal the phenotypes of B cell responses during HTNV infection and explored the transcriptomic features of reactive B cell subsets. A total of 166 HFRS patients, including 65 paired HFRS samples, were employed to profile the IgG-Fc glycosylation pattern and to investigate the potential regulatory role of IgG-Fc glycosylation in HFRS pathogenesis.
B cell compositional characteristics in HFRS patients
To characterize the humoral immune profiles in HFRS patients, we enrolled 166 suspected HTNV-infected patients who were admitted to Baoji Central Hospital in Shaanxi Province, China, between October 2019 and January 2022. Among them, 65 met the inclusion criteria and were included in the study (
). We identified a total of eight cell subpopulations, including subsets of CD4 T cells, CD8 T cells, CD14 monocytes, NK cells, B cells, platelets, endothelial progenitor cells, and red blood cells (
). The proportions of these cell types were comparable between acute HFRS patients and healthy controls, with no significant batch effects observed (
). CD4 T cells (31.4%) were the predominant subset prior to HTNV infection, whereas CD8 T cells (44%) became the dominant population post-infection. Notably, the proportions of NK cells (15.9–5.6%, p<0.001) and platelets (3.1–0.6%, p<0.01) significantly decreased, whereas the level of CD14 monocytes (15.9–32.3%, p<0.05) nearly doubled. The overall