Viral infections are a significant concern for public health, as viruses, regardless of their genetic and capsid structures, play pivotal roles in human infections and diseases. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infect approximately 295.9 million and 57.8 million people worldwide, respectively, and are major inducers of liver cancer (1). Around 38 million people worldwide are living with human immunodeficiency virus (HIV). Persistent HIV infection induces immune activation, chronic inflammation, multiorgan damage (2). Since the emergence of the Coronavirus Disease 2019 (COVID-19), it has rapidly evolved from a localized issue into a global pandemic. This epidemic presents unprecedented challenges to the global public health infrastructure and exerts profound impacts on the socio-economic landscape and individual lifestyles (3). The threat to global public health is exacerbated by numerous viral infectious diseases for which vaccines, antiviral treatments, and diagnostic markers are often lacking, particularly for newly emerging viruses (4). Consequently, understanding immune responses to viral infections and developing antiviral strategies can help reduce the spread and impact of these pathogens.

Viral infections elicit inflammation and immune responses-processes pivotal to antiviral defense. Upon viral invasion, the innate immune system (encompassing macrophages, NK cells, and the secretion of proinflammatory cytokines) first orchestrates an immediate, non-antigen-specific defense cascade to constrain early viral replication and dissemination (5). This innate response further drives the activation of the adaptive immune system: professional antigen-presenting cells (e.g., dendritic cells) mature upon sensing viral components, process and present viral epitopes to T lymphocytes. Activated T cells (especially follicular helper T cells, Tfh) in turn activate B lymphocytes via Cluster of Differentiation 40 and its ligand Cluster of Differentiation 40 Ligand (CD40-CD40L) interaction and cytokine secretion (6). As a core effector molecule of adaptive immunity, immunoglobulin G (IgG) fulfills indispensable roles in antiviral defense. IgG participates in antiviral immune responses through multiple mechanisms, including virus neutralization, phagocytosis promotion, and complement system activation (7). Additionally, the interaction between the crystallizable fragment (Fc) of IgG and Fcγ receptors is critical for antibody-mediated effector functions, which, together with antigen-binding fragments (Fab) segment-mediated viral neutralization, mobilizes effector cells to participate in immune responses and enhances antiviral defense (8).

IgG function is tightly regulated by N-glycosylation, a post-translational modification essential for its immune activities; distinct glycosylation patterns can drive divergent immune response outcomes (9). Over recent decades, IgG N-glycosylation has emerged as a critical correlate of multiple pathologies: studies demonstrate its high sensitivity in distinguishing healthy individuals from patients with autoimmune diseases, infectious diseases, and cancer (10). The N-glycosylation profile of IgG exhibits variability across different diseases, indicating its potential utility as a specific biomarker (11). Notably, alterations in IgG N-glycosylation have also been observed after infections with bacterial and parasitic pathogens. For instance, IgG1 galactosylation was associated with Mycobacterium tuberculosis infection, while changes in fucosylation patterns may affect IgG-mediated clearance of Plasmodium (12, 13). In addition to IgG, immunoglobulins such as Immunoglobulin A (IgA), Immunoglobulin M (IgM), and Immunoglobulin E (IgE) can also undergo N-glycosylation modifications, which are associated with certain pathogenic infections. For example, sialylation of IgA has been reported to correlate with disease severity in both COVID-19 and influenza A (14, 15). Additionally, increased levels of high-mannose and sialylated IgM isoforms are linked to greater severity of COVID-19 in a separate investigation (16). While these studies have progressively elucidated the importance of alterations in immunoglobulin glycosylation modifications in the onset and progression of various diseases, comprehensive research on glycosylation modifications of immunoglobulins other than IgG in various pathological conditions remains limited. Furthermore, considering that IgG is the most abundant immunoglobulin in human serum and serves as a crucial effector molecule in humoral immunity, this review focuses on the investigation of IgG N-glycosylation.

This article investigates the intrinsic connection between viral infections and immune responses, with a particular emphasis on recent research on alterations in IgG N-glycosylation in human serum or plasma during infections, and systematically elucidates the critical role of various IgG N-glycosylation modifications in disease progression and immune regulation.

Millions of deaths occur annually due to viral infections, including chronic viral pathogens (e.g., HBV, HCV) and emerging zoonotic viruses (e.g., COVID-19, influenza A/H5N1) (17, 18). These viral infections, whether chronic or acute, impose a major global public health burden. Upon viral invasion, the host initiates a sequentially activated and synergistically coordinated immune response, in which the innate immune system acts as the first line of defense. This rapid-acting response is mediated by pattern recognition receptors (PRRs) expressed on innate immune cells (e.g., macrophages, dendritic cells, and natural killer cells) (19). PRRs conservatively recognize conserved pathogen-associated molecular patterns (PAMPs) derived from viral components (e.g., viral RNA, glycoproteins) and damage-associated molecular patterns (DAMPs) released by infected or stressed cells (20). Engagement of PRRs triggers downstream inflammatory signaling cascades (e.g., NF-κB, IRF pathways), leading to the production of pro-inflammatory cytokines (interleukin (IL)-6, tumor necrosis factor (TNF)-α), chemokines (CCL2, CXCL10), and type I interferons (IFN-I) (21, 22). These soluble mediators not only directly inhibit viral replication and spread but also recruit and activate other immune cells, thereby laying the foundation for the subsequent adaptive immune response.

The adaptive immune response is activated following antigen presentation initiated by the innate immune response. Professional antigen-presenting cells (APCs), primarily dendritic cells (DCs), phagocytose viral particles or infected cells, process viral antigens into peptide fragments, and present these peptides on major histocompatibility complex (MHC) class I and class II molecules (23). MHC class I-presented viral peptides are recognized by CD8+ T cells, which require two signals for activation and differentiation into cytotoxic T lymphocytes (CTLs): the first signal is the binding of T cell receptor (TCR) to the MHC-I-peptide complex, and the second signal is provided by DC-derived co-stimulatory molecules and cytokines (24). Once activated, CTLs specifically recognize and eliminate virus-infected cells by releasing perforin and granzyme, or by inducing apoptosis via the Fas-Fas ligand (FasL) pathway. Concurrently, MHC class II-presented peptides are recognized by CD4+ T cells, which differentiate into specialized T helper (Th) cell subsets (e.g., Th1, Th2, Tfh cells) depending on the cytokine microenvironment. Tfh cells migrate to germinal centers (GCs) in secondary lymphoid organs, where they interact with B cells through cell-cell contact (e.g., CD40-CD40L) and secretion of cytokines (e.g., IL-21, IL-4), providing essential signals for B cell activation and maturation (25, 26).

Activated B cells undergo clonal expansion and differentiate into either short-lived plasmablasts or long-lived plasma cells, which secrete large quantities of antigen-specific antibodies. Additionally, a subset of B cells differentiates into memory B cells, enabling rapid and robust immune responses upon re-exposure to the same virus (27). Among the five antibody isotypes (IgM, IgG, IgA, IgD, IgE), IgG is the predominant isotype in the late phase of the systemic primary immune response and the entire systemic secondary immune response, while secretory IgA (sIgA) dominates the mucosal secondary immune response (28). IgG production is tightly regulated by Tfh cell-derived cytokines and B cell-intrinsic signaling pathways (29). The resulting IgG antibodies exert multiple antiviral effects, including neutralization of viral particles (preventing viral entry into host cells), activation of the complement system (mediating lysis of infected cells), and antibody-dependent cellular cytotoxicity (ADCC) or phagocytosis (recruiting NK cells or macrophages to eliminate infected cells) (30, 31). Collectively, B cell-mediated humoral immunity (predominantly IgG secretion) and T cell-mediated cellular immunity (predominantly CTL activity) are core effector mechanisms of the adaptive immune response, which synergistically contribute to the clearance of viral infections and the establishment of long-term protective immunity (Figure 1).

IgG, an abundant immunoglobulin in human serum, is a Y-shaped glycoprotein composed of four polypeptide chains: two identical heavy chains (H chains) and two identical light chains (L chains). Papain cleavage of IgG at the hinge region yields two identical Fab and Fc (32). The Fab region, containing the variable light (VL), variable heavy (VH), constant light (CL) and constant heavy 1 (CH₁) domains, mediates antigen binding, while the Fc region, consisting of the constant heavy 2 (CH₂) and constant heavy 3 (CH₃) domains of the two heavy chains, interacts with cell surface Fc receptors (FcRs) and does not bind antigens (33). Glycosylation, a sophisticated post-translational modification of proteins, regulates protein stability, folding, cellular trafficking, signaling transduction, and interactions with other macromolecules (34). Protein glycosylation is categorized into N-linked (occurring on asparagine residues) and O-linked (occurring on serine or threonine residues) glycosylation (35). IgG O-linked glycosylation is challenging to characterize due to its heterogeneous core structures and the absence of conserved consensus sequences (36). In contrast, N-linked glycosylation of IgG has been extensively investigated and well characterized. A conserved N-linked glycosylation site at asparagine 297 (Asn297) of the IgG Fc region critically modulates the structure and function of the Fc domain (37).

The conserved pentasaccharide core of IgG N-glycans consists of three mannose (Man) residues and two N-acetylglucosamine (GlcNAc) residues. Within the Golgi apparatus, mannosidases trim excess Man residues from the core glycans, laying the foundation for subsequent branch (antenna) formation (38). N-acetylglucosaminyltransferases (GnTs) catalyze the attachment of GlcNAc to the trimmed Man residues, generating a biantennary core precursor. For the addition of a bisecting GlcNAc, β1,4-linked N-acetylglucosamine is attached to the core β-mannose residue (the central Man residue linking the two branch Man residues in the pentasaccharide core). The biantennary core precursor can be further extended with galactose (Gal) and N-acetylneuraminic acid (Neu5Ac) on the antenna GlcNAc residues, while core fucose (Fuc) is attached to the innermost GlcNAc residue of the pentasaccharide core, together forming complex biantennary N-glycan structures (Figure 2) (39). The structure of IgG N-glycans is highly heterogeneous due to variations in glycan chain length, antenna number, and monosaccharide modification. Human serum IgG predominantly harbors complex N-glycans with biantennary (two branches) structures, with minor populations of triantennary (three branches) or tetraantennary (four branches) variants, whereas IgG Fc fragments exclusively contain complex biantennary N-glycans. These Fc-associated biantennary N-glycans exhibit more than 30 potential structural combinations, driven by differences in galactosylation, sialylation, core fucosylation and bisecting GlcNAc (40).

The IgG Fc domain enhances effector functions by interacting with Fcγ receptors (FcγRs) on myeloid cells and NK cells, or by initiating complement activation. IgG antibodies are classified into four subclasses (IgG1–IgG4) based on amino acid sequence differences in their heavy chain constant regions, with each subclass exhibiting distinct binding affinities for members of the FcγR family (FcγRI–FcγRIII) (41). Importantly, IgG N-glycosylation modulates these effector functions by regulating the binding affinity of the Fc domain for FcγRs or complement component C1q, including ADCC, complement-dependent cytotoxicity (CDC), and antibody-dependent cell phagocytosis (ADCP) (42).

While some studies have reported alterations in serum IgG N-glycosylation in patients with certain viral infections, the precise mechanisms underlying these changes remain largely unclear. Furthermore, it has not yet been determined whether there are consistent patterns and correlations in N-glycosylation alterations induced by different viral infections. In this study, we reviewed IgG N-glycosylation alterations associated with various viral infections (Figure 3), focusing on changes in galactosylation, sialylation, fucosylation and bisecting GlcNAc as well as their underlying causes (Figure 4). Additionally, we evaluated the potential of these glycosylation alterations as biomarkers for the early diagnosis and prognosis of viral diseases.

Currently, viral nucleic acid detection is the standard method for identifying viral infections. While accurate, this method cannot track disease progression or predict clinical outcomes (89). Given the alterations in IgG N-glycosylation patterns during viral infections, numerous researchers have investigated IgG N-glycosylation-related indicators and explored their potential as diagnostic and prognostic biomarkers. Once IgG N-glycosylation enters the circulation, it remains stable (except for sialylation), which reflects the host’s immune status and provides valuable information for the diagnosis and prognostic evaluation of related diseases (90). Thus, IgG N-glycosylation biomarkers may serve as promising diagnostic and prognostic indicators.

For instance, HBV and HCV carriers are at high risk of developing cirrhosis and HCC. Liver biopsy is the gold standard for diagnosing fibrosis stages but is invasive, which deters many patients. The diagnostic efficacy of alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) in early HCC is limited. A study involving 760 patients with CHB revealed that serum IgG N-glycans can be used for non-invasive diagnosis of liver fibrosis. In this study, 7 peaks (NGA2F, NGA2FB, NG1A2F, NA2, NA2FB, NA3, NA4Fb) were selected from differential N-glycan peaks through LASSO regression to construct the Px model. The results showed that the Px model was significantly superior to liver stiffness measurement, aspartate aminotransferase to platelet ratio index, and fibrosis - 4 index (AUC = 0.766) (91). Serum IgG L3% (IgG with high Lens culinaris agglutinin (LCA) affinity and high fucosylation) exhibited a diagnostic accuracy of 81.3% in distinguishing HCC from non-HCC, surpassing AFP’s 78.0%. It also outperformed AFP in differentiating liver cirrhosis (LC) from HCC, suggesting its potential as a diagnostic biomarker. Additionally, serum IgG L3% could serve as a prognostic indicator, as higher levels in HCC patients correlate with poorer prognosis and increased postoperative recurrence (75). Furthermore, IgG N-glycan A2G1 (6) FB accurately distinguishes HCC from LC (area under the curve (AUC) = 0.9614) (92). The N-linked glycans of anti-Gal IgG in healthy individuals were mainly FcA2G2 (core fucosylated biantennary, containing 2 galactoses). In patients with HCV infection-related liver cirrhosis, the anti-Gal IgG was mainly FcA2G0 (core fucosylated biantennary, without galactose). Galactose-deficient anti-Gal IgG could be used as a marker for liver fibrosis/cirrhosis (AUC = 0.93), and its efficacy was better than some traditional indicators (such as serum γ-globulin) (45).

Following HIV infection, IgG N-glycans can track disease progression, including the time to HIV rebound during ART, which is associated with IgG G2 levels. IgG galactosylation and sialylation patterns can predict COVID-19 progression, with higher G0 levels often indicating poor prognosis (48). Specifically, IgG G2, IgG1 G0, and IgG2&3 G2 can independently predict patient prognosis (AUC = 0.722, 0.714, and 0.705, respectively), and their combination significantly improves the prediction of COVID-19 progression (AUC = 0.729) (50). In dengue virus infection, reduced IgG1 fucosylation predicted disease severity. This association was supported by the finding that patients who developed severe manifestations, including dengue hemorrhagic fever and dengue shock syndrome, displayed significantly elevated levels of heightened levels of afucosylated IgG1 (76). Additionally, the fucosylation status of maternal anti-dengue IgG predicted infant susceptibility in a separate study (77). These IgG glycan-related indicators show good sensitivity and specificity, indicating their potential as diagnostic and prognostic biomarkers.

Viral infections can stimulate the host immune system to elicit a response, and the activation of immune effector mechanisms such as ADCC, ADCP, and CDC is closely associated with the composition of IgG Fc N-glycans. Following viral infection, alterations in IgG N-glycosylation are observed, typically characterized by decreased galactosylation and sialylation; however, changes in fucosylation and bisecting GlcNAc exhibit a more complex pattern. The underlying mechanisms driving these changes warrant further investigation. Additionally, accumulating evidence suggests that IgG N-glycosylation alterations may serve as biomarkers for tracking the progression of various viral diseases and predicting their severity. Consequently, the analysis of serum IgG N-glycosylation changes in patients may provide novel insights for the diagnosis and treatment of viral infection-associated diseases.