{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE329nnn/GSE329962/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE329962"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Pathogenic IgG sialylation drives macrophage immunometabolic dysfunction and lung immunopathology via a Siglec-1–FcγR–VDAC1 axis","description":"Immunoglobulin G (IgG) Fc glycosylation critically regulates antibody effector functions, yet the pathogenic potential of early glycoform dynamics during acute viral infection remains poorly understood. Here, we identify a transient enrichment of sialylated IgG (Sia-IgG) during the early phase of SARS-CoV-2 infection that acts as a key driver of lung immunopathology. Contrary to the conventional anti-inflammatory role of sialylation, early-phase Sia-IgG fails to confer protection upon secondary viral challenge and instead aggravates lung injury despite reduced viral burden. Single-cell transcriptomic analysis of COVID-19 lungs reveals a selectively expanded SIGLEC1⁺ monocyte-derived macrophage population as a potential cellular target of this pathogenic signaling. Functional assays show that acute-phase IgG drives macrophage inflammatory infiltration in an FcγR-dependent manner. Moreover, acute-phase serum impairs phagocytic capacity and downregulates expression of the homeostatic marker CD206 in macrophages, indicative of a phenotypic shift toward a pro-inflammatory, dysfunctional state. Mechanistically, Sia-IgG coordinates the synergistic engagement of Siglec-1 and FcγRs, triggering mitochondrial immunometabolic collapse via VDAC1 oligomerization, excessive mitochondrial reactive oxygen species production, and impaired oxidative phosphorylation. Collectively, our findings define pathogenic IgG sialylation as a critical determinant of macrophage reprogramming, establishing a Siglec-1-FcγR-VDAC1 signaling axis that links humoral glycomic shifts to severe respiratory immunopathology during viral infection.","dates":{"publication":"2026/05/12"},"accession":"GSE329962","cross_references":{"GSM":["GSM9714090","GSM9714092","GSM9714091","GSM9714094","GSM9714093","GSM9714096","GSM9714095","GSM9714098","GSM9714097"],"GPL":["29480"],"GSE":["329962"],"taxon":["Homo sapiens"]}}