Pathogenic IgG sialylation drives macrophage immunometabolic dysfunction and lung immunopathology via a Siglec-1–FcγR–VDAC1 axis

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.