Abstract
Severe COVID-19 is an immunological disorder characterized by a hyper-inflammatory reaction of the immune system. SARS-CoV-2 anti-spike antibodies of the IgG isotype are known to strongly contribute to this hyperinflammation by overactivation of alveolar macrophages. However, while the pathogenic function of IgG has been extensively studied, very little is known about the function of IgA, the most abundant immunoglobulin isotype in the airways. Although IgA is generally considered noninflammatory, in this study, we show that anti-spike IgA induces pronounced proinflammatory responses. We demonstrate that stimulation of macrophages with anti-spike IgA immune complexes in combination with a viral stimulus amplifies proinflammatory cytokine production. This IgA-induced inflammation is particularly driven by IgA2, the IgA subclass that is increased in the plasma of severely ill COVID-19 patients. We identified that IgA2-induced inflammation is predominantly dependent on FcαRI-Syk signaling. Mechanistically, IgA2-induced inflammation is linked to enhanced glycolysis and altered mitochondrial function, indicating subclass-specific immunometabolic reprogramming. Taken together, these data indicate a pathogenic role for IgA2 in severe COVID-19 and highlight its signaling cascades and metabolic pathways as potential druggable targets to counteract hyperinflammation in severe coronavirus infections, such as COVID-19, SARS, MERS, and potential future outbreaks.