SARS-CoV-2 seeds IAPP aggregation and β-cell failure

Abstract The global diabetes incidence has surged post-COVID-19, yet how SARS-CoV-2 drives long-term beta cell (β-cell) failure remains incompletely elucidated. We identified a mechanism whereby SARS-CoV-2 structural proteins directly hijack islet amyloid polypeptide (IAPP) to induce pathogenic amyloid deposition, disrupting insulin granule maturation, trafficking, and secretion in an age-susceptible islet microenvironment. In macaque models, aged subjects showed extensive islet IAPP aggregation with increased β-cell necroptosis, whereas adult infected animals exhibited minimal IAPP pathology. Multiplex fluorescence in situ hybridization detecting viral sense and antisense RNAs with IAPP immunostaining revealed focal overlap of active viral replication foci with IAPP-rich amyloid regions in aged islets. Molecular docking was used as a hypothesis-generating tool, whereas coimmunoprecipitation, proximity ligation assays, and surface plasmon resonance experimentally confirmed direct spike/nucleocapsid-IAPP binding; interface-guided peptide mutagenesis further showed that five predicted IAPP contact residues are required for binding. Thioflavin-T kinetics and electron microscopy demonstrated that the spike/nucleocapsid markedly accelerated IAPP monomer conversion into dense fibrillar networks. In β cells and primary hIAPP-overexpressing mouse islets, spike/nucleocapsid expression or protein exposure reduced insulin content and induced endoplasmic reticulum stress and inflammatory programs. Integrated spatial islet proteomics linked IAPP-viral complexes to complement activation and vesicle transport dysfunction. Crucially, primary islet qPCR and immunoblotting revealed stalled insulin mRNA with compensatory upregulation of trafficking/exocytosis transcripts but accumulation of insulin precursor proteins, consistent with impaired granule maturation/processing. Thus, SARS-CoV-2 proteins act as pathogenic “seeds” for IAPP assembly, establishing an IAPP aggregation-impaired granule maturation-complement activation-vesicle transport blockade axis underlying age-associated vulnerability to post-COVID-19 diabetes.