Antibody imprinting is well recognized, yet its long-term dynamics and epitope specificity remain poorly understood. Here, we studied individuals sequentially infected with SARS-CoV-1 (SARS-1) and SARS-CoV-2 (SARS-2) over two decades and found durable imprinting of antibody responses following SARS-2 BF.7 breakthrough infection. Approximately 60% of isolated monoclonal antibodies were SARS-1 imprinted and targeted conserved receptor-binding domain regions, whereas 37% overcame imprinting to recognize the SARS-2 receptor-binding motif overlapping the ACE2-binding site. Notably, some SARS-1-only antibodies retained germline-like features and neutralizing activity 20 years after infection. One exceptionally imprinted broadly neutralizing antibody, THZ937, protected hamsters against contact and airborne transmission of Omicron EG.5.1, demonstrating the functional relevance of durable imprinted antibodies. Together, these findings define the remarkable longevity and molecular basis of antibody imprinting and provide insights for pan-sarbecovirus vaccine design.
Severe COVID-19 is characterized by profound dendritic cell (DC) dysfunction, yet the molecular drivers remain poorly defined.
To evaluate DC heterogeneity during COVID-19, we longitudinally immunophenotyped circulating DC subsets in mild and severe cases. We then performed immune correlation analyses across 23 antigen-specific readouts, T cell responses, antibody titers, and inflammatory markers. High-parameter flow cytometry was used to identify drivers of SARS-CoV-2—associated DC dysfunction. Single-cell RNA sequencing (scRNA-seq) profiled peripheral blood DC subsets, and transcriptional analyses evaluated downstream mediators.
We demonstrated that IL-6—enriched patient plasma and supernatant from Delta-infected lung epithelial cells reduce CD86 expression on cDC2s and expand the immunosuppressive CD163+ DC3 subset, a phenotype reversible with IL-6 receptor blockade. Single-cell RNA-sequencing revealed the expanded CD163+ DC3 population drives immunosuppression in severe COVID-19 patients. Mechanistically, we implicate the transcription factor C/EBPβ as a critical downstream mediator, based on its disease-associated expression and established role in myeloid cell programming.
Overall, this study unveils a novel immune-evasion pathway wherein SARS-CoV-2-induced IL-6 expands immunosuppressive DC3s via C/EBPβ, highlighting IL-6 and C/EBPβ as promising therapeutic targets for ameliorating DC dysfunction in severe COVID-19 and related hyperinflammatory disorders.
Hong Kong Collaborative Research Fund (CRF): C7156-20G
Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)
Run-Hong Zhou, Zhiwei Chen, Na Liu· Journal of Immunology· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
