Decoding lymphoid tissue adaptive immune responses connected with Long COVID

Project Summary:

The study is working to determine if Long COVID is connected to altered immune responses in lymphoid tissue. The project team is the first in the world to collect cervical lymphoid tissue from Long COVID study participants via a biopsy procedure called a Fine Needle Aspirate (FNA). They are using techniques including high-parameter flow cytometry and combined single-cell proteomic and transcriptomic analyses to perform a series of in-depth experiments on the tissue samples.

The experiments test the hypothesis that inefficient or aberrant germinal center responses in lymphoid tissue are connected with the development of Long COVID neurological symptoms. Germinal centers are specialized microstructures that form in lymphoid tissues, producing long-lived antibody-secreting plasma cells and memory B cells that are important for the control of pathogen activity. The project is determining if aberrant germinal center responses in Long COVID are related to 1) A failure of Long COVID patients to clear the SARS-CoV-2 (viral reservoir) 2) Reactivation of latent viruses such as Epstein-Barr virus 3) SARS-CoV-2 promoting the amplification of autoreactive B cells.

Additional Project information: 

Germinal center reactions in secondary lymphoid organs are crucial for the generation of most memory B cell and long-lasting antibody responses that can confer protection from pathogen infection. Propelled by the COVID-19 pandemic, several studies by the project team and others have connected efficient germinal center formation with the generation of protective immunity following immunization with SARS-CoV-2 messenger RNA (mRNA) vaccines and during SARS- CoV-2 infection. Conversely, inefficient germinal center and/or altered B cell responses have been associated with poor COVID-19 prognosis, as indicated by the fact that in severe COVID-19 cases germinal centers are ablated and antibody responses are focused on the nucleocapsid instead of the spike component of SARS-CoV-2. 

Building on these findings, the project now integrates next-generation technologies to uncover the drivers of this immune dysfunction. These include PrimeFlow assays to detect latent and lytic Epstein-Barr virus within SARS-CoV-2–specific B cells, CITE-seq to jointly profile immune cell gene expression and surface proteins, and B cell receptor sequencing to assess clonal expansion and antibody maturation. The team is also using tonsil organoid systems to experimentally model co-infection with SARS-CoV-2 and Epstein Barr Virus, and spatial transcriptomics to map how B cells and T cells interact within lymph node architecture. These approaches will determine whether viral co-infections and disrupted lymph node organization redirect B cells away from germinal center pathways—resulting in weaker, short-lived immune responses.

Together, this work provides a first-in-class view of immune dysfunction directly within lymphoid tissue in Long COVID. By linking impaired B cell maturation, viral persistence, and potential Epstein Barr Virus reactivation, the project aims to define measurable biomarkers of disease and identify new targets for diagnostics and therapeutic intervention.

 Image courtesy of Normal Pathology