Decoding lymphoid tissue adaptive immune responses connected with Long COVID

Project Summary:

This study will determine if Long COVID is connected to altered immune responses in lymphoid tissue. The project team will be 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 will use 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 will 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 will determine if aberrant germinal center responses in Long COVID could be 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 Coronavirus disease 2019 (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. 

The current project will build on this research to determine if inefficient or misdirected germinal center responses contribute to the Long COVID disease process. By probing the immune response triggered by or in response to SARS-CoV-2 in lymphoid tissue, the study will create a blueprint of the immunological features connected with the development of Long COVID. Knowledge gained from the study has the potential to guide the therapeutic modulation of aberrant/suboptimal germinal center responses in Long COVID and to inform possible mechanisms of immune dysregulation behind other debilitating infection-associated chronic conditions.

 Image courtesy of Normal Pathology