Tissue-Based T Cell Activation and Viral RNA Persist for Up to Two Years Following SARS-CoV-2 Infection

• Published in: Science translational medicine 2024-07, Vol.16 (754), p.eadk3295-eadk3295
• Main Authors: Peluso, Michael J., Ryder, Dylan, Flavell, Robert, Wang, Yingbing, Levi, Jelena, LaFranchi, Brian H., Deveau, Tyler-Marie, Buck, Amanda M., Munter, Sadie E., Asare, Kofi A., Aslam, Maya, Koch, Walter, Szabo, Gyula, Hoh, Rebecca, Deswal, Monika, Rodriguez, Antonio, Buitrago, Melissa, Tai, Viva, Shrestha, Uttam, Lu, Scott, Goldberg, Sarah A., Dalhuisen, Thomas, Vasquez, Joshua J., Durstenfeld, Matthew S., Hsue, Priscilla Y., Kelly, J. Daniel, Kumar, Nitasha, Martin, Jeffrey N., Gambhir, Aruna, Somsouk, Ma, Seo, Youngho, Deeks, Steven G., Laszik, Zoltan G., VanBrocklin, Henry F., Henrich, Timothy J.
• Format: Article
• Language: English
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.adk3295

The mechanisms of post-acute medical conditions and unexplained symptoms following SARS-CoV-2 infection (Long COVID; LC) are incompletely understood. There is growing evidence that viral persistence, immune dysregulation, and T cell dysfunction may play major roles. We performed whole-body positron emission tomography (PET) imaging in a well-characterized cohort of 24 participants at time points ranging from 27 to 910 days following acute SARS-CoV-2 infection using the radiopharmaceutical agent [ 18 F]F-AraG, a selective tracer that allows for anatomical quantitation of activated T lymphocytes. Tracer uptake in the post-acute COVID-19 group, which included those with and without continuing symptoms, was higher compared to pre-pandemic controls in many regions, including the brain stem, spinal cord, bone marrow, nasopharyngeal and hilar lymphoid tissue, cardiopulmonary tissues, and gut wall. T cell activation in the spinal cord and gut wall was associated with the presence of LC symptoms. In addition, tracer uptake in lung tissue was higher in those with persistent pulmonary symptoms specifically. Increased T cell activation in these tissues was also observed in many individuals without LC. Given the high [ 18 F]F-AraG uptake detected in the gut, we obtained colorectal tissue for in situ hybridization of SARS-CoV-2 RNA and immunohistochemical studies in a subset of five participants with LC symptoms. We identified intracellular SARS-CoV-2 single-stranded Spike protein-encoding RNA in rectosigmoid lamina propria tissue in all five participants and double-stranded Spike protein-encoding RNA in three participants up to 676 days following initial COVID-19, suggesting that tissue viral persistence could be associated with long-term immunologic perturbations. Total-body PET imaging and microscopy analysis of rectosigmoid biopsies reveal prolonged T cell activation and SARS-CoV-2 RNA persistence following COVID-19.