Tissue-based T cell activation and viral RNA persist for up to 2 years after SARS-CoV-2 infection

MICHAEL J. PELUSO HTTPS://ORCID.ORG/0000-0003-0585-6230, DYLAN RYDER HTTPS://ORCID.ORG/0009-0008-4873-2493, ROBERT R. FLAVELL HTTPS://ORCID.ORG/0000-0002-8694-1199, YINGBING WANG, JELENA LEVI HTTPS://ORCID.ORG/0000-0002-0846-0795, BRIAN H. LAFRANCHI HTTPS://ORCID.ORG/0009-0007-2019-3494, TYLER-MARIE DEVEAU HTTPS://ORCID.ORG/0000-0002-9834-8616, AMANDA M. BUCK HTTPS://ORCID.ORG/0000-0001-7193-0617, SADIE E. MUNTER, [...], AND TIMOTHY J. HENRICH

DOI: 10.1126/scitranslmed.adk3295

Editor’s summary

The term “Long Covid” covers a diverse array of symptoms that an individual might experience weeks to years after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many drivers of Long Covid have been proposed, with supporting data for each. Here, Peluso et al. provide compelling evidence for two potential contributors: persistent SARS-CoV-2 and aberrant T cell activation. The authors used whole-body positron emission tomography imaging with a tracer that selectively tags activated T cells to show that those with Long Covid had certain tissues that were enriched for activated T cells in comparison with those without Long Covid. Moreover, because the gut was one of the sites of activated T cell enrichment, the authors analyzed gut biopsies from a subset of individuals with Long Covid. In these samples, the authors were able to identify the presence of SARS-CoV-2 RNA; this feature was consistent across all five samples analyzed. These data suggest that viral persistence and sustained immune activation are linked to Long Covid. —Courtney Malo

Abstract

The mechanisms of postacute medical conditions and unexplained symptoms after 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 imaging in a well-characterized cohort of 24 participants at time points ranging from 27 to 910 days after acute SARS-CoV-2 infection using the radiopharmaceutical agent [18F]F-AraG, a selective tracer that allows for anatomical quantitation of activated T lymphocytes. Tracer uptake in the postacute COVID-19 group, which included those with and without continuing symptoms, was higher compared with prepandemic 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 [18F]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 after initial COVID-19, suggesting that tissue viral persistence could be associated with long-term immunologic perturbations.

https://www.science.org/doi/10.1126/scitranslmed.adk3295