The Role of Viral Persistence and Immune Dysregulation in Long COVID: Insights from Whole-Body Positron Emission Tomography Imaging

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The etiologic mechanisms underlying post-acute medical morbidities and unexplained symptoms, commonly known as Long COVID, following SARS-CoV-2 infection remain elusive.

Recent evidence points to potential involvement of viral persistence and immune dysregulation in the development of these long-term sequelae. This article presents a comprehensive study that utilized whole-body positron emission tomography (PET) imaging with the novel radiopharmaceutical agent [18F]F-AraG to investigate activated T lymphocytes in 24 participants at different time points after acute SARS-CoV-2 infection.

The results reveal increased T cell activation in various anatomical regions, including the brain stem, spinal cord, bone marrow, nasopharyngeal and hilar lymphoid tissue, cardiopulmonary tissues, and gut wall, in individuals with post-acute COVID symptoms compared to pre-pandemic controls.

Additionally, the study provides insights into the association between T cell activation in specific tissues and the presence of Long COVID symptoms, as well as the detection of cellular SARS-CoV-2 RNA in rectosigmoid lamina propria tissue, suggesting a potential link between tissue viral persistence and long-term immunological perturbations.

Introduction

Post-acute medical morbidities and unexplained symptoms, collectively termed Long COVID, have emerged as a significant concern following acute SARS-CoV-2 infection. Despite extensive research, the underlying etiological mechanisms responsible for these persistent symptoms remain incompletely understood.

Recent evidence has suggested a potential role of viral persistence and immune dysregulation in the development of Long COVID. To investigate this further, a study was conducted using whole-body positron emission tomography (PET) imaging with [18F]F-AraG, a highly selective tracer allowing quantitation of activated T lymphocytes in various anatomical regions, in a cohort of 24 participants at different time points following acute SARS-CoV-2 infection.

Methods

The study enrolled 24 participants with a history of SARS-CoV-2 infection, spanning time points ranging from 27 to 910 days post-infection. This cohort included individuals both with and without Long COVID symptoms. The novel radiopharmaceutical agent, [18F]F-AraG, was used for PET imaging to visualize and quantify activated T lymphocytes in different tissues. Pre-pandemic controls were also imaged for comparison.

Results

The PET imaging revealed significantly higher tracer uptake of activated T lymphocytes in various anatomical regions in the post-acute COVID group, compared to pre-pandemic controls. The affected regions included the brain stem, spinal cord, bone marrow, nasopharyngeal and hilar lymphoid tissue, cardiopulmonary tissues, and gut wall. Remarkably, this increased T cell activation persisted in participants imaged up to 2.5 years following their initial SARS-CoV-2 infection.

Furthermore, the study observed an association between T cell activation in the spinal cord and gut wall and the presence of Long COVID symptoms. Additionally, higher tracer uptake in lung tissue was correlated with the persistence of pulmonary symptoms. Notably, these observations were not limited to individuals with Long COVID symptoms, as many participants without Long COVID also exhibited increased T cell activation in these tissues.

To explore the potential link between viral persistence and immunological perturbations, colorectal tissue samples were collected from a subset of participants with Long COVID symptoms. In situ hybridization for SARS-CoV-2 RNA and immunohistochemical studies revealed cellular SARS-CoV-2 RNA in rectosigmoid lamina propria tissue of all these participants, even up to 676 days post-acute illness. This finding suggests that tissue viral persistence might contribute to long-term immunological abnormalities.

Conclusion

This study provides valuable insights into the etiologic mechanisms of Long COVID by employing whole-body PET imaging with [18F]F-AraG to investigate T cell activation in various anatomical regions. The findings suggest that viral persistence and immune dysregulation may play a significant role in the development of post-acute medical morbidities and unexplained symptoms following SARS-CoV-2 infection.

The presence of cellular SARS-CoV-2 RNA in rectosigmoid lamina propria tissue further supports the hypothesis that tissue viral persistence could lead to long-term immunological perturbations. Further research is warranted to understand the precise mechanisms underlying Long COVID, with potential implications for the development of targeted therapeutics and management strategies.


reference link : https://www.medrxiv.org/content/10.1101/2023.07.27.23293177v1

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