ZSFG and UCSF Researchers Shed Light on Long COVID with a Cover Story in Science Translational Medicine
Long COVID (LC) has challenged the medical community with lingering questions about its mechanisms and symptoms. A team of researchers from ZSFG and UCSF’s Department of Radiology and Biomedical Imaging sheds light on this complex condition by exploring viral persistence and immune responses post-COVID-19.
The researchers report on their work in “Tissue-based T cell activation and viral RNA persist for up to 2 years after SARS-CoV-2 infection” published as the cover story in Science Translational Medicine (Vol. 16, No. 754). First author Michael Peluso, MD, and senior authors Henry F. VanBrocklin, PhD, and Timothy Henrich, MD, in collaboration with a team of multidisciplinary researchers, used whole-body positron emission tomography (PET) imaging with the innovative radiopharmaceutical agent [18F]F-AraG from Cellsight Technologies. This agent is pivotal in mapping activated T lymphocytes in the body, providing a unique insight into immune responses following SARS-CoV-2 infection. The study included a cohort of 24 participants, imaged between 27 to 910 days post-infection, offering a broad perspective on the temporal dynamics of Long Covid.
Reflecting on the impetus for this study, Peluso noted that, “We have seen since April 2020 that many of our study participants were experiencing unexplained symptoms following COVID-19 that lasted for weeks, months, or longer. Some are very debilitated and almost all have experienced an effect on their quality of life. We are very motivated to get answers for the tens of millions of people suffering from this condition, which still has no approved diagnostic tests or treatments. With our background in virology and immunology, one of the first questions we always ask when we encounter a patient with unexplained symptoms is What could be going on with their immune system? We are fortunate at UCSF to have amazing researchers and resources who can help answer these questions with technologies that do not exist anywhere else.”
The study results are compelling. Participants with post-acute COVID-19 exhibited heightened [18F]F-AraG uptake compared to pre-pandemic controls in several anatomical regions, notably the brain stem, spinal cord, bone marrow, lymphoid tissues, cardiopulmonary areas, and the gut wall. This elevated uptake highlights increased T cell activation, a marker of immune system engagement.
Interestingly, T cell activation in the spinal cord and gut wall was closely linked with LC symptoms. Persistent pulmonary symptoms correlated with increased lung tissue activation. These observations were consistent even in participants without overt LC symptoms, indicating a broader immune response pattern post-infection.
In a subset of five participants with LC symptoms, colorectal tissue analysis revealed the presence of SARS-CoV-2 RNA. Single-stranded spike protein-encoding RNA was detected in the rectosigmoid lamina propria tissue of all five participants, with double-stranded RNA found in three. This finding, observed up to 676 days post-infection, suggests a potential link between viral persistence and long-term immune disturbances.
Peluso said, “This was the first study to investigate immune activation on a total body level (previously almost all had been in blood), and the results were shocking - a history of having had COVID-19, regardless of whether a person had Long COVID symptoms - seemed to result in ongoing inflammation for months or years. Even though this was more pronounced in people with Long COVID, it was present even in people who felt fine. We are only beginning to understand the implications of this observation, but it is possible that this ongoing inflammation is a reason for many of the negative health consequences of COVID-19 over the long term.”
This research represents a significant stride in Long COVID research, emphasizing the role of viral persistence and immune dysregulation. The innovative use of [18F]F-AraG PET imaging offers a noninvasive method to explore these mechanisms, paving the way for future investigations and potential therapeutic interventions. This research was supported by the PolyBio Foundation.
“This study provides strong evidence of persistent disease and may inform clinical trials to alleviate Long COVID symptoms. It also provides confirmation to patients that there is an underlying cause related to their symptoms and hope that treatment for their suffering may be possible,” adds Dr. VanBrocklin.
Imaging Long COVID. The cover shows severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein–encoding single-stranded RNA (ssRNA, green) in rectosigmoid tissue collected from an individual with Long COVID nearly 2 years after their acute SARS-CoV-2 infection. Nuclei are shown in blue. Peluso et al. performed whole-body positron emission tomography imaging with a tracer that tags activated T cells in a cohort of 24 individuals up to 910 days after acute SARS-CoV-2 infection. The authors found that individuals with Long COVID symptoms had more tracer uptake than those without symptoms, including in the gut. Further, rectosigmoid tissue collected from five participants with Long COVID consistently harbored SARS-CoV-2 spike protein-encoding ssRNA. These data suggest that ongoing T cell activation and viral persistence may be drivers of Long COVID.
Reference
Michael J. Peluso et al. Tissue-based T cell activation and viral RNA persist for up to 2 years after SARS-CoV-2 infection. Sci. Transl. Med.16, eadk3295(2024). DOI:10.1126/scitranslmed.adk3295
First and Senior Authors
Michael Peluso, MD MPhil MHS DTM&H
Assistant Professor of Medicine
Division of HIV, Infectious Diseases, and Global Medicine
Zuckerberg San Francisco General Hospital and University of California, San Francisco
Henry VanBrocklin, PhD
Professor In Residence
Director, Radiopharmaceutical Research, Center for Molecular and Functional Imaging (CMFI)
University of California, San Francisco
Timothy Henrich, MD
Professor In Residence
University of California, San Francisco