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Imaging Study Reveals Viral RNA Persists for Years in Tissues of Long COVID Patients

Cell images showing SARS-CoV-2 spike protein-encoding RNA present in the tissues of long COVID patients
SARS-CoV-2 spike protein-encoding RNA (green) identified in rectosigmoid tissue of an individual with long COVID 676 days after COVID-19 infection with no known or suspected reinfection. Credit: Henrich Laboratory, UCSF Division of Experimental Medicine
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Long COVID patients display signs of abnormal immune cell activation and possess leftover SARS-CoV-2 RNA in the gut, a study published in the journal Science Translational Medicine has found.

The findings add to mounting evidence that viral persistence and sustained immune activation are key factors underpinning long COVID symptoms.

Imaging reveals a hiding place for SARS-CoV-2 RNA

The term “long COVID” refers to a diverse group of symptoms that can persist in people who have recovered from infection with SARS-CoV-2. Common symptoms range from fatigue, shortness of breath and brain fog to heart disease.

Survey data from one study has suggested that an estimated 18 million US adults could be living with long COVID. Despite this burden, there are still no approved treatments for the condition more than 4 years since the COVID-19 pandemic began.

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Data regarding SARS-CoV-2 persistence in non-blood tissues are sparse, with clinical studies in living individuals involving limited tissue quantities obtained through non-invasive biopsies. Additionally, sites of interest for studying SARS-CoV-2 persistence such as the brain, spinal cord and heart cannot be sampled in living individuals.

“There has been a large amount of inferential data supporting a view that a key factor underpinning long COVID may be that some people do not properly clear the virus and harbor reservoirs of SARS-CoV-2 in their tissues,” said Danny Altmann, professor of immunology at Imperial College London. “It’s been hard to prove this case – evidence has come from a small number of studies in which long Covid symptoms were correlated with presence of virus analyzed from gut biopsies.”

Using full-body positron emission tomography (PET) imaging, researchers from the University of California San Francisco set out to interrogate the biological roots of long COVID and explore how immune responses in tissues differ in individuals with long COVID symptoms.

The researchers conducted PET scans on a cohort of 24 recovered COVID-19 patients, ranging from 27 to 910 days after they were initially infected. A radiopharmaceutical agent, [18F] F-AraG (fluorine-18–labeled arabinofuranosyl-guanine), was used to trace the location of activated T cells, which areindicative of an activated immune response.

Imaging revealed that, compared to a pre-pandemic control group, post-acute COVID-19 participants showed signs of activated T cells in regions including the brain, spinal cord, gut and lung tissues. Furthermore, this T cell activation correlated with long COVID symptoms, for example, T cell activation in lung tissue corresponded with persistent pulmonary symptoms.

“This is a small but important long COVID study that should be seen as a significant step in advancing our understanding of this disease process and thus shifting nearer to treatments that could offer hope to the tens of millions of patients,” said Altmann.

Given the evidence of T cell activation in the gut, the researchers proceeded to obtain colorectal tissue for in situ hybridization of SARS-CoV-2 RNA and immunohistochemical studies in a subset of 5 participants with long COVID symptoms.

Intracellular SARS-CoV-2 single-stranded spike protein–encoding RNA was identified in the gut of all 5 participants and double-stranded spike protein–encoding RNA was identified in 3 participants up to 676 days after initial COVID-19, suggesting that tissue viral persistence could be associated with long-term immunologic perturbations.

Future studies with a larger cohort will be needed to further define the relationships between immune responses at the tissue level and specific long COVID symptoms.

“Overall, these observations challenge the paradigm that COVID-19 is a transient acute infection, building on recent observations in blood,” the researchers concluded.

Reference: Peluso MJ, Ryder D, Flavell RR, et al. Tissue-based T cell activation and viral RNA persist for up to 2 years after SARS-CoV-2 infection. Sci Transl Med. 2024;16(754):eadk3295. doi: 10.1126/scitranslmed.adk3295