08/11/2026
Breaking: New Study Reveals Substantial Tissue-Level Immune Dysfunction Near Persistent Viral Reservoirs in Long COVID
👉🏻 PolyBio-funded UCSF research finds persistent SARS-CoV-2 RNA alongside an altered gut immune response that may impair viral clearance
A new preprint from researchers at the University of California, San Francisco (UCSF) provides new insight into how persistent SARS-CoV-2 and an altered tissue immune response may contribute to Long COVID.
The study, supported by PolyBio Research Foundation’s Long COVID Research Consortium, analyzed colorectal tissue biopsies and blood from 44 people with Long COVID and 13 people who reported feeling fully recovered from COVID-19. Researchers used a suite of advanced technologies – including metagenomic sequencing, single-cell RNA sequencing, spatial transcriptomics, proteomics, and in-situ viral detection – to simultaneously investigate SARS-CoV-2 persistence and the neighboring host immune response.
Evidence of SARS-CoV-2 persistence was detected in colorectal tissue from 12 of 44 people with Long COVID (27%) compared with one of 13 recovered controls (7.7%). Viral RNA was identified within the intestinal epithelium and also deeper tissue compartments. Because intestinal epithelial cells normally turn over within days, the presence of viral RNA in these cells months to years after initial infection is suggestive of ongoing viral activity or re-seeding of the tissue.
Importantly, the researchers caution that the study likely underestimates the prevalence of SARS-CoV-2 persistence. Persistent viral RNA is present at extremely low abundance relative to human RNA, making it technically difficult to detect. Moreover, the endoscopic biopsy samples collected by the research team contain only a minute fraction of the ~25-30 foot (7-9 meter) long gastrointestinal tract. Viral reservoirs could therefore be focal, intermittent or concentrated in nearby or distant anatomical locations that were not sampled, meaning a negative colorectal biopsy does not rule out persistence elsewhere.
The study identified a dysregulated immune environment in Long COVID tissue in which the two branches of the immune system that normally work together – the innate and the adaptive immune systems – showed strikingly different responses. Innate immune cells showed continued inflammatory and viral-sensing activity, while the adaptive pathways needed to recognize and eliminate infected cells including antigen presentation, phagocytosis, and cytotoxic immune function were downregulated.
The human gastrointestinal tract must allow contact with foreign materials (i.e., food) without triggering immune activation, and the SARS-CoV-2 virus may have immune evasion tactics to take advantage of this environment. The study’s tissue biopsy results are evidence that SARS-CoV-2 exploits, or is inadvertently protected by, the gastrointestinal tract’s uniquely tolerogenic immune environment that restrains adaptive immune activation (such as antibodies or T cells), while viral reservoirs continued driving innate immune activation (i.e., inflammation).
“These findings suggest that Long COVID may involve a tissue immune environment that continues to sense persistent viral activity while failing to effectively clear virus-containing cells,” said Amy Proal, PhD, President and Research Director of PolyBio Research Foundation. “The fact that these inflammation-driving reservoirs may be extremely low-abundance and unevenly distributed across tissues also underscores why persistent virus can be so difficult to detect.”
Strikingly, abnormalities were far more apparent in tissue than blood. Researchers identified 240 significantly altered genes in colorectal tissue but only three in matched peripheral blood immune cells, suggesting that important Long COVID biology may be compartmentalized within tissues and poorly reflected in conventional blood measurements.
The findings provide a rationale for treatment strategies that target both persistent viral reservoirs and the tissue immune dysfunction that may allow them to remain.
Read the preprint: https://www.biorxiv.org/content/10.64898/2026.08.07.743616v1
Full press release: https://polybio.org/new-study-reveals-substantial-tissue-level-immune-dysfunction-near-persistent-viral-reservoirs-in-long-covid/
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The preprint, “Multiomic and Spatial Profiling of Colorectal Tissue Reveals Viral Persistence and Immune Dysregulation in Long COVID,” was jointly supervised by UCSF investigators Michael Peluso MD, and Timothy Henrich MD.
