Multimodal Molecular Imaging Reveals Tissue-Based T Cell Activation and Viral RNA Persistence for Up to Two Years Following COVID-19, 2023, Peluso +

https://twitter.com/user/status/1808571017448538440


AI generated summary of Tim Henrich's talk that Amy linked to:

  • Introduction
    • The speaker is continuing a discussion on molecular imaging and digital spatial profiling in long COVID
    • The talk aims to highlight the promise of immunotherapy clinical trials
    • This presentation is part of the larger LIINC (Long-term Impact of Infection with Novel Coronavirus ) structure
    • The pathogenesis-based team oversees tissue processing, hypothesis testing, and cohort infrastructure trials
  • Long COVID as a Tissue-Based Disease
    • Long COVID is primarily a tissue-based process, not a disease of circulating blood
    • Novel methods are needed to identify abnormal immune responses, viral protein persistence, replication, and inflammatory responses
    • The team is focusing on non-invasive nuclear imaging and digital spatial profiling
    • Work is supported by Poly-Bio Foundation funding
  • PET Imaging Study
    • Using Positron Emission Tomography (PET) with CT scanning
    • Tracer specific for activated T-cells
    • Study included 24 participants with documented COVID-19, imaged between 27 days to 2.5 years post-infection
    • Some participants had long COVID symptoms (up to 15 symptoms), while others had fully recovered
    • Pre-COVID healthy controls were also included
  • PET Imaging Results
    • Increased T-cell activation observed in various tissues post-COVID:
      • Nasopharyngeal lymphoid space
      • Gut wall
      • Bone marrow
      • Lymph nodes
      • Lung parenchyma
      • Brain stem
      • Spinal cord
      • Adrenal tissue
    • Persistence of T-cell activation seen up to two years post-infection
    • Some decrease in signal over time, but still significantly higher than pre-COVID controls
    • Modest association between vaccine timing and imaging results
    • Suggestion of higher T-cell activation in symptomatic individuals
    • COVID-19 vaccines do not appear to elicit the same long-term T-cell phenotype as initial infection
  • Direct Tissue Analysis
    • SARS-CoV-2 RNA persistence observed in tissue samples:
      • Detected 158 days post-infection without known reinfection
      • Found in lamina propria, some in macrophages and other immune cells
      • Persistence seen up to 676 days post-infection
    • Double-stranded RNA detected, suggesting ongoing viral life cycling or persistence
    • Clusters of double-stranded RNA positive cells with immune infiltrate observed
  • Granuloma-like Structures ("Coronialoma")
    • Dense clusters of double-stranded RNA positive cells observed
    • These clusters are surrounded by immune infiltrate, including CD68+ macrophages
    • The structure resembles a granuloma, leading to the coined term "coronialoma" or "viroma"
    • These structures suggest areas of viral persistence that are eliciting inflammation but evading immune clearance
  • Viral Persistence and Reactivation
    • Potential intersection between SARS-CoV-2 RNA and EBV (Epstein-Barr Virus) transcriptional activity in the gut
    • Hypothesis of EBV reactivation potentially linked to SARS-CoV-2 replication in tissues
    • Ongoing deeper investigation into the relationship between SARS-CoV-2, EBV, and other viruses
  • Digital Spatial Omics Profiling
    • Using Xenium 10x system for deep transcriptomic analysis
    • Integrating SARS-CoV-2, EBV, CMV, HIV, and other viral transcripts
    • Analyzing up to 500 transcripts for both virus and host
    • Observed transcriptional differences in tissues between long COVID and non-long COVID individuals
    • Unique patterns in macrophages near infected cells:
      • Upregulation of genes inhibiting granzyme B activity
      • Inhibition of natural killer cell activation
      • Downregulation of genes important for tissue defense response
    • Reduced granzyme B production observed in areas directly infected with SARS-CoV-2
  • Hypothesis and Potential Treatment
    • SARS-CoV-2 evades innate and adaptive immune responses in tissue, leading to viral persistence
    • Chronic inflammation induced despite evasion
    • Need to boost tissue-based immune recognition and removal of infected cells
  • INTERRUPT-LC Trial
    • Using IL-15 agonist super-agonist (N-803), recently approved for bladder cancer
    • Stimulates CD8+ T cells, NK cells, and peripheral immune cell function
    • Helps immune cells traffic to recognize and kill infected cells
    • Two doses given approximately two weeks apart
    • Aims to reduce infected cells in viral reservoirs and improve symptoms
    • Called "No Gain No Pain" study due to temporary inflammation post-injection
    • Will assess both reduction in viral reservoir and symptomatic improvement
  • Conclusion
    • The LIINC study is conducting deep, comprehensive work
    • The immunotherapy trial with N-803 represents a paradigm shift in treating infection-associated chronic disease
    • Acknowledgment of the team's efforts, particularly Michael Peluso's leadership in clinical aspects
 
I haven't read the paper only the summary.

T-cells in the spinal cord and brainstem = ME. Just saying.

If this turns out to be true and the findings are replicated by other teams, it’s fair to say that doubters of persistence are now on the back foot.

If LC is, to some degree, caused by persistence that manifests as T-cell infiltration in sites historically thought to be implicated in ME (brainstem, spinal cord, gut, etc.), this indicates that something similar might be occurring in ME.

If there are T-cells in these compartments, why don't we see classical markers of neurodegeneration pop up more consistently though?

I am also very interested in the macrophage findings, as this seems similar to what Hanson found in ME patients.
 
I had forgotten we had seen at least the abstract a year ago. I looked at the images - because I am used to working with images - without looking at the descriptions first, to see if I could work out what was supposed to be abnormal. I couldn't see anything that wasn't consistent with v various non-specific patterns familiar with PET or histology.

The gut tissue sections l look. very normal. There are rather few T cells around - certainly no obvious active response. There are some clusters of macrophages but in gut there usually are. The fluorescent tag seems to show up where the macrophages are but then it would be likely to since macrophages are there to hoover up any garbage around.

If there was an immune response going on around this supposed virus I would expect to see way more T cells - fifty times as many.

I agree with @Hutan that sometimes it seems that we should not forget John Chia's suggestion of residual virus but note that John Chia's pictures look nothing whatever like these. And again the staining was in tissues that otherwise looked morphologically normal.
 

https://www.sciencemediacentre.org/...tion-and-viral-rna-persistence-in-long-covid/

expert reaction to study looking at T cell activation and viral RNA persistence in long Covid

Prof Danny Altmann, Professor of Immunology, Imperial College London, said:

“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. 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 harbour reservoirs of SARS-CoV-2 in their tissues. This would be expected to drive the inflammatory and immune processes causing Long Covid symptoms. 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 analysed from gut biopsies. At the centre of this new study is a novel approach whereby PET scanning is done using a novel tracer that allows them to map activated T cells in the body. They find patterns of long term T cell activation that may help to explain patterns of Long Covid symptoms. For example, people with respiratory symptoms showed long-term homing of activated T cells to the lung. In a small number of people they then go on to check biopsies and find evidence for presence of a long-term virus reservoir. At a time when there’s desperate need for new clinical trials, studies like this help to point the way.”
 
ScienceAlert: COVID's Hidden Toll: Full-Body Scans Reveal Long-Term Immune Effects
By Carly Cassella

"When 24 patients who had recovered from COVID-19 had their whole bodies scanned by a PET (positron emission tomography) imaging test, their insides lit up like Christmas trees.

A radioactive drug called a tracer revealed abnormal T cell activity in the brain stem, spinal cord, bone marrow, nose, throat, some lymph nodes, heart and lung tissue, and the wall of the gut, compared to whole-body scans from before the pandemic.

This widespread effect was apparent in the 18 participants with long COVID symptoms and the six participants who had fully recovered from the acute phase of COVID-19.

The activation of immune T cells in some tissues, like the spinal cord and the gut wall, was higher in patients who reported long COVID symptoms compared to those who made a complete recovery. Participants with ongoing respiratory issues also showed increased uptake of the PET tracer in their lungs and pulmonary artery walls.

That said, even those who recovered fully from COVID-19 still showed persistent changes to their T cell activity in numerous organs compared to pre- pandemic controls, in some cases two and a half years after they first contracted the virus.

'In some individuals, this activity may persist for years following initial COVID-19 onset and be associated with systemic changes in immune activation as well as the presence of [long COVID] symptoms,' researchers at UCSF conclude.

'Together, these observations suggest that even clinically mild infection could have long-term consequences on tissue-based immune homeostasis and potentially result in an active viral reservoir in deeper tissues.'"

"Some studies even suggest an infection of the SARS-CoV-2 virus can 'reawaken' other dormant viruses in the body, like the Epstein barr virus, which has been linked to chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).

CFS/ME shares many of the same symptoms as long COVID, and some scientists suspect they may be one and the same. Brain scans have found that long COVID changes to the brain parallel the effects of CFS/ME, and recently, a landmark study confirmed that CFS/ME is "unambiguously biological" with multiple organ systems affected.

Today, long COVID is increasingly recognized as having neurological underpinnings, and the recent discovery of T cell abnormalities in the spinal cord and brain stem suggest that these overactive immune cells are being 'trafficked' to tissues of the central nervous system.

'Overall, these observations challenge the paradigm that COVID-19 is a transient acute infection, building on recent observations in blood,' the team from UCSF concludes.

The findings need to be confirmed among larger cohorts, now that this new technique for mapping the immune effects of long COVID in the body shows such great promise."
 
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But do we have any evidence for the viral persistence having anything to do with the immune activation?
It seems to me that there are a lot more unanswered questions out there than Peluso is claiming.

In EBV there is viral perisistence. There is also prolonged immune activation involving CD8 CD57 T cells and that prolonged activation may relate to the post-viral fatigue. But that still does not mean that it has anything particular to do with the viral persistence - which goes on lifelong in quite healthy people.
 
Jonathan Edwards said:
But that still does not mean that it has anything particular to do with the viral persistence - which goes on lifelong in quite healthy people.
Click to expand...
One possibility here is that these apparently healthy people do have some, probably quite minor, adverse effects from the viral persistence, but that the way reduced health status is currently defined and screened for is not picking up these effects, including misattribution to other factors.

Another is that they have some yet-to-be-identified factor that protects (or mitigates) against adverse health effects from viral persistence, that the more seriously affected lack.

Not saying any of this is likely, nor that it might have a clinically significant effect size even if it exists, but it is not something that can be completely ruled out, I think. One of those always keep in the back of the mind possibilities.
 
Sean said:
One possibility here is that these apparently healthy people do have some, probably quite minor, adverse effects from the viral persistence, but that the way reduced health status is currently defined and screened for is not picking up these effects, including misattribution to other factors.
Click to expand...

I don't think that for now that is a reasonable possibility suggested by any evidence. Billions of people have had multiple Covid infections and remain healthy and perform at the same cognitive and athletic levels etc. Nothing suggests that they are not perfectly healthy.

The BPS equivalent would be: Everyone suffers from FND, in ME/CFS patients it is more apparent.

Sean said:
Another is that they have some yet-to-be-identified factor that protects (or mitigates) against adverse health effects from viral persistence, that the more seriously affected lack.
Click to expand...

This seems like the more part interesting part to me. However, the study didn't have gut biopsies of healthy controls, nor can we really know when LC patients had their last Covid infection etc. For all I can see we might just be seeing a very ordinary immunological response to a Covid infection which doesn't tell us where things went wrong or what any of this has to do with LC.

I think the EBV example is quite fitting. Almost every person in the world has viral persistence of EBV, but only comparably few of those people develop MS. That doesn't mean healthy people have "lingering but undetectable MS", nor does it mean that it's the viral persistence that somehow drives MS, it may as we well be driven by a hit & run event of the initial EBV infection that cascade down in a minority of people. Figuring out what role EBV plays in MS has remained elusive, figuring out whether there is an immunological response to SARS-COV-2 viral persistence which somehow explains symptomology will probably remain elusive for years, if not decades, until research improves.
 
EndME said:
I don't think that for now that is a reasonable possibility suggested by any evidence. Billions of people have had multiple Covid infections and remain healthy and perform at the same cognitive and athletic levels etc. Nothing suggests that they are not perfectly healthy.

The BPS equivalent would be: Everyone suffers from FND, in ME/CFS patients it is more apparent.
Click to expand...
I did not mean every one of them, I should have made that clear.

But I think it quite plausible that at least some people who otherwise appear healthy can have subtle long-term reductions in performance without noticing it.
 
Sean said:
I did not mean every one of them, I should have made that clear.

But I think it quite plausible that at least some people who otherwise appear healthy can have subtle long-term reductions in performance without noticing it.
Click to expand...

Sure that can definitely be the case in a hypothetical scenario. But IIRC within this study all healthy controls looked pretty similar and they also looked pretty similar to pwLC.
 
Commentary in Science Immunology —

Enough already: T cell inflammation and SARS-CoV-2 virus persist in Long Covid (Aug 2024)
Rachael A. Clark

It is estimated that 6% of American adults currently suffer from persistent symptoms that can linger for weeks to years after COVID-19 infection. Some studies suggest that viral persistence and immune dysregulation may be to blame. Peluso and co-authors carried out whole-body positron emission tomography (PET) imaging of 24 patients 27 to 910 days after COVID-19 infection using a radioactive tracer that specifically identifies activated CD8 and CD4 lymphocytes. Imaging identified persistent T cell activation in patients after COVID compared with prepandemic controls. Post-COVID inflammation was detected in many tissues, including the brainstem, spinal cord, bone marrow, lymphoid tissues, heart, lungs, and gut. Inflammation was even observed in patients who did not have persistent COVID symptoms.

Patients with symptomatic Long Covid tended to have persistent inflammation in the spinal cord and intestinal wall; uptake in the lower lungs was only observed in patients with persistent pulmonary symptoms. Five individuals with Long Covid consented to biopsies of the rectum or sigmoid colon 158 to 676 days after COVID infection. Viral spike protein–encoding single-stranded RNA was detected in multiple biopsies from four of five patients, and biopsies from three patients had viral double-stranded RNA, suggesting ongoing productive viral infection.

The results suggest that tissue-based inflammation and viral persistence contribute to Long Covid symptoms and that even clinically mild COVID infection can cause lingering inflammation in peripheral tissues. Additional studies are needed to determine where and how the virus persists in peripheral tissues and identify why dysfunctional T cells cause inflammation but fail to clear the infection.

Link | PDF (Science Immunology)
 
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