Long COVID News: Microvasculature Alterations, Distinct Transcriptomic Signatures In Skeletal Muscles And Macrophage Infiltration Found In Long COVID!

Long COVID News: News: A new German study has found that capillary alterations, distinct transcriptomic signatures in skeletal muscle and macrophage infiltration are features of Long COVID!


 
The German study team was led by researchers from Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt Universität zu Berlin, Berlin Institute of Health and also involved scientists from Max Delbrück Center for Molecular Medicine, Leibniz-Institut für Analytische Wissenschaften – ISAS, Charité Vivantes GmbH, Heinrich-Heine-University, University Children's Hospital-University of Duisburg-Essen, Heimer-Institut für Muskelforschung am Bergmannsheil, Cluster of Excellence, NeuroCure; Berlin, German Center for Neurodegenerative Diseases (DZNE) Berlin and Max Delbrueck Center for Molecular Medicine.
 
The study team presented an in-depth analysis of skeletal muscle biopsies obtained from eleven patients suffering from enduring fatigue and post-exertional malaise after an infection with SARS-CoV-2.
 
The study findings showed that compared to two independent historical control cohorts, patients with post-COVID exertion intolerance had fewer capillaries, thicker capillary basement membranes and increased numbers of CD169+ macrophages.
 
However, SARS-CoV-2 RNA could not be detected in the muscle tissues, but transcriptomic analysis revealed distinct gene signatures compared to the two control cohorts, indicating immune dysregulations and altered metabolic pathways.
 
The study team hypothesizes that the initial viral infection may have caused immune-mediated structural changes of the microvasculature, potentially explaining the exercise-dependent fatigue and muscle pain.
 
The study findings were published on a preprint server and is currently being peer reviewed.
https://www.medrxiv.org/content/10.1101/2023.02.15.23285584v1
 
In our previous Long COVID News coverages, we had already shown that SARS-CoV-2 can also cause decreases in vascular density and can also cause other vascular issues.
https://www.thailandmedical.news/news/breaking-german-study-shows-persistent-capillary-rarefication-a-reduction-in-vascular-density-even-18-months-after-covid-19-infection
 
https://www.thailandmedical.news/news/breaking-boston-university-discovers-that-vascular-protein-vimentin-assists-sars-cov-2-access-into-cells,-contributing-to-vascular-complications
 
e">https://www.thailandmedical.news/news/german-and-danish-scientists-using-new-innovative-x-ray-imaging-shockingly-discover-that-sars-cov-2-causes-extensive-heart-vascular-damage
 
https://www.thailandmedical.news/news/must-read-covid-19-is-nothing-but-a-microvascular-and-endothelial-disease-that-kills-fast-or-slowly-depending-on-the-human-host-health-status
 
https://www.thailandmedical.news/news/breaking-study-alarmingly-reveals-that-sars-cov-2-infections-causes-widespread-prevalence-of-inflammatory-microvasculopathy-in-brains-of-infected
 
https://www.thailandmedical.news/news/university-of-texas-study-findings-validates-that-sars-cov-2-spike-protein-causes-endothelial-vascular-dysfunction
 
https://www.thailandmedical.news/news/u-s-nih-s-and-u-s-army-s-neurocovid-study-shows-that-sars-cov-2-infections-causes-serious-damage-to-microvessels-in-the-brain
 
https://www.thailandmedical.news/news/study-shows-sars-cov-2-infections-downregulates-ace2-expression-while-upregulating-ang-ii-levels-in-plasma,-resulting-in-pulmonary-vascular-damage
 
https://www.thailandmedical.news/news/breaking-irish-study-shows-that-integrins-could-be-receptors-for-sars-cov-2-and-integrin-signaling-upon-infection-leads-to-vascular-dysregulation
 
https://www.thailandmedical.news/news/israeli-scientist-identify-nsp2,-nsp5-c145a-and-nsp7-as-key-sars-cov-2-proteins-that-damage-human-host-endothelial-cells-of-blood-vessels
 
https://www.thailandmedical.news/news/breaking-german-scientists-discover-that-sars-cov-2-main-protease-mpro-causes-microvascular-brain-pathology
 
https://www.thailandmedical.news/news/long-covid-news-study-shows-majority-of-young-healthy-adults-will-exhibit-peripheral-macrovascular-and-microvascular-complications-following-covid-19
 
https://www.thailandmedical.news/news/covid-19-endotheliopathy-yale-researchers-finds-that-early-detection-of-blood-vessel-injury-via-diagnostics-critical-to-predicting-survival-in-covid-1
 
https://www.thailandmedical.news/news/must-read-covid-19-swiss-research-indicates-that-sars-cov-2-coronavirus-attacks-the-lining-of-blood-vessels-across-the-body-in-severe-covid-19-stages
 
To date, this German study is the first case-control study examining skeletal muscle tissue obtained from patients with persisting post-infectious fatigue and exercise intolerance that newly occurred after an infection with SARS-CoV-2.
 
One past study had shown histological changes and capillary alterations in deltoid muscles of patients with post-COVID syndrome.
https://pubmed.ncbi.nlm.nih.gov/35661354/
 
In the current study, it was found, on the morphological level, capillary alterations consisting of a decreased capillary-to-fiber ratio and an increased capillary basement membrane thickness.
 
Patients with Long COVID had smaller muscle fibers and increased numbers of CD169+ macrophages in close vicinity to skeletal muscle capillaries, but no evidence of overt myositis.
 
Upper leg MRI also did not reveal signs of myositis, which is consistent with recently published radiological findings.
https://pubmed.ncbi.nlm.nih.gov/36693812/
 
However, biopsies were taken almost a year after acute infection and several case reports of biopsy-proven myositis after SARS-CoV-2 have been published, and the study team themselves histologically diagnosed non-specific myositis in some patients in the subacute aftermath of mild or moderate COVID.
https://pubmed.ncbi.nlm.nih.gov/36353621/
 
https://jmedicalcasereports.biomedcentral.com/articles/10.1186/s13256-022-03680-5
 
https://pubmed.ncbi.nlm.nih.gov/35950722/
 
Interestingly, no SARS-CoV-2 specific RNA could be detected in any of the muscle samples by ultra-sensitive qPCR, strongly arguing against an unresolved infection of skeletal muscle tissues as the cause for the patients’ symptoms.
 
The fact that the number of CD169+ macrophages is increased in mildly altered skeletal muscle tissue is remarkable. CD169+ macrophages are increased in idiopathic inflammatory myopathies, indicating a prominent role in type I Interferon-related immune processes.
 
CD169+ macrophages have further been implicated in antiviral defense, being the primary cell infected and able to capture viral particles in the blood and subsequently presenting them to B cells. As numbers of circulating CD169+ monocytes are increased in acute stages of mild COVID-19, the study team hypothesized that they could play a key role at the muscle/capillary interface in the cohort of patients with Long COVID.
 
 
On the transcriptional level, unbiased analysis revealed a certain heterogeneity within the Long COVID cohort, but clustering based on immune cell markers, complement pathway and type I and III interferon related genes allowed a clear separation of the patient’s samples from the controls.
 
Long COVID samples not only showed an upregulation of immune regulatory genes such as tumor necrosis factor alpha (TNFA), but also of genes related to extracellular matrix organization and cell-cell adhesion, while pathways related to oxidative phosphorylation, mitochondria and cell respiration were downregulated.
 
This leads to the speculation that the observed morphological alterations of the capillaries (reduced C/F; thickened CBM) are indeed responsible for metabolic disturbances, possibly explaining the exercise-dependent symptomatology.
 
Physiological perspective, an increased CBM (capillary basement membrane) thickness results in a reduced diffusion of oxygen.
 
Impaired oxygen delivery to skeletal muscles has been previously described in patients with ME/CFS, consisting mainly of a reduced peak oxygen uptake during physical activity and oxygen therapy has been shown to improve the symptoms.
https://pubmed.ncbi.nlm.nih.gov/10545311/
 
https://pubmed.ncbi.nlm.nih.gov/30557887/
 
https://pubmed.ncbi.nlm.nih.gov/35011770/
 
Endothelial damage and capillary pathology have been extensively described in acute as well as in post-acute sequelae of SARS-CoV-2 infection in both human and animal studies.
https://pubmed.ncbi.nlm.nih.gov/34675436/
 
https://pubmed.ncbi.nlm.nih.gov/32762140/
 
https://pubmed.ncbi.nlm.nih.gov/33032965/
 
https://pubmed.ncbi.nlm.nih.gov/32949574/
 
https://pubmed.ncbi.nlm.nih.gov/35317812/
 
Hence, it appears plausible that a capillaropathy contributes or even might be the cause for the described symptoms in a subset of patients with post-COVID syndrome.
 
Viral infections are well-known triggers for a multitude of autoimmune processes
https://pubmed.ncbi.nlm.nih.gov/31430946/
 
https://pubmed.ncbi.nlm.nih.gov/35025605/
 
The study findings suggest persistent local immune responses in subsets of patients with Long COVID even one year after initial infection, which in the absence of evidence for an unresolved infection and the presence of autoantibodies in some individuals from the cohort, may point towards immune system dysregulations or an autoreactivity, consistent with multiple observations in patients with acute and post-acute COVID-19.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246018/
 
https://pubmed.ncbi.nlm.nih.gov/35027728/
 
https://pubmed.ncbi.nlm.nih.gov/35857629/
 
https://pubmed.ncbi.nlm.nih.gov/35078982/

The study team concludes that acute infection may have caused persistent structural changes of the microvasculature in skeletal muscles in some patients, potentially explaining the exercise-dependent symptoms.
 
Furthermore, the increased presence of CD169+ macrophages and the above-mentioned transcriptomic changes at the tissue level approximately one year after infection, together with the absence of SARS-CoV-2-specific RNA suggest that a sustainably dysregulated immune response could be responsible for the microvascular alterations in skeletal muscles of affected patients.
 
The study team says that larger studies may allow to identify a “capillaropathy subset” among patients suffering from Long COVID, ME/CFS or other post-infectious syndromes, thus opening new doors for differential diagnosis and personalized therapies.
 
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