BREAKING! COVID-19 News: German Study Finds That SARS-CoV-2 Has A High Affinity For Infecting Carotid Arteries With Disturbing Implications

COVID-19 News: German researchers from the University Medical Center-Hamburg, Leibniz Institute for Experimental Virology, German Center for Infection Research, Institute of Neuropathology-Hamburg and the Medical Clinic and Polyclinic-Hamburg have in a new study discovered that the SARS-CoV-2 coronavirus has a high affinity manifesting replicative infection in the carotid arteries of the human host and hence affects the vascular responses.


 
According to the German researchers this could have a profound bearing on the understanding of the disease and its clinical treatment.
 
The study findings were published on a preprint server but are currently being peer-reviewed. https://www.biorxiv.org/content/10.1101/2020.10.10.334458v1
 
The COVID-19 pandemic has ravaged the population worldwide, mostly causing respiratory symptoms. A sizable percentage of patients have developed acute respiratory distress syndrome (ARDS) and multi-organ failure, and over a million have died. Older and sicker individuals are disproportionately prone to severe or critical disease.
 
In critically ill patients, who often present with viremia, the virus has been detected in multiple organs. https://www.nejm.org/doi/full/10.1056/NEJMc2011400
 
Significantly in many of these COVID-19 patients, the SARS-CoV-2 coronavirus has been found in the bloodstream and in organs other than the lung. In one series of autopsies carried out on a large group of patients who had succumbed to the infection, the researchers discovered the presence of pulmonary artery embolism or deep vein thrombosis in ~40% of cases. https://link.springer.com/article/10.1007/s00414-020-02317-w
 
This indicates that the SARS-Cov-2 virus produces abnormalities in coagulation.
 
In five younger patients, stroke due to the involvement of large vessels, including the carotid artery in at least one case, was shown to have occurred. https://www.nejm.org/doi/full/10.1056/NEJMc2009787
 
Importantly other instances of vascular abnormalities associated with COVID-19 have been shown. These include brain-related symptoms. The underlying pathology may be inflammation of the endothelial lining of the blood vessels. https://pubmed.ncbi.nlm.nih.gov/32294339/ and https://www.nejm.org/doi/full/10.1056/NEJMoa2015432
 
The study team in this study used real-time PCR to measure viral RNA titers in the typical carotid artery samples from 32 patients, with matched lung and throat samples. In all cases, the viral loads in the lung were high, indicating the presence of viral pneumonia.
 
Alarmingly, in over 80% of the samples, viral RNA was found in the carotid arteries, with the viral loads being similarly high in this tissue.
 
Detailed microscopic examination of carotid artery tissue showed the vessels to show the expected features for the patient's age, but with moderate inflammation.
 
However no signs of endothelial inflammation or vasculitis were observed.
 
The study team then tried to isolate infectious viral particles from the carotid artery samples and another 10 matching samples of tissue from 7 patients. In five of these patients, viremia had been confirmed before death. The virus was successfully isolated from 75% of the carotid artery and saphenous vein samples and from the lung, throat, and jejunum.
 
Interestingly the viral RNA from all these sites was sequenced and found to be identical in the lung and carotid artery samples from the same patients.
 
It was noted however, there were single nucleotide variations in the strains sequenced from different patients. All recovered viral RNA sequences belong to the most commonly circulating European strains.
 
The study team researchers concluded that infectious SARS-CoV-2 virus could be isolated from the organs of non-surviving patients only if viremia occurs before death, and the rate of isolation closely corresponds with the viral load in each organ. However, they could not retrieve the virus from other tissues such as the liver or the brain.
 
Significantly the presence of replicating virus in both lung and five of the seven carotid arteries was confirmed by finding plentiful subgenomic SARS-CoV-2 RNAs. The remaining two artery samples showed low RNA quality and could not be sequenced. The replication levels were as high as or higher than those observed in the lung samples.
 
The study team concluded, "Together these data indicate that SARS-CoV-2 infects and replicates in carotid arteries."
 
The study team examined the carotid artery structure in detail by using SARS-CoV-2 plus-strand RNA in situ hybridization, and immunological methods like immunofluorescence and immunohistochemistry directed against the viral spike antigen, to detect the exact cells in the carotid artery tissue that harbored the actively replicating virus. This showed that the viral RNA was in the endothelial layer.


(a) Overview shows a cross section of an A. carotis counterstained with Hematoxylin and subjected to in situ SARS-CoV-2 RNA hybridization. (b) Close up of boxed region B in (a). (c) Close up of boxed region C, which depicts immunohistochemical staining of SARS-CoV-2 spike protein in a section consecutive to (a). (d) Immunofluorescence staining of nuclei and spike protein in endothelial cells seen in a section consecutive to the section shown in (a). Scale bars represent 300 μm (a) and 20 μm (b, c, d).

Detailed transcriptomics in arterial tissue from two of the patients, versus two control patients without COVID-19, showed reduced expression of type I and type II interferon pathways in the SARS-CoV-2 infected arteries. This agrees with recent reports showing that innate immunity and interferon-related signaling pathways are downregulated in cells infected by this virus and animal models.
 
The study team found that genes which should be strongly expressed in case of endothelial inflammation and angiogenesis, such as VCAM and NFκB, and TIE1 and EGR1, respectively, were instead markedly downregulated in the infected arteries.
 
The study team says that this indicates "that SARS-CoV-2 infection induces a strong anti-inflammatory and anti-proliferative state in blood vessels."
 
The study finding is also in agreement with recent studies that show the virus to have a significant modulatory effect on immunity. Further studies will be needed to confirm this effect, however, given that these patients had acute myeloid leukemia and myelofibrosis, respectively, which may have contributed to the immunosuppression.
 
The researchers postulate that once viremia occurs, the SARS-CoV-2 virus infects the vascular endothelium and establishes replication.
 
This then leads to a downregulation of normal vascular responses and the further spread of the virus into multiple organs.
 
According this could explain the occurrence of the pediatric condition called MIS-C or multi-inflammatory syndrome in children in which medium-caliber arteries are inflamed in children with COVID-19.
 
The study team proposes that after entering the bloodstream, SARS-CoV-2 infects and replicates in vascular endothelial cells, where it modulates vascular responses and further migrates into organs.
 
However further detailed  research will undoubtedly shed light on the role played by carotid artery and other vascular infection by the virus in the pathogenesis, clinical phenotype and organ involvement in COVID-19.
 
There are many implications to this findings but one that is most important is that once the carotid arteries are infected, the SARS-CoV-2 coronavirus can easily ‘migrate’ to various organs and the not easily reachable tissues of the body and ‘wreak havoc.’ More studies are ongoing on this and Thailand Medical News will continue to provide updates.
 
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