COVID-19 News: SARS-CoV-2 Structural Proteins Affects Oral Health By Causing Periodontal Fibrosis Via Deregulating Mitochondrial B-Oxidation

COVID-19 News: A new study by researchers from the University of Plymouth-UK has alarmingly found that SARS-CoV-2 structural proteins affects oral health by causing periodontal fibrosis via deregulating mitochondrial b-oxidation.


 
Worryingly, the study findings revealed that the SARS-CoV-2 membrane and envelope proteins alter fatty acid degradation pathways in the mitochondria that are essential to maintain energy homeostasis. The dysregulation of the mitochondrial β-oxidation pathway leads to the hyperproliferation of periodontal fibroblasts, causing fibrosis, and increased apoptosis and senescence.
 
Periodontal fibrosis is a serious oral health condition that can lead to various oral conditions besides causing systemic inflammation and also lead to both heart and liver complications.
 
The ongoing global COVID-19 crisis is a major challenge for health professionals and patients. SARS-CoV-2 virus mutate predominantly in the spike proteins, whilst the other key viral components remain stable.
 
Past COVID-19 News coverages have already showed that the human oral cavity is also an important transmission route of SARS-CoV-2 and can potentially act as reservoir of the SARS-CoV-2 virus and COVID-19 is likely to be connected with poor periodontal health.
 
https://www.thailandmedical.news/news/more-studies-are-showing-that-covid-19-can-cause-various-oral-health-issues-and-even-damage-your-gums-and-teeth
 
https://www.thailandmedical.news/news/covid-19-latest-study-shows-that-oral-infection-and-transmission-of-sars-cov-2-through-the-mouth-is-more-prevalent-than-thought
 
https://www.thailandmedical.news/news/study-finds-that-sars-cov-2-infects-mouth-cells-and-implicates-saliva-as-a-potential-route-of-sars-cov-2-transmission
 
https://www.thailandmedical.news/news/breaking-u-s-scientists-say-that-sars-cov-2-can-hide-in-salivary-glands-and-maybe-even-cause-relapses-or-reinfection-u-s-nih-funds-new-research
 
https://www.thailandmedical.news/news/breaking-covid-19-news-study-confirms-that-sars-cov-2-infects-and-replicates-in-the-salivary-glands-and-that-the-mouth-is-also-a-point-of-direct-entry
https://www.thailandmedical.news/news/breaking-news-covid-19-symptoms-enanthem-or-mouth-rash-emerging-as-another-clinical-symptom-of-covid-19
 
https://www.thailandmedical.news/news/study-published-in-journal-of-dental-research-adds-xerostomia-or-dry-mouth-as-new-covid-19-symptom-especially-infection-by-delta-variants
 
To date however, the detailed consequence of SARS-CoV-2 viral infection on human oral health has not been systematically examined.
 
The study team from University of Plymouth aimed to study the pathogenicity of SARS-CoV-2 viral components on human periodontal health.
 
The study team found that human periodontal tissues, particularly the fibroblasts highly expressed ACE2 and TMPRSS2. Shockingly, exposure to SARS-CoV-2, especially by the viral envelope and membrane proteins induced fibrotic pathogenic phenotypes, including periodontal fibroblast hyperproliferation, concomitant with increased apoptosis and senescence.
 
The fibrotic degeneration was mediated by a down-regulation of mitochondrial β-oxidation. Fatty acid β-oxidation inhibitor, etomoxir treatment could mirror the same pathological consequence on the fibroblasts, similar to SARS-CoV-2 infection.
 
The study findings therefore provide novel mechanistic insights into how SARS-CoV-2 infection can affect human periodontal health at the cell and molecular level.
 
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.biorxiv.org/content/10.1101/2022.12.15.520561v1
 
The study team examined in detail the pathological impacts of the structural components of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on human periodontal cells and tissue to understand the association between coronavirus disease 2019 (COVID-19) and deteriorating oral health.
Already numerous studies have shown that the symptoms of long coronavirus disease (COVID) manifest beyond the pulmonary system, with persistent complications also occurring in the cardiac, renal, and neurological systems.
 
Besides nasal swabs, saliva samples have been used to test for SARS-CoV-2, and the oral cavity is thought to be a viral reservoir.
 
Hence, SARS-CoV-2 infections could pose a serious risk to periodontal health since periodontal tissues are vulnerable to infectious diseases. However, the pathology of deteriorating periodontal health due to COVID-19 remains unclear.
 
While the spike protein region of SARS-CoV-2 is the most studied structural part of the virus since most mutations that give rise to variants with increased transmissibility, and immune evasion occur in the receptor binding domain of the spike protein, SARS-CoV-2 also consists of three other structural components ie the envelope, membrane, and nucleocapsid proteins, whose pathology roles have not been comprehensively explored.
 
The study team used cultured human periodontal ligament fibroblasts (HPLFs) and human gingival epithelial cells (HGEPp) to investigate the pathology of COVID-19-related periodontal fibrosis.
 
Detailed immunofluorescence analysis was used to detect the expression of angiotensin-converting enzyme-2 (ACE-2) and transmembrane serine protease 2 (TMPRSS2) receptors in gingival epithelial and periodontal ligament cells, which was confirmed using Western blot analysis.
 
The potential of SARS-CoV-2 to infect HPLFs was explored by treating the cells with SARS-CoV-2 spike protein conjugated with a polyhistidine tag (His Tag). Anti-His Tag allophycocyanin (APC) conjugated antibodies were then used to locate the spike protein through immunofluorescence analysis.
 
In order to investigate whether COVID-19 caused fibrosis in periodontal tissues, HPLFs were either infected with lentiviruses carrying plasmids for the envelope, membrane, and nucleocapsid proteins of SARS-CoV-2 or treated with recombinant SARS-CoV-2 spike proteins.
 
For the study, acute and long infections were stimulated in the periodontal fibroblasts, and the cell proliferation was evaluated through immunostaining for anti-Bromodeoxyuridine (BrdU) antibodies.
 
Also, Western blotting was used to determine the production of collagen I and metalloproteinase-1 (MMP1) in the extracellular matrix to assess periodontal ligament tissue integrity.
 
In the study, the periodontal ligament fibroblasts treated with SARS-CoV-2 structural components were subjected to proteomic analysis to determine molecular mechanisms regulating COVID-19 pathology. Additionally, the Seahorse Mito stress test was conducted to understand the effects of SARS-CoV-2 infections on the function of mitochondrial fatty acid pathways.
 
The study findings were validated using etomoxir, which inhibits the mitochondrial β-oxidation pathway.
 
The study findings revealed that ACE-2 and TMPRSS2 were expressed in high levels in the periodontal tissues, and exposure to SARS-CoV-2 structural components such as the membrane and envelope proteins increased hyperproliferation of periodontal fibroblasts, along with apoptosis and senescence.
 
It was found that the molecular mechanisms mediating the fibrosis of periodontal tissues mainly consisted of the downregulation of β-oxidation in the mitochondria by SARS-CoV-2 membrane and envelope proteins.
 
It should be noted that past studies have revealed associations between downregulated mitochondrial β-oxidation and fibrosis in lungs and kidneys.
 
The study findings also highlighted the role of SARS-CoV-2 structural components other than the spike protein in disease pathology.
 
The study team stressed that various studies also identified the alternate mechanisms through which the envelope proteins increased the pathogenicity of SARS-CoV-2, including increased pH within the Golgi apparatus and the formation of cation channels.

The study team also conducted terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) to understand the involvement of SARS-CoV-2 structural components in increasing apoptosis and senescence.
 
These study findings indicated that the spike or nucleocapsid proteins did not contribute to an increase in apoptosis and senescence, and only the envelope and membrane proteins did.
 
Interestingly, the membrane and envelope proteins also upregulated collagen I production and decreased MMP1 enzyme production in the extracellular matrix, contributing to periodontal fibrosis.
 
The study findings are the first to provide novel insights into the impact of SARS-CoV-2 infections on periodontal health.
 
The research findings revealed that the SARS-CoV-2 membrane and envelope proteins alter fatty acid degradation pathways in the mitochondria that are essential to maintain energy homeostasis. The dysregulation of the mitochondrial β-oxidation pathway leads to the hyperproliferation of periodontal fibroblasts, causing fibrosis, and increased apoptosis and senescence.
 
The study findings could contribute to a better understanding of the long COVID symptoms manifesting in other organ systems and provide targets for treatment.
 
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