
Long Covid Molecular
Oral Cavity Serves as Long-Term COVID-19 Reservoir with Increased Periodontal and Viral Disease Risk
Background: SARS-CoV-2 infection can lead to long-term health problems affecting multiple body systems termed long COVID. Currently, limited information exists about long-term oral health manifestations in COVID-19 patients with limited healthcare access. Methods: We conducted a sequential, cross-sectional study (December 2020-March 2024) to assess how racial/ethnic differences (Black/Hispanic vs White/Asian) and health disparities affect oral and non-oral long COVID symptoms and their relationship with COVID-19 vaccination. We retrospectively reviewed patients oral health record from University of Illinois Chicago dental clinics before vaccination (December 2020; N=1150; Covid+/- N=575/group) and after vaccination (December 2021; N=592; Covid+/- N=292/group). Participants were recruited in two separate prospective groups of COVID-19 positive subjects (February-April 2021; pre-vaccination: N=158; January-March 2024; post-vaccination: N=171), we examined clinical indicators of oral (periodontal and salivary glands) and non-oral (neurologic) sequalae 3-6 months after initial exposure. We measured viral S protein by flow cytometry and quantified inflammatory markers, viral entry receptors, and oral viral load to correlate molecular, and cellular changes in COVID-19 positive subjects before and after vaccination. Results: Our results identified racial disparity indicating oral associated post-acute sequelae (PASC) primarily manifested as periodontal (gum) disease (COVID-19 positive: ~73% vs COVID-19 negative: ~33%) and correlated with higher rates of dry mouth (57.5%), taste disturbance (47%), and smell loss (20%). Vaccination reduced oral PASC in COVID-19 positive subjects; however, periodontal disease indicators persisted compared to the COVID-19 negative group. Notably, 3-6 months post-infection, while SARS-CoV-2 Spike (S) transcript was rarely detected in saliva (~6%), its protein was commonly detected (~70%) in the COVID-19 positive subjects indicating incomplete viral clearance. This correlates with significantly higher salivary expression of viral entry receptors (ACE2, and TRMPSS2), and inflammatory mediators (IL-6, IL-8 and MMP-8), in COVID-19 positive subjects. This finding was further supported by higher prevalence of other oral viruses including Epstein-Barr Virus (70.5%), Herpes Simplex Virus (8.1%), and Human Papillomavirus (17.5%) in COVID-19 positive subjects. Interpretation: COVID-19 history significantly correlates with severe oral health complications in predominantly Black communities, while vaccination reduced but did not eliminate these issues. The oral cavity serves as a long-term viral reservoir, and periodontal inflammation with increased oral viral presence in COVID-positive patients may increase susceptibility to oral and non-oral viral diseases and identify risk for long COVID.
### Competing Interest Statement
The authors have declared no competing interest.
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Large-scale genomic surveillance reveals immunosuppression drives mutation dynamics in persistent SARS-CoV-2 infections
Persistent SARS-CoV-2 infections have been hypothesized to play a key role in the emergence of variants of concern. However, the factors determining which individuals are at risk and their viral molecular signatures during infection remain poorly understood. Using the extensive COVID-19 surveillance database in Denmark, comprising over 700,000 genomes, we identified 303 persistent infections and, critically, linked them to health and sociodemographic data. Our analysis confirms the hypothesis that immunocompromised individuals are at the highest risk of experiencing persistent infections. Other disease groups associated with mortality, such as diabetes, showed no such associations. Among these persistent infections, the viral sequences exhibited signs of diversifying selection, with recurrent mutations linked to treatment resistance. Our findings suggest that immunosuppression plays a key role in the emergence of novelty in persistent infections.
### Competing Interest Statement
The authors have declared no competing interest.
### Funding Statement
SB, CM, CW and NMF acknowledge funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/X020258/1), funded by the UK Medical Research Council (MRC). This UK-funded award is carried out in the frame of the Global Health EDCTP3 Joint Undertaking. SB, CM, and NFM are funded by the National Institute for Health and Care Research (NIHR) Health Protection Research Unit in Modelling and Health Economics, a partnership between the UK Health Security Agency, Imperial College London and LSHTM (grant code NIHR200908). Disclaimer: The views expressed are those of the author(s) and not necessarily those of the NIHR, UK Health Security Agency or the Department of Health and Social Care. SB acknowledges support from the Novo Nordisk Foundation via The Novo Nordisk Young Investigator Award (NNF20OC0059309) which also supports FPL. SB acknowledges the Danish National Research Foundation (DNRF160) through the chair grant which also supports MPK, JCS, and NS. SB acknowledges support from The Eric and Wendy Schmidt Fund For Strategic Innovation via the Schmidt Polymath Award (G-22-63345), who also support CM. DAD acknowledges funding from the Novo Nordisk Foundation Emerging Data Science Investigator Award (NNF23OC0084647). PJ and TGV acknowledge funding from EU under Grant Agreements 101094685 LEAPS and 101102733 DURABLE; views and opinions expressed do not necessarily reflect those of the EU or the granting authorities, neither the EU nor the granting authorities can be held responsible for them. M.U.G.K. acknowledges funding from The Rockefeller Foundation, Google.org, the Oxford Martin School Pandemic Genomics programme, European Unions Horizon Europe programme projects MOOD (grant code 874850) and E4Warning (grant code 101086640), the John Fell Fund, a Branco Weiss Fellowship and Wellcome Trust grants 225288/Z/22/Z, 226052/Z/22/Z and 228186/Z/23/Z, United Kingdom Research and Innovation (grant code APP8583) and the Medical Research Foundation (MRF-RG-ICCH-2022-100069).
### Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
This study was conducted using data from national registers only. According to Danish law, ethics approval is not needed for this type of research. All data management and analyses were carried out on the secure research servers of Statistics Denmark. The study only contains aggregated results and no personal data.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
Yes
The data utilized in this study is accessible under restricted conditions under Danish data protection laws, since the information pertains to sensitive individual-level data. Researchers can request access to the data, including SARS-CoV-2 consensus genomes, from The Danish Health Data Authority and Statens Serum Institut, complying with Danish data protection regulations and any necessary permissions. No data collection or sequencing was conducted specifically for this study.
https://github.com/MLGlobalHealth/sars-cov2-persistent
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