An international team of scientists has found evidence that SARS-CoV-2, the virus that causes COVID-19, infects cells in the mouth. Although it is well known that the upper respiratory tract and lungs are the primary sites of SARS-CoV-2 infection, there are indications that the virus can infect cells in other parts of the body, such as the digestive system, blood vessels, kidneys and, as this new study shows, the mouth. The potential of the virus to infect multiple parts of the body could explain the broad symptoms in patients with COVID-19, including oral symptoms such as loss of taste, dry mouth, and blistering. Moreover, the findings indicate the possibility that the mouth plays a role in transmitting SARS-CoV-2 to the lungs or digestive system via saliva full of virus from infected oral cells. A better understanding of oral involvement could serve as strategies to reduce viral transmission inside and outside the body. The team was led by researchers from the National Institutes of Health and the University of North Carolina at Chapel Hill.
“Thanks to NIH’s response to the pandemic, researchers at the National Institute of Dental and Craniofacial Research have been able to quickly turn around and apply their expertise in oral biology and medicine to answer key questions about COVID-19,” said NIDCR Director Rena D’Souza, DDS, MS, Ph.D. “The strength of this approach is illustrated by the efforts of this scientific team, which has identified the likely role of the mouth in SARS-CoV-2 infection and transmission, a discovery that adds knowledge critical to fighting the disease.”
The study was published online on March 25, 2021 Nature Medicine, led by Blake M. Warner, Ph.D. DDS, MPH, Assistant Clinical Investigator and Head of the NIDCR Salivary Disorders Unit, and Kevin M. Byrd, DDS, Dr., at the time an assistant professor at Adams School of Dentistry at the University of North Carolina at Chapel Hill. Byrd is now a researcher at Anthony R. Volpe at the Scientific and Research Institute of the American Dental Association. Ni Huang, dr. From the Wellcome Sanger Institute in Cambridge, UK, and others. Paola Perez from NIDCR were co-authors.
Researchers already know that the saliva of people with COVID-19 can contain high levels of SARS-CoV-2, and studies suggest that saliva testing is almost as reliable as deep nasal wiping for a diagnosis of COVID-19. However, what scientists do not know completely is where SARS-CoV-2 comes from in saliva. In people with COVID-19 who have respiratory symptoms, the virus in saliva may come in part from nasal drainage or sputum coughed up from the lungs. But according to Warner, this may not explain how the virus enters the saliva of people who lack these respiratory symptoms.
“Based on data from our labs, we suspected that at least part of the virus in saliva could come from infected tissues in the mouth itself,” Warner said.
To investigate this possibility, researchers examined oral tissues in healthy people to identify regions of the mouth susceptible to SARS-CoV-2 infection. Vulnerable cells contain RNA instructions for making “input proteins” that the virus should enter the cells. RNA for two key proteins – known as the ACE2 receptor and the TMPRSS2 enzyme – has been found in certain cells of the salivary glands and tissues lining the oral cavity. In a small proportion of salivary gland and gingival (gum) cells, RNA for ACE2 and TMPRSS2 was expressed in the same cells. This indicated an increased vulnerability, as the virus is thought to need both input proteins to gain access to the cells.
“Input factor expression levels are similar to those in regions known to be susceptible to SARS-CoV-2 infection, such as the tissues lining the nasal passages of the upper airway,” Warner said.
Once the researchers confirmed that parts of the mouth were sensitive to SARS-CoV-2, they sought evidence of infection in oral tissue samples from people with COVID-19. In samples collected at the NIH from deceased patients with COVID-19, SARS-CoV-2 RNA was present in slightly more than half of the salivary glands examined. In salivary gland tissue from one deceased person, as well as from a living person with acute COVID-19, the scientists discovered specific sequences of viral RNA that indicated that the cells were actively making new copies of the virus – further reinforcing the evidence for infection.
Once the team found evidence of oral tissue infection, they wondered if those tissues could be the source of the virus in saliva. That seems to be the case. In people with mild or asymptomatic COVID-19, cells spilled from the mouth into saliva have been found to contain SARS-CoV-2 RNA as well as RNA for input proteins.
To determine if the virus in the saliva was contagious, the researchers exposed the saliva of eight people with asymptomatic COVID-19 healthy cells grown in a vessel. The saliva of two volunteers led to infection of healthy cells, increasing the possibility that even asymptomatic people could transmit infectious SARS-CoV-2 to others through saliva.
Finally, to investigate the association between oral symptoms and saliva virus, the team collected saliva from a separate group of 35 NIH volunteers with mild or asymptomatic COVID-19. Of the 27 people who experienced symptoms, those with the saliva virus were more likely to report loss of taste and odor, suggesting that oral infection could be the basis of COVID-19 oral symptoms.
The researchers said that the findings of the study suggest that the mouth through infected oral cells plays a greater role in SARS-CoV-2 infection than previously thought.
“When infected saliva is swallowed or tiny particles are inhaled, we think it can potentially transmit SARS-CoV-2 further into our throat, lungs or even into the intestines,” Byrd said.
More research will be needed to determine the findings of a larger group of people and to determine the exact nature of the proportion of the mouth in SARS-CoV-2 infection and transmission inside and outside the body.
“By discovering the potentially underappreciated role of the oral cavity in SARS-CoV-2 infection, our study could open up new research pathways leading to a better understanding of the course of infection and disease. Such information could also serve to fight viruses and alleviate oral symptoms COVID-19, ”Warner said.
This research was supported by the Department of Internal Party Research NIDCR. Support also came from grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) DK034987 and NIDDK intramural programs, the National Cancer Institute, the NIH Clinical Center, and the National Institute of Allergies and Infectious Diseases. Additional support was provided by the American Academy of Periodontology / Sunstar Foundation, the American Lung Association and the Cystic Fibrosis Foundation.
About the National Institute for Dental and Craniofacial Research:
NIDCR is a leading national donor of research on oral, dental and craniofacial health.
About the National Institutes of Health (NIH):
The NIH, the national medical research agency, includes 27 institutes and centers and is a component of the U.S. Department of Health and Human Services. The NIH is the primary federal agency that conducts and supports basic, clinical, and translational medical research and investigates the causes, treatment, and treatment of common and rare diseases.