Scientists find evidence that the new coronavirus infects cells in the mouth: saliva may play a role in the transmission of COVID

RNA for SARS-CoV-2 (pink) and the ACE2 receptor (white) was found in human salivary gland cells, which are outlined in green. Credit: Paola Perez, PhD, Warner Lab, NIDCR

NIH-funded findings point to a role for saliva in SARS-CoV-2 transmission.

An international team of scientists has found evidence that SARS-CoV-2, the virus that causes COVID-19, infects the cells of the mouth. While it is well known that the upper respiratory tract and lungs are the main sites of infection for SARS-CoV-2, there are indications that the virus can infect cells in other parts of the body, such as the digestive system, blood vessels, the kidneys and, as this new study shows, the mouth.

The virus’s potential to infect multiple areas of the body could help explain the wide range of symptoms that COVID-19 patients experience, including oral symptoms such as loss of taste, dry mouth, and blisters. Furthermore, the findings point to the possibility that the mouth plays a role in the transmission of SARS-CoV-2 to the lungs or digestive system via virus-laden saliva from infected oral cells. A better understanding of mouth involvement could inform strategies to reduce viral transmission in and out of the body. The team was led by researchers from the National Institutes of Health and the University of North Carolina at Chapel Hill.

“Due to the NIH’s direct response to the pandemic, researchers from the National Institute for Dental and Craniofacial Research were 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 power of this approach is exemplified in the efforts of this scientific team, which identified a possible role of the mouth in the infection and transmission of SARS-CoV-2, a finding that adds to the fundamental knowledge to combat this disease.”

The study, published online March 25, 2021 at Nature medicine, was led by Blake M. Warner, DDS, Ph.D., MPH, assistant clinical researcher and chief of the NIDCR’s Salivary Disorders Unit, and Kevin M. Byrd, DDS, Ph.D., at the time assistant professor at the Adams School of Dentistry at the University of North Carolina at Chapel Hill. Byrd is now an Anthony R. Volpe Research Fellow at the American Dental Association’s Science and Research Institute. Neither Huang, Ph.D., from the Wellcome Sanger Institute in Cambridge, UK, and Paola Perez, Ph.D., from NIDCR, were the first 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 tests are almost as reliable as deep nasal swabs in diagnosing COVID-19. However, what scientists don’t fully know is where the SARS-CoV-2 in saliva comes from. In people with COVID-19 who have respiratory symptoms, the virus in saliva possibly comes in part from nasal drainage or sputum expelled from the lungs. But according to Warner, that may not explain how the virus reaches the saliva of people who lack those respiratory symptoms.

“Based on data from our labs, we suspect that at least some of the virus in saliva could come from infected tissues in the mouth,” Warner said.

To explore this possibility, the researchers examined the oral tissues of healthy people to identify the regions of the mouth susceptible to SARS-CoV-2 infection. Vulnerable cells contain RNA Instructions for making “entry proteins” that the virus needs to enter cells. RNA for two key entry proteins, known as the ACE2 receptor and the TMPRSS2 enzyme, was found in certain cells of the salivary glands and the tissues that line the oral cavity. In a small portion of cells from the salivary and gingival glands (gums), the RNA for ACE2 and TMPRSS2 was expressed in the same cells. This indicated increased vulnerability because the virus is believed to need both input proteins to access cells.

“The expression levels of the entry factors are similar to those in regions known to be susceptible to SARS-CoV-2 infection, such as the tissue lining the nasal passages of the upper respiratory tract,” Warner said. .

Once the researchers confirmed which parts of the mouth are susceptible to SARS-CoV-2, they looked for evidence of infection in oral tissue samples from people with COVID-19. In samples collected at NIH from deceased COVID-19 patients, SARS-CoV-2 RNA was present in just over half of the salivary glands examined. In salivary gland tissue from one of the people who had died, as well as from a living person with acute COVID-19, the scientists detected specific sequences of viral RNA that indicated that the cells were actively making new copies of the virus, thereby which further strengthens the evidence. for infection.

Once the team found evidence of oral tissue infection, they wondered if those tissues could be a source of the virus in saliva. This seems to be the case. In people with mild or asymptomatic COVID-19, cells shed from the mouth into saliva were found to contain RNA for SARS-CoV-2, as well as RNA for input proteins.

To determine whether the virus in saliva is infectious, the researchers exposed the saliva of eight people with asymptomatic COVID-19 to healthy cells grown in a dish. Saliva from two of the volunteers caused the infection of healthy cells, raising the possibility that even people without symptoms could transmit infectious SARS-CoV-2 to others through saliva.

Finally, to explore the relationship between oral symptoms and the virus in saliva, 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 viruses in their saliva were more likely to report loss of taste and smell, suggesting that oral infection could be the basis for oral COVID-19 symptoms.

Taken together, the researchers said, the study findings suggest that the mouth, through infected oral cells, plays a larger role in SARS-CoV-2 infection than previously thought.

“When infected saliva is ingested or tiny particles of it are inhaled, we believe that it can potentially transmit SARS-CoV-2 to our throat, our lungs or even our guts,” Byrd said.

More research will be needed to confirm the findings in a larger group of people and to determine the exact nature of the mouth’s role in the infection and transmission of SARS-CoV-2 inside and outside the body.

“By revealing a potentially underestimated role of the oral cavity in SARS-CoV-2 infection, our study could open up new avenues of investigation that lead to a better understanding of the course of infection and disease. Such information could also inform interventions to combat the virus and alleviate oral symptoms of COVID-19, ”Warner said.

Reference: “SARS-CoV-2 infection of the oral cavity and saliva” by Ni Huang, Paola Pérez, Takafumi Kato, Yu Mikami, Kenichi Okuda, Rodney C. Gilmore, Cecilia Domínguez Conde, Billel Gasmi, Sydney Stein, Margaret Beach, Eileen Pelayo, Jose O. Maldonado, Bernard A. Lafont, Shyh-Ing Jang, Nadia Nasir, Ricardo J. Padilla, Valerie A. Murrah, Robert Maile, William Lovell, Shannon M. Wallet, Natalie M. Bowman, Suzanne L. Meinig, Matthew C. Wolfgang, Saibyasachi N. Choudhury, Mark Novotny, Brian D. Aevermann, Richard H. Scheuermann, Gabrielle Cannon, Carlton W. Anderson, Rhianna E. Lee, Julie T. Marchesan, Mandy Bush, Marcelo Freire , Adam J. Kimple, Daniel L. Herr, Joseph Rabin, Alison Grazioli, Sanchita Das, Benjamin N. French, Thomas Pranzatelli, John A. Chiorini, David E. Kleiner, Stefania Pittaluga, Stephen M. Hewitt, Peter D. Burbelo , Daniel Chertow, NIH COVID-19 Autopsy Consortium, HCA Oral and Craniofacial Biological Network, Karen Frank, Janice Lee, Richard C. Boucher, Sarah A. Teichma nn, Blake M. Warner and Kevin M. Byrd, March 25, 2021, Nature medicine.
DOI: 10.1038 / s41591-021-01296-8

This research was supported by the NIDCR Intramural Research Division. Support also came from grant DK034987 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and intramural programs from NIDDK, the National Cancer Institute, the NIH Clinical Center, and the National Institute of Allergy and Infectious Diseases. Additional support came from the American Academy of Periodontology / Sunstar Foundation, the American Lung Association, and the Cystic Fibrosis Foundation.

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