Another great reason to keep your mask on

CHAPEL HILL, NC—An international team, led by scientists at the National Institutes of Health and the University of North Carolina at Chapel Hill, has found evidence that SARS-CoV-2 infects cells in the mouth.

The study, published in Nature Medicine, was led by Dr. Blake M. Warner, assistant clinical investigator and chief of the National Institute of Dental and Craniofacial Research (NIDCR) Salivary Disorders Unit, as well as Dr. Kevin M. Byrd, previously an assistant professor in the Adams School of Dentistry at the University of North Carolina at Chapel Hill, and currently an Anthony R. Volpe Research Scholar at the American Dental Association Science and Research Institute.

“Due to NIH’s all-hands-on-deck response to the pandemic, researchers at the National Institute of Dental and Craniofacial Research were able to quickly pivot and apply their expertise in oral biology and medicine to answering key questions about COVID-19,” stated Dr. Rena D’Souza, director of NIDCR. “The power of this approach is exemplified by the efforts of this scientific team, who identified a likely role for the mouth in SARS-CoV-2 infection and transmission, a finding that adds to knowledge critical for combatting this disease.”

The upper airways and lungs are primary sites of SARS-CoV-2 infection, and there are clues that the virus can infect cells in other parts of the body like the digestive system, blood vessels, kidneys, and — as this new study shows — the mouth. The virus’ potential to infect multiple areas of the body could help to explain the wide-ranging symptoms experienced by COVID-19 patients, including oral symptoms like loss of taste, dry mouth, and blistering. The findings also point to the possibility that the mouth plays a role in transmitting SARS-CoV-2 to the lungs or digestive system via saliva laden with virus from infected oral cells.

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 swabbing for diagnosing COVID-19. In people who have respiratory COVID-19 symptoms, virus in the saliva possibly comes in part from nasal drainage or sputum coughed up from the lungs. But Warner noted that it wouldn’t explain how the virus transmits into the saliva of people who lack those respiratory symptoms. 

“Based on data from our laboratories, we suspected at least some of the virus in saliva could be coming from infected tissues in the mouth itself,” Warner explained.

The researchers surveyed oral tissues from healthy people to identify mouth regions susceptible to SARS-CoV-2 infection. RNA for the ACE2 receptor and the TMPRSS2 enzyme was found in certain cells of the salivary glands and tissues lining the oral cavity. In a small portion of salivary gland and gingival cells, RNA for both ACE2 and TMPRSS2 was expressed in the same cells. This indicated increased vulnerability because the virus is thought to need both entry proteins to gain access to cells.

“The expression levels of the entry factors in 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 airway,” added Warner.

The researchers looked for evidence of infection in oral tissue samples from people with COVID-19. In samples collected at NIH from COVID-19 patients who had died, SARS-CoV-2 RNA was present in 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 cells were actively making new copies of the virus — bolstering the evidence for infection.

With evidence of oral tissue infection, researchers wondered whether those tissues could be a source of the virus in saliva. This appeared to be so. In people with mild or asymptomatic COVID-19, cells shed from the mouth into saliva contained SARS-CoV-2 RNA, as well as RNA for the entry proteins.

The researchers exposed saliva from eight people with asymptomatic COVID-19 to healthy cells grown in a dish, to determine if virus in saliva is infectious. Saliva from two of the volunteers led to infection of the healthy cells — raising the possibility that asymptomatic people could transmit infectious SARS-CoV-2 to others via 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 virus in their saliva were more likely to report loss of taste and smell, suggesting that oral infection might underlie oral symptoms of COVID-19. Taken altogether, the study’s findings suggest that the mouth plays a bigger role in SARS-CoV-2 infection than previously thought, through infected oral cells. 

“When infected saliva is swallowed or tiny particles of it are inhaled, we think it can potentially transmit SARS-CoV-2 further into our throats, our lungs, or even our guts,” said Byrd.

Researchers say more research is needed to confirm the findings in a larger group of people, and to determine the exact nature of the mouth’s involvement in SARS-CoV-2 infection and its transmission within and outside of the body.

“By revealing a potentially under-appreciated role for the oral cavity in SARS-CoV-2 infection, our study could open up new investigative avenues leading 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 concluded.