April 6, 2021

SARS-CoV-2 may infect mouth cells

At a Glance

  • Researchers found that SARS-CoV-2, the virus that causes COVID-19, can infect cells in the mouth.
  • A better understanding of the mouth’s role in SARS-CoV-2 infection could help to develop interventions and treat oral symptoms of COVID-19.
Fluorescent microscopy image of RNA for SARS-CoV-2 and ACE2 receptor in human salivary gland cells RNA for SARS-CoV-2 (pink) and the ACE2 receptor (white) was found in salivary gland cells, which are outlined in green. Paola Perez, Ph.D., NIDCR

The activities known to spread SARS-CoV-2—speaking, breathing, coughing, sneezing, and even singing — all involve the mouth. About half of COVID-19 patients experience oral symptoms, including loss of taste, dry mouth, and mouth lesions. However, it wasn’t clear whether SARS-CoV-2 could directly infect and replicate in the mouth’s tissues.

It’s known that SARS-CoV-2 infects cells in the nose, upper airways, and lungs. If mouth tissues are involved in early infection, they could play a role in helping the virus spread to the lungs or digestive system. People with COVID-19 can have high levels of SARS-CoV-2 in their saliva. Researchers suspected that, at least in some cases, the virus-laden saliva might come from infected tissues in the mouth, rather than nasal drainage or material coughed up from the lungs.

To investigate the mouth’s role in COVID-19, a research team led by Drs. Blake Warner of the NIH’s National Institute of Dental and Craniofacial Research (NIDCR) and Kevin Byrd, now at the American Dental Association Science and Research Institute, conducted a series of experiments. The results appeared on March 25, 2021 in Nature Medicine.

The researchers began by studying oral tissues from healthy people to determine whether mouth cells were susceptible to SARS-CoV-2 infection. Cells that produce certain “entry proteins”—the ACE2 receptor and the TMPRSS2 enzyme—are vulnerable to SARS-CoV-2 because the virus uses them to get into cells. The team tested for the RNA molecules that provide the instructions for cells to make these proteins.

RNA for the entry proteins was found in certain mouth cells, including glands that produce saliva and the tissues lining the oral cavity. This showed that parts of the mouth may be susceptible to SARS-CoV-2.

The team then looked for evidence of infection in oral tissue samples from people with COVID-19. They examined samples from COVID-19 patients who had died. SARS-CoV-2 RNA was present in more than half of the salivary glands.

Further experiments showed that infected oral tissues were one probable source of the virus in saliva. In people with mild or asymptomatic COVID-19, cells shed from the mouth into saliva were found to contain SARS-CoV-2, as well as RNA for the entry proteins.   

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

Finally, the scientists explored the relationship between oral symptoms and the virus in saliva. Among 27 people with mild COVID-19, those with virus in their saliva were more likely to report loss of taste and smell.

Together, these findings suggest that the mouth, via infected oral cells, may play a bigger role in SARS-CoV-2 infection than previously thought. Saliva infected by these cells might help infect the lungs when it is breathed in and the gut when it is swallowed.

“By revealing a potentially underappreciated 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,” Warner says. “Such information could also inform interventions to combat the virus and alleviate oral symptoms of COVID-19.”

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References: SARS-CoV-2 infection of the oral cavity and saliva. Huang N, Pérez P, Kato T, Mikami Y, Okuda K, Gilmore RC, Conde CD, Gasmi B, Stein S, Beach M, Pelayo E, Maldonado JO, Lafont BA, Jang SI, Nasir N, Padilla RJ, Murrah VA, Maile R, Lovell W, Wallet SM, Bowman NM, Meinig SL, Wolfgang MC, Choudhury SN, Novotny M, Aevermann BD, Scheuermann RH, Cannon G, Anderson CW, Lee RE, Marchesan JT, Bush M, Freire M, Kimple AJ, Herr DL, Rabin J, Grazioli A, Das S, French BN, Pranzatelli T, Chiorini JA, Kleiner DE, Pittaluga S, Hewitt SM, Burbelo PD, Chertow D; NIH COVID-19 Autopsy Consortium; HCA Oral and Craniofacial Biological Network, Frank K, Lee J, Boucher RC, Teichmann SA, Warner BM, Byrd KM. Nat Med. 2021 Mar 25. doi: 10.1038/s41591-021-01296-8. Online ahead of print. PMID: 33767405.

Funding: NIH’s National Institute of Dental and Craniofacial Research (NIDCR), National Center for Advancing Translational Sciences (NCATS), and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); American Lung Association; Cystic Fibrosis Foundation.