Tackling Dry Mouth, Restoring Saliva Flow

Blake Warner, D.D.S., Ph.D., M.P.H., can’t sit still. As a third grader, he played with electric circuits and batteries while his teachers gave lessons. During high school, he exhausted all the science courses and took up woodworking and metalworking. In college, he majored in biochemistry, minored in molecular biology, and taught water fitness. Dr. Warner also ran a successful lawn mowing business and worked at factories making car parts.

“I’m a little unsettled,” said Dr. Warner. “Some people use that as a positive source of energy. It keeps me going, keeps me on edge. And I think true discovery really lies at that edge.”

Today, he is a dentist-scientist caring for patients in the clinic and running a lab to investigate the cause of an autoimmune disorder called Sjögren’s disease.

People with Sjögren’s have immune cells that mistakenly attack the salivary glands, reducing saliva production and leading to dry mouth. Without saliva’s protective effect on the mouth, people are at higher risk for tooth decay, gum disease, and oral infections. Dry mouth can also alter taste and speech. Sjögren’s is a relatively common disorder, affecting 1 to 4 million people in the U.S., and women are nine times more likely to have it than men.

“We can treat cancer better than we can treat Sjögren’s disease,” said Dr. Warner, who joined NIDCR in 2016 as a clinical research fellow. While he can address symptoms with drugs to suppress immune flare-ups and medicine to promote saliva production, they are short-term solutions and not for every patient. Eventually, patients’ salivary glands will fail. “That doesn’t sit well with me,” he said. Wanting to offer more than temporary relief, Dr. Warner set out to find treatments that can get to the root of the disease.

In 2018, Dr. Warner took the lead on an NIDCR clinical study to understand the nature and course of Sjögren’s disease in patients. To date, the study has enrolled 115 participants, and study staff examine them every two years over a 10-year period. What the team learns from the patients informs ongoing research in the lab to untangle the disease and explore potential treatments.

In 2022, Warner became an Earl Stadtman Tenure-Track Investigator. The Stadtman program is designed to recruit exceptional, creative, early-stage scientists to intramural tenure-track positions at NIH. To enable high-impact research, Stadtman investigators are given a lab, resources, personnel, and a budget so they can hit the ground running.

A JAKed Up Immune Response in Sjögren’s Disease

A clue to better treat Sjögren’s came from Dr. Warner’s patients. His translational team found that a biological signaling process called the JAK-STAT pathway was highly active in samples taken from the salivary glands of Sjögren’s patients. Cells normally use this pathway to recruit the immune system to fight an infection or foreign invader. But in the absence of an infection, an overactive JAK-STAT pathway is thought to lead to an excessive immune response that can damage healthy tissue, such as in autoimmune diseases like Sjögren’s.

 “We made a logical leap that we may be able to treat patients by inhibiting the JAK-STAT pathway with tofacitinib,” said Dr. Warner. Tofacitinib is an FDA-approved drug for curbing overactive immune responses in autoimmune disorders like rheumatoid arthritis. “If effective, this might be a shorter path to therapy for patients,” he said.

In salivary gland cells from patients with Sjögren’s disease, tofacitinib treatment eased the overly active genes and quieted the frenzied immune response related to the JAK-STAT pathway. The hope is to test the drug in Sjögren’s patients in future clinical trials.

Dr. Warner’s team is also investigating why immune cells infiltrate and attack salivary glands in the first place. In Sjögren’s patients, clinicians often see salivary glands waste away or develop scar tissue. The NIDCR scientists suspect overzealous immune cells underlie these physical changes.

A New Challenge: COVID-19 and the Salivary Glands

When the pandemic hit, Dr. Warner pivoted his research. Tapping into his expertise in salivary gland biology, he and a team of international scientists investigated how SARS-CoV-2, the virus that causes COVID-19, impacts the mouth. They found evidence that the virus can infect oral cells, particularly the salivary glands.

In examining salivary gland samples collected from patients with COVID-19, the researchers found that half of the samples contained traces of the virus. Further experiments showed that saliva from asymptomatic individuals with COVID-19 could infect healthy, lab-grown cells. These results indicated that infected oral cells are a likely source of virus in the saliva, and that the virus could possibly be transmitted via saliva. Their work could inform strategies to reduce viral transmission and may also have wider implications for autoimmune diseases.

“We know that viral infections increase susceptibility for autoimmune disease,” said Dr. Warner. “Whether SARS-CoV-2 can increase the risk of Sjögren’s disease is something for the research community to monitor and study further.”

Dr. Warner and his colleagues also found clues suggesting that SARS-CoV-2 infection may disrupt oral health. They discovered that the viral infection in salivary gland cells of COVID-19 patients reduced the production of a protein that protects against fungal overgrowth in the mouth. These findings suggest that COVID-19 can weaken the mouth’s natural defenses, making it more vulnerable to infections from fungi like Candida albicans, which causes oral thrush.

From unraveling the roots of Sjögren’s disease to searching for therapies for dry mouth to understanding SARS-CoV-2’s role in the mouth, Dr. Warner fully enjoys his work. He takes pride in his research, where knowledge gathered from patients guides lab discoveries that in turn may make a full circle back to improve patients’ lives.

“There’s going to be lots of failure along the way in science, but it’s ok to fail,” said Dr. Warner. “You’ve got to have fun with it. I’m an optimistic person, and the lab is like a new episode of a TV show for me, with each day presenting the opportunity for unexpected discoveries.”

Related links

• Turning the Tap Back On
• Scientists Find Evidence that Novel Coronavirus Infects the Mouth’s Cells

References

• Gupta S, Yamada E, Nakamura H, Perez P, Pranzatelli TJ, Dominick K, et al. Inhibition of JAK-STAT pathway corrects salivary gland inflammation and interferon driven immune activation in Sjögren's disease. Ann Rheum Dis. 2024 Jul 15;83(8):1034-1047. doi: 10.1136/ard-2023-224842.
• Huang N, Pérez P, Kato T, Mikami Y, Okuda K, Gilmore RC, et al. SARS-CoV-2 infection of the oral cavity and saliva. Nat Med. 2021 May;27(5):892-903. doi: 10.1038/s41591-021-01296-8. Epub 2021 Mar 25.
• Alfaifi AA, Wang TW, Perez P, Sultan AS, Meiller TF, Rock P, et al. SARS-CoV-2 infection of salivary glands compromises the production of a secreted antifungal peptide with potential implications for development of oral candidiasis. PLoS Pathog. 2024 Dec 12;20(12):e1012375. doi: 10.1371/journal.ppat.1012375.

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