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Study Demonstrates Saliva Can Spread Novel Coronavirus

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Light microscopy showing pink RNA for SARS-CoV-2
Caption: SARS-CoV-2 (pink) and its preferred human receptor ACE2 (white) were found in human salivary gland cells (outlined in green). Credit: Paola Perez, Warner Lab, National Institute of Dental and Craniofacial Research, NIH

COVID-19 is primarily considered a respiratory illness that affects the lungs, upper airways, and nasal cavity. But COVID-19 can also affect other parts of the body, including the digestive system, blood vessels, and kidneys. Now, a new study has added something else: the mouth.

The study, published in the journal Nature Medicine, shows that SARS-CoV-2, which is the coronavirus that causes COVID-19, can actively infect cells that line the mouth and salivary glands. The new findings may help explain why COVID-19 can be detected by saliva tests, and why about half of COVID-19 cases include oral symptoms, such as loss of taste, dry mouth, and oral ulcers. These results also suggest that the mouth and its saliva may play an important—and underappreciated—role in spreading SARS-CoV-2 throughout the body and, perhaps, transmitting it from person to person.

The latest work comes from Blake Warner of NIH’s National Institute of Dental and Craniofacial Research; Kevin Byrd, Adams School of Dentistry at the University of North Carolina, Chapel Hill; and their international colleagues. The researchers were curious about whether the mouth played a role in transmitting SARS-CoV-2. They were already aware that transmission is more likely when people speak, cough, and even sing. They also knew from diagnostic testing that the saliva of people with COVID-19 can contain high levels of SARS-CoV-2. But did that virus in the mouth and saliva come from elsewhere? Or, was SARS-CoV-2 infecting and replicating in cells within the mouth as well?

To find out, the research team surveyed oral tissue from healthy people in search of cells that express the ACE2 receptor protein and the TMPRSS2 enzyme protein, both of which SARS-CoV-2 depends upon to enter and infect human cells. They found the proteins may be expressed individually in the primary cells of all types of salivary glands and in tissues lining the oral cavity. Indeed, a small portion of salivary gland and gingival (gum) cells around our teeth, simultaneously expressed the genes encoding ACE2 and TMPRSS2.

Next, the team detected signs of SARS-CoV-2 in just over half of the salivary gland tissue samples that it examined from people with COVID-19. The samples included salivary gland tissue from one person who had died from COVID-19 and another with acute illness.

The researchers also found evidence that the coronavirus was actively replicating to make more copies of itself. In people with mild or asymptomatic COVID-19, oral cells that shed into the saliva bathing the mouth were found to contain RNA for SARS-CoV-2, as well its proteins that it uses to enter human cells.

The researchers then collected saliva from another group of 35 volunteers, including 27 with mild COVID-19 symptoms and another eight who were asymptomatic. Of the 27 people with symptoms, those with virus in their saliva were more likely to report loss of taste and smell, suggesting that oral infection might contribute to those symptoms of COVID-19, though the primary cause may be infection of the olfactory tissues in the nose.

Another important question is whether SARS-CoV-2, while suspended in saliva, can infect other healthy cells. To get the answer, the researchers exposed saliva from eight people with asymptomatic COVID-19 to healthy cells grown in a lab dish. Saliva from two of the infected volunteers led to infection of the healthy cells. These findings raise the unfortunate possibility that even people with asymptomatic COVID-19 might unknowingly transmit SARS-CoV-2 to other people through their saliva.

Overall, the findings suggest that the mouth plays a greater role in COVID-19 infection and transmission than previously thought. The researchers suggest that virus-laden saliva, when swallowed or inhaled, may spread virus into the throat, lungs, or digestive system. Knowing this raises the hope that a better understanding of how SARS-CoV-2 infects the mouth could help in pointing to new ways to prevent the spread of this devastating virus.

Reference:

[1] SARS-CoV-2 infection of the oral cavity and saliva. Huang N, Pérez P, Kato T, Mikami Y, 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, et. al Nat Med. 2021 Mar 25.

Links:

COVID-19 Research (NIH)

Saliva & Salivary Gland Disorders (National Institute of Dental and Craniofacial Research/NIH)

Blake Warner (National Institute of Dental and Craniofacial Research/NIH)

Kevin Byrd (Adams School of Dentistry at University of North Carolina, Chapel Hill)

NIH Support: National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Center for Advancing Translational Sciences


Two Studies Show COVID-19 Antibodies Persist for Months

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Antibodies against SARS-CoV-2
Caption: Artistic rendering of SARS-CoV-2 virus (orange) covered with antibodies (white), generated by an immune B cell (gray) at the bottom left. Credit: iStock/selvanegra

More than 8 million people in the United States have now tested positive for COVID-19. For those who’ve recovered, many wonder if fending off SARS-CoV-2—the coronavirus that causes COVID-19—one time means their immune systems will protect them from reinfection. And, if so, how long will this “acquired immunity” last?

The early data brought hope that acquired immunity was possible. But some subsequent studies have suggested that immune protection might be short-lived. Though more research is needed, the results of two recent studies, published in the journal Science Immunology, support the early data and provide greater insight into the nature of the human immune response to this coronavirus [1,2].

The new findings show that people who survive a COVID-19 infection continue to produce protective antibodies against key parts of the virus for at least three to four months after developing their first symptoms. In contrast, some other antibody types decline more quickly. The findings offer hope that people infected with the virus will have some lasting antibody protection against re-infection, though for how long still remains to be determined.

In one of the two studies, partly funded by NIH, researchers led by Richelle Charles, Massachusetts General Hospital, Boston, sought a more detailed understanding of antibody responses following infection with SARS-CoV-2. To get a closer look, they enrolled 343 patients, most of whom had severe COVID-19 requiring hospitalization. They examined their antibody responses for up to 122 days after symptoms developed and compared them to antibodies in more than 1,500 blood samples collected before the pandemic began.

The researchers characterized the development of three types of antibodies in the blood samples. The first type was immunoglobulin G (IgG), which has the potential to confer sustained immunity. The second type was immunoglobulin A (IgA), which protects against infection on the body’s mucosal surfaces, such as those found in the respiratory and gastrointestinal tracts, and are found in high levels in tears, mucus, and other bodily secretions. The third type is immunoglobulin M (IgM), which the body produces first when fighting an infection.

They found that all three types were present by about 12 days after infection. IgA and IgM antibodies were short-lived against the spike protein that crowns SARS-CoV-2, vanishing within about two months.

The good news is that the longer-lasting IgG antibodies persisted in these same patients for up to four months, which is as long as the researchers were able to look. Levels of those IgG antibodies also served as an indicator for the presence of protective antibodies capable of neutralizing SARS-CoV-2 in the lab. Even better, that ability didn’t decline in the 75 days after the onset of symptoms. While longer-term study is needed, the findings lend support to evidence that protective antibody responses against the novel virus do persist.

The other study came to very similar conclusions. The team, led by Jennifer Gommerman and Anne-Claude Gingras, University of Toronto, Canada, profiled the same three types of antibody responses against the SARS-CoV-2 spike protein, They created the profiles using both blood and saliva taken from 439 people, not all of whom required hospitalization, who had developed COVID-19 symptoms from 3 to 115 days prior. The team then compared antibody profiles of the COVID-19 patients to those of people negative for COVID-19.

The researchers found that the antibodies against SARS-CoV-2 were readily detected in blood and saliva. IgG levels peaked about two weeks to one month after infection, and then remained stable for more than three months. Similar to the Boston team, the Canadian group saw IgA and IgM antibody levels drop rapidly.

The findings suggest that antibody tests can serve as an important tool for tracking the spread of SARS-CoV-2 through our communities. Unlike tests for the virus itself, antibody tests provide a means to detect infections that occurred sometime in the past, including those that may have been asymptomatic. The findings from the Canadian team further suggest that tests of IgG antibodies in saliva may be a convenient way to track a person’s acquired immunity to COVID-19.

Because IgA and IgM antibodies decline more quickly, testing for these different antibody types also could help to distinguish between an infection within the last two months and one that more likely occurred even earlier. Such details are important for filling in gaps in our understanding COVID-19 infections and tracking their spread in our communities.

Still, there are rare reports of individuals who survived one bout with COVID-19 and were infected with a different SARS-CoV-2 strain a few weeks later [3]. The infrequency of such reports, however, suggests that acquired immunity after SARS-CoV-2 infection is generally protective.

There remain many open questions, and answering them will require conducting larger studies with greater diversity of COVID-19 survivors. So, I’m pleased to note that the NIH’s National Cancer Institute (NCI) recently launched the NCI Serological Sciences Network for COVID19 (SeroNet), now the nation’s largest coordinated effort to characterize the immune response to COVID-19 [4].

The network was established using funds from an emergency Congressional appropriation of more than $300 million to develop, validate, improve, and implement antibody testing for COVID-19 and related technologies. With help from this network and ongoing research around the world, a clearer picture will emerge of acquired immunity that will help to control future outbreaks of COVID-19.

References:

[1] Persistence and decay of human antibody responses to the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 patients. Iyer AS, Jones FK, Nodoushani A, Ryan ET, Harris JB, Charles RC, et al. Sci Immunol. 2020 Oct 8;5(52):eabe0367.

[2] Persistence of serum and saliva antibody responses to SARS-CoV-2 spike antigens in COVID-19 patients. Isho B, Abe KT, Zuo M, Durocher Y, McGeer AJ, Gommerman JL, Gingras AC, et al. Sci Immunol. 2020 Oct 8;5(52):eabe5511.

[3] What reinfections mean for COVID-19. Iwasaki A. Lancet Infect Dis, 2020 October 12. [Epub ahead of print]

[4] NIH to launch the Serological Sciences Network for COVID-19, announce grant and contract awardees. National Institutes of Health. 2020 October 8.

Links:

Coronavirus (COVID-19) (NIH)

Charles Lab (Massachusetts General Hospital, Boston)

Gingras Lab (University of Toronto, Canada)

Jennifer Gommerman (University of Toronto, Canada)

NCI Serological Sciences Network for COVID-19 (SeroNet) (National Cancer Institute/NIH)

NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences; National Cancer Institute


The Science of Saliva

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Artificial salivary glands

Credit: Swati Pradhan-Bhatt, Christiana Care Health System, Newark, DE

Whether it’s salmon sizzling on the grill or pizza fresh from the oven, you probably have a favorite food that makes your mouth water. But what if your mouth couldn’t water—couldn’t make enough saliva? When salivary glands stop working and the mouth becomes dry, either from disease or as a side effect of medical treatment, the once-routine act of eating can become a major challenge.

To help such people, researchers are now trying to engineer replacement salivary glands. While the research is still in the early stages, this image captures a crucial first step in the process: generating 3D structures of saliva-secreting cells (yellow). When grown on a scaffold of biocompatible polymers infused with factors to encourage development, these cells cluster into spherical structures similar to those seen in salivary glands. And they don’t just look like salivary cells, they act like them, producing the distinctive enzyme in saliva, alpha amylase (blue).