The mouth is home to over 700 species of bacteria. It’s a site where bacteria interact with host cells, viral particles, and each other. “[Bacteria are] modulating the host, and then at the same time, [they’re] trying to fight other pathogens including viruses,” said Mark Cayabyab, a microbiologist and virologist at Nova Southeastern University. These interactions between bacteria and viruses could have implications for developing new antiviral therapeutics.
Cayabyab and his team recently examined these interactions in the context of oral bacteria and SARS-CoV-2 (1). “When I started the study, there was really no research surrounding the connection between the oral cavity or the mouth with COVID,” he said.
Previous research in the field revealed that Porphyromonas gingivalis, the bacteria behind periodontitis, has antiviral activity, so the team started there. To investigate how P. gingivalis affected SARS-CoV-2, they first created a “pseudovirus” by expressing the SARS-CoV-2 spike protein in a lentivirus. This pseudovirus allowed them to monitor viral infection without using the actual SARS-CoV-2 virus.
When the team incubated the pseudovirus with human cell lines along with supernatants from P. gingivalis cultures, they saw that P. gingivalis supernatants inhibited pseudovirus infection. “P. gingivalis is a really interesting thing to start with first because it's so well studied and well known in driving inflammatory disease,” said Kevin Byrd, an immunologist at the American Dental Association Science and Research Institute who was not involved in this study.
The team tested supernatants from other oral bacteria in their pseudovirus infection assay, finding that some bacteria, such as certain Actinobacillus and Actinomyces species, inhibited the pseudovirus while others, such as some Streptococcus species, did not.
To pinpoint the exact compounds behind this antiviral activity, the team first focused on P. gingivalis compounds with known immunomodulatory effects or antiviral activity against other viruses: phosphoglycerol dihydroceramide (PGDHC), lipopolysaccharide (LPS), and gingipains. They found that PGDHC and gingipains inhibited pseudovirus infection, while LPS did not. Although the mechanism behind PGDHC’s antiviral activity remains unknown, the scientists found that gingipains killed the host cells. They also saw that while P. gingivalis supernatants did not affect virus binding to host cells, they affected the fusion between virus and host cells.
Unexpectedly, when the researchers knocked out the genes for PGDHC and gingipains in P. gingivalis, the bacteria still retained their antiviral activity, indicating that other molecules are also at play. “We found that there are other compounds that are even more potent. At this point, we are currently trying to identify what these potent compounds are,” said Cayabyab.
When I started the study, there was really no research surrounding the connection between the oral cavity or the mouth with COVID.
- Mark Cayabyab, Nova Southeastern University
Expanding the assay further to include the contributions of other oral microbiome members, the team turned to saliva samples from uninfected individuals, finding mixed results. Saliva from uninfected individuals inhibited viral infection, enhanced infection, or had no effect. This could explain why some people are more susceptible or resistant to SARS-CoV-2 infection than others.
While P. gingivalis supernatants seem to inhibit SARS-CoV-2 infection in this study, previous work found that periodontitis correlates with more severe COVID-19 infections (2). “It’s surprising, and it makes total sense,” said Cayabyab. P. gingivalis induces inflammation, which can lead to severe COVID-19. At the same time, bacteria evolve mechanisms to protect themselves from viruses. Byrd added, “I thought this was really interesting that that particular bug, which shows up more in inflammation, is actually preventing possibly another disease, which we know causes inflammation.”
Once they identify these inhibitory compounds and further study them, the molecules could be potential candidates for treating or preventing COVID-19. “What we envision is using this as an oral spray or a nasal spray,” Cayabyab said. “For example, there's an epidemic going on in your location. You just spray your mouth and your nose. This compound would coat the mucosal surface of the nose and mouth, and it would prevent you from catching the virus or prevent you from transmitting the virus.”
References
- Bontempo, A. et al. Inhibition of SARS-CoV-2 infection by Porphyromonas gingivalis and the oral microbiome. Microbiol Spectr 12, e00599-24 (2024).
- Haghgoo, J.M. et al. Association between the severity of periodontitis, COVID-19, C-reactive protein and interleukin-6 levels in hospitalized patients: a case-control study. BMC Oral Health 23, 556 (2023).