Dental applications of phage therapy: Using viruses to fight oral diseases

There has been a lot of talk in 2020 about SARS-CoV-2, the virus we’ve all come to dread. We have done everything to try to keep ourselves safe from this virus, but it is still easy to feel powerless against such a threatening infectious agent. Yet believe it or not, a virus is not always something to fear. There are other viruses in the world that have potentially beneficial applications in our bodies. There is an expanding field of research in the area of phage therapy, and it holds much promise. This type of treatment uses a naturally occurring phenomenon to attack bacterial invaders and infect them with a disease that will destroy them. With this type of innovative treatment, viruses can be our friends.

If you have never heard of phage therapy, you’re not alone. The name is a bit intimidating, but the concept is fairly simple. Phages, which are also known as bacteriophages, are viruses that target bacteria. Their name literally means bacteria eaters.¹ Just as certain viruses seek out humans as their intended victims, this prevalent virus seeks out bacteria to fulfill its life cycle. Interestingly, these tiny life forms are the most abundant biology entity on earth, and they play a critical role in controlling bacterial populations.²

Phages have several characteristics that make them a unique type of genetic entity. These same characteristics can also make phages an invaluable asset in fighting diseases. First, they are specific to certain types of bacteria. Second, since phages are naturally occurring, they are nontoxic to humans. Next, since phages are a type of virus, they are self-proliferating, which means one virus and its progeny can destroy many bacteria. Finally, one of the most impressive characteristics of phages is that they are able to penetrate into bacterial biofilms.³

The history of phage therapy

Surprisingly, the specialty of phage therapy has been around for just over 100 years. Phages were initially used as a treatment method for dysentery, which is caused by the bacterial species Shigella dysenteriae.² Early on, bacteriophages were also found to be an effective treatment for cholera, which is caused by the bacteria Vibrio cholerae. James Watson and Francis Crick, who are well-known for their DNA research, were early pioneers in this field.³

Very little was known about phages at the time the field began to develop, and this obstacle led to difficulty in implementing this form of treatment into actual practice. These bacterial viruses could not even be seen until the electron microscope was developed in the 1940s, and there was a controversy as to whether these phages even existed. Phage therapy, which in many ways was too complicated in relation to the available technology at the time, was for the most part abandoned when antibiotics were discovered.²

How phages work

In order to understand how phages work, it helps to have some background about viruses. This type of biological entity is distinct because it lies in the gray area between living and nonliving states. When on their own outside of a host, viruses are metabolically inactive. They simply exist as a protein coat that is sometimes enclosed by a membrane. Inside this protein coat is DNA or RNA. When a virus encounters a host cell, it can inject its genetic material into a host cell in order to complete its life cycle. Initially, the virus may remain dormant, which is called the lysogenic phase. The active or lytic phase is when it reproduces. Once enough new viruses have formed, the cells burst or lyse, and the viruses are released to infect new cells.⁴

When bacteriophages attack, they inject their DNA into their targeted bacterial species and reproduce in that host. They typically have a narrow range of species that they prey on, usually just a few strains within a bacterial species. This property enables phages to destroy pathogens while leaving normal resident bacteria unaffected. When the new phages are ready to be released, they break open the bacterium, thereby killing it. Some species do not do this immediately and instead remain a part of their host for several generations, until they are ready to be set free.³

Benefits of phage therapy

Naturally, anywhere from 100 million to 10 billion phages exist in 1 ml of human saliva.⁵ So whether you think about it or not, an enormous number of phages are at work within the oral cavity, each type targeting a different species of bacteria. With phage therapy, you can actively use this natural process of bacterial control to tip the balance toward oral health.

One of the main benefits of using phage therapy is that it does not encourage antibiotic resistance. Since this type of therapy is specific to certain strains of bacteria, it has a clear advantage over traditional antibiotic medications.² The World Health Organization has classified antibiotic resistance as one of the biggest threats to global health.⁶ According to the Centers for Disease Control and Prevention, in the United States alone, 2.8 million people acquire an antibiotic resistant infection each year and more than 35,000 people die from them.⁷ One of the secondary benefits of avoiding the use of antibiotics is that the overgrowth of yeast is avoided. When yeast proliferates a region of the body, protective bacterial species can inadvertently be destroyed.³

Another advantage of using phage therapy to fight disease is that the bacteria are able to penetrate biofilms. These complex bacterial communities are highly resistant and resilient to conventional antibiotic therapy, making it extremely difficult to treat these infections.³ When these biofilm infections occur in the oral cavity, they can spread systemically and affect regions throughout the body, making their eradication a priority. Bacteriophages weaken biofilms by lysing, or breaking open, and surrounding bacteria. They can also be engineered to release biofilm-degrading enzymes that chemically break down the biofilm. This has even been done with the periodontally implicated bacteria Aggregatibacter actinomycetemcomitans.^3,8

Future dental applications of phage therapy

In dentistry, bacteria have been identified over and over again as the causative factors in numerous forms of oral disease. Bacterial biofilms specifically play a role in the development of nearly every infectious disease in the mouth. Whether a person is suffering from periodontal disease, caries, gingivitis, or peri-implantitis, a dangerous colony of bacteria is steadily producing deleterious effects.⁹ Therein lies the question that asks how can these bacteria be effectively controlled?

Over 700 species of bacteria have been identified in the human oral cavity, with distinct bacteria playing a role in oral health and disease.¹⁰ Current treatment modalities, including most forms of oral hygiene care, lack specificity and target oral bacteria in their entirety, destroying both dangerous and beneficial strains in the process. This means that healthy strains of bacteria, which normally function to prevent the spread of pathogenic biofilms, are being regularly removed from the oral cavity.⁸ This is where phage therapy can step in and target only the disease-causing species of bacteria and leave healthy resident strains of bacteria unharmed.

Much of the research pertaining to phage therapy in the oral cavity is still in the preliminary stages. Phages that are active against Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum, and a number of Streptococcus species have been identified.³ Ideally, phages that are active against Streptococcus mutans could be used to decrease dental caries, but that has not been put into actual practice yet. Subjects with healthy periodontal tissues have been found to have a richer bacteriophage community than people who suffer from a disease state. Further research in this area could help discover which particular phages yield these results. Bacteriophages that attach well to the surface of zirconia have been identified. This type of phage may potentially be useful is disrupting biofilm formation that causes peri-implantitis.¹

Phage therapy holds much promise as a potential treatment for many forms of oral disease, but there is a lot of research that remains to be done. This is especially true when figuring out which types work best together to treat a wide range of virulent bacteria.³ Despite the measures the dental profession has taken, oral disease is still highly prevalent.⁸ The overuse of conventional antibiotic therapy has created resistant bacterial strains that have become a serious health threat.⁶ The time has come to think beyond traditional methods of reducing bacteria and consider using a method that nature has found to be effective for thousands of years.

References

1. Steier L, Dias de Oliveira S, Poli de Figueiredo JA. Bacteriophages in dentistry–State of the art and perspectives. MDPI Dent J. 2019;7(1). doi:10.3390/dj7010006
2. Lin DM, Koskella B, Lin HC. Phage Therapy: An alternative to antibiotics in the age of multi-drug resistance. World J Gastrointest Pharmacol Ther. 2017;8(6). doi:10.4292/wjgpt.v8.i3.162
3. Szafranski SP, Winkel A, Stiesch M. The use of bacteriophages to biocontrol oral biofilms. J Biotech. 2017;250(5);29-44. doi:10.1016/j.jbiotec.2017.01.002
4. Introduction to the viruses. Berkley. https://ucmp.berkeley.edu/alllife/virus.html
5. Naidu M, Robles-Sikisaka R, Abeles SR, Boehm TK, Pride DT. Characterization of bacteriophage communities and CRISPR profiles from dental plaque. BMC Microbiol. 2019(14);175. doi:10.1186/1471-2180-14-175
6. Antibiotic resistance. World Health Organization. February 2018. https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance
7. Antiobiotic/antimicrobial resistance. Centers for Disease Control and Prevention. February 2020. https://www.cdc.gov/drugresistance/index.html
8. Castillo-Ruiz M, Vines ED, Montt C, et al. Isolation of a novel Aggregatibacter actinomycetemcomitans serotype b bacteriophage capable of lysing bacteria within a biofilm. Appl Environ Microbiol. 2011;77(9):3157–3159. doi:10.1128/AEM.02115-10
9. Schlezinger M, Khalifa L, Houri-Haddad Y, et al. Phage Therapy: A new horizon in the antibiotic treatment of oral pathogens. Curr Top in Med Dent. 2017;17(10). doi:10.2174/1568026616666160930145649
10. Aas JA, Paster BJ, Stokes LN, Olsen I, Dewhirst FE. Defining the normal bacterial flora of the oral cavity. J Clin Microbiol. 2005;43(11):5721–5732. doi:10.1128/JCM.43.11.5721-5732.2005

Amber Metro-Sanchez, BA, RDH, practices dental hygiene with Chris Bible, DDS, at Comfort Dental in Fort Wayne, Indiana. She also works as a professional educator on behalf of Waterpik. Amber was a member of the 2015 Colgate Oral Health Advisory Board. She is also a contributing author for the Colgate Professional and Colgate Oral Care Center web pages. Reach her at [email protected].