The Oral Virome in Health and Disease

Abstract

Background:

Despite estimates suggesting over 380 trillion viruses reside within the body, an order of magnitude greater than the number of bacteria, the human virome remains largely unexplored. Pandemics and worldwide threats over the past century have highlighted our limited knowledge of viral pathogens in the body. Moreover, knowledge of what constitutes a healthy human virome is lacking, representing a significant knowledge gap. The NIH Human Virome Program (HVP) aims to fill this gap by defining all facets of the human virome across the life and health span in diverse individuals.

Types of Studies Reviewed:

This review summarizes the known information and challenges related to interrogating the human virome across the oral-gut-brain axis and its implications for oral health and clinical dental practice.

Results:

Viruses are the most abundant and diverse biological entities on the planet, and distinct viral communities inhabit individual human body sites. Most studies have focused on viruses linked to systemic disease, however, commensal viruses have the potential for conferring health and therapeutic benefits. The HVP aims to characterize commensal viruses in the human body across the lifespan.

Practical Implications:

Human virome characterization will advance our understanding of “healthy” viromes, promote advances in biomedical research, enable identification of disease-associated disruptions, and improve our capacity to detect, diagnose, and discover viruses that may pose threats to human health. For the dental community, an understanding of the oral virome will be essential for correlating viral signatures with patient health, treatment response, and predicting future oral health risks.

Introduction

Viral outbreaks, epidemics and pandemics have been frequent over the past century, wherein the 1918 Spanish Flu (H1N1), the 1958 Asian Flu (H2N2), and the 1968 Hong Kong Flu (N3N2) were responsible for nearly 60 million deaths combined worldwide, with more than 50 million attributed to the Spanish Flu alone¹ (Figure 1, Figure 2). Eclipsing all of these, the number of deaths due to smallpox viral infections accounted for an estimated 300–500 million deaths before a smallpox vaccine was discovered and globally distributed between 1958–1977^{2, 3}, after which time smallpox was eliminated (Figure 1). The smallpox vaccine was among the first successful implementations of a viral vaccine on a global scale. However, the Human Immunodeficiency Virus (HIV) outbreak beginning in 1981 resulted in an estimated 44 million deaths worldwide⁴, and the development of potent vaccines targeting HIV have been slow to implement, most likely attributed to the complexities of the HIV virus structure, its mechanism of infection, and its ability to thwart existing therapeutic strategies.

Figure 1. Timelines of viral outbreaks and genomic scientific landmark events from 1900–2025.

Left: Viral outbreaks organized by year. Right: Genomic scientific landmark events by year that include DNA structure determination, PCR and sequencing discoveries, as well as genome characterization consortia timelines.

Figure 2. Comparison of estimated global infections and deaths due to individual viral outbreaks from 1900–2025.

Bar plots of the estimated number of infections and deaths (in millions) from significant viral outbreaks in the 20th and 21st centuries, compared with deaths due to cancer (https://www.who.int/news-room/fact-sheets/detail/cancer), cardiovascular disease (https://www.who.int/health-topics/cardiovascular-diseases#tab=tab_1) and road traffic accidents (https://www.who.int/news-room/fact-sheets/detail/road-traffic-injuries). The World Health Association (WHO) source for HIV/AIDS is: https://www.who.int/news-room/fact-sheets/detail/hiv-aids; the 2009 H1NI pandemic: https://archive.cdc.gov/#/details?url=https://www.cdc.gov/flu/pandemic-resources/2009-h1n1-pandemic.html; Dengue: https://worldhealthorg.shinyapps.io/dengue_global/; and COVID-19: https://data.who.int/dashboards/covid19/cases?n=o. The X-axis break is used to improve visualization. Data estimates drawn from Bloom and Cadarette (2019)⁷¹, the Centers for Disease Control and Prevention and the WHO (accessed November 2025).

Shortly after the 2002 Severe Acute Respiratory Syndrome (SARS) outbreak, Dr. Norman Anderson and colleagues proposed an ambitious mission to screen and characterize viral pathogens in human blood samples⁵. Their vision aimed to allow the timely identification and mitigation of future viral outbreaks in human populations by expanding knowledge of viruses that exist in overwhelming abundance throughout the biosphere, for which so little was, and still is, known. In this context of detecting human viral pathogens, the term “human virome” was first coined, referring to the collection of viruses associated with and residing within the human body^{5, 6}. At the time, marine biologists had successfully performed large-scale sequencing of viral particles in ocean water^{7, 8}. Considering the human body as another complex and dynamic ecosystem, Anderson and his team anticipated that mapping the human virome could be feasible within just a few years⁵.

Currently, the critical roles of viruses in human health remain a pressing and uncertain reality, underscored in recent decades by HIV, Ebola, Dengue, MERS, Zika⁹, the 2019 outbreak of SARS-CoV-2 (COVID-19), and other emerging viral threats worldwide (Figure 1). The COVID-19 pandemic not only claimed more than 1.2 million lives in the United States alone (https://data.who.int/dashboards/covid19/deaths) but also resulted in economic frailty and widespread disruptions. Scientists and experts already fear another viral pandemic given our increased connectivity across the globe and the lack of knowledge about pathogenic viruses. The COVID-19 pandemic sounded the collective global alarm regarding our limited knowledge of the virome and highlighted the need for proactive strategies rather than the reactive responses employed in past outbreaks.

Although Dr. Anderson’s 2003 vision for characterizing the human virome was an important conceptual launching pad, comprehensive virome characterization efforts have since faced several challenges. First, although the SARS outbreak was responsible for over 8,700 infections and 774 deaths⁹, its impact was largely confined to Asia, with no reported deaths in the United States. Consequently, there was not a strong impetus to appropriate funds toward virome studies. Second, government research funds were used for other high-profile endeavors including The Cancer Genome Atlas research network (TCGA, https://www.cancer.gov/ccg/research/genome-sequencing/tcga) from 2006–2014 for multi-omics human genome characterization of 10,000 primary tumors (Figure 1), and the Human Microbiome Project (HMP, https://commonfund.nih.gov/hmp) from 2007–2016, in which microbiome genome sequence reference sets were assembled followed by longitudinal analyses of preterm birth, inflammatory bowel disease, and type 2 diabetes. Third, in 2003, whole genome sequencing was low throughput, high-cost, and predated the first commercially-available next-generation sequencing platforms. Finally, virome reference sequence databases were not yet established, and even remain incomplete to this day, with a substantial number of viral sequencing reads classified as “dark matter” and not alignable to known virus reference sequences.

The Human Genome Project reshaped the landscape of biological science and revealed that protein-coding genes accounted for only about 20% of what was expected¹⁰, prompting heightened interest in launching the HMP to characterize the commensal bacterial communities that inhabit the human body¹¹. As a result, the concepts of commensal microbes coexisting within human cells is widely accepted. In this regard, viruses share a historical parallel with bacteria, as both were once viewed solely as pathogenic. In fact, seminal studies have highlighted the critical role of the microbial world in shaping important aspects of human health and development¹².

The Human Virome Program: Shedding Light on Dark Matter

The human virome remains largely unknown. Our knowledge of zoonotic pathogens within the human body, and more broadly, the foundational understanding of what constitutes the commensal virome in healthy tissues (the “healthy virome”), is limited. Indeed, prior virome metagenomic sequencing studies revealed that many sequences do not align with existing database information, and thus, represent viral “dark matter” as alignment and mapping tools were not developed, hence, sequencing data that contain such novel viral sequences are not analyzable. Filling these gaps through detailed virome mapping across diverse human cohorts throughout the lifespan can redefine our relationship with the viral world, improve our capacity to detect, diagnose, and discover viruses that may pose threats to human populations^{13, 14}, and improve our understanding of the commensal viruses that are positively linked to human health. Sequencing data mapping can unveil novel viral content with advanced artificial intelligence (AI) based bioinformatics to formally characterize dark matter content.

At the nexus of these knowledge gaps, sequencing technology advancements, and the looming threat of future pandemics, the NIH reached a pivotal point where launching the Human Virome Program (HVP) was the logical next step. The HVP will explore the vast world of viruses present in the human body – entities that are estimated to outnumber bacterial cells 10-to-1¹⁵ yet remain largely unknown components of the human microbiome (Figure 3). As part of this initiative, coordinated efforts are underway across five HVP Human Virome Characterization Centers (VCCs) with expanded aims that reflect the field’s evolution since the original vision proposed by Anderson and colleagues: 1) catalog the human virome across individuals, specimen types and ages from prospective and retrospective cohort collections of human specimens, 2) develop and innovate methods, models and tools for virome analyses, 3) interrogate the relationships between the human virome and the human body and 4) enable sharing of data created by HVP researchers with the scientific community. While each VCC has unique goals, all VCCs share a common focus to both identify viruses cohabitating body sites and define their roles in human health (https://commonfund.nih.gov/humanvirome). Specifically, the HVP VCCs focus on: 1) the oro-respiratory-gut virome axis over space and time (University of Pennsylvania), 2) viruses and host responses in a minoritized population of adults and children (Vanderbilt University), 3) diverse human populations (Broad Institute), 4) virome dynamics across race, ethnicity, age, physiology and lifestyle (Stanford University), and 5) the Oral-Gut-Brain Axis (UCLA).

Figure 3. The Human Virome.

The main components of the human microbiome are comprised of viruses, bacteria, fungi and archaea. Plot shows the abundance of each type in the human body.

The initial goal of the HVP is to characterize viruses in healthy specimens. These data will help shape our knowledge of the commensal virome, and can dovetail with other projects, namely the Global Virome Project, that is specifically aimed to identify nearly 1 million potential zoonotic viruses to improve global disease surveillance and prevent future outbreaks. However, utilizing the HVP as a reporting mechanism for viral outbreaks is challenging. The HVP is a research based effort, so clinical decisions cannot be made if novel viruses are identified. Also, the HVP will characterize large numbers of retrospectively-collected specimens, therefore, data production, analysis and deposition timelines will be longer than typically used by government agencies to investigate potential outbreaks. Nonetheless, HVP data will be publicly-available and frequently deposited and expedited peer-reviewed reports of HVP data will be published, thereby enabling access by the scientific community and global research organizations.

Identifying the Commensal Virome - the Good Guys

Compared to human and bacterial genomes, viral genomes display increased complexity, functioning through either DNA or RNA genomes. The three-dimensional structures and biochemical compositions of the viral capsid enclosing the genome also vary across viruses and influence their stability, virulence, and infectivity. Viruses are the most abundant and diverse biological entities on our planet, with an estimated 10³¹ particles, including both bacteriophages¹⁶ that infect bacteria and eukaryotic viruses that infect human cells, cause acute infections, and/or establish long-term latency. Quantitatively, approximately 10⁷ virus-like particles (VLPs) are found per milliliter of ocean water, while a milliliter of human saliva and a gram of feces contain approximately 10⁸ and 10⁹ VLPs, respectively — highlighting the vast complexity of the human virome^{16, 17}. It is estimated that there are 10¹³ VLPs per individual, coupled with a highly personalized and heterogeneous species composition¹⁶.

While early research delved into understanding the molecular and structural complexities of viruses, most studies focused almost exclusively on viruses in the context of disease, thereby reinforcing the perception of viruses solely as pathogens that threaten human health. In this regard, viruses share similar trajectories with bacteria: both were initially studied primarily as pathogens, and their characterization has been constrained by limited biotechnological tools, low throughput and high costs. However, advancements have revealed that many viruses establish benign colonization and stable associations with hosts that are not associated with disease states.

Current findings reveal that, as with bacteria, distinct viral communities inhabit various body sites, each differing in composition and abundance. Given the abundance of commensal bacteria and since most viruses are bacteriophages (phages) that infect bacteria, it is logical that most human viruses infect commensal bacteria. Double-stranded DNA (dsDNA) tailed bacteriophages are generally classified within the class Caudoviricetes and the order Crassvirales that includes the crAssphage lineage. CrAssphages are abundant in the fecal virome of Western populations and approximately 77% of the global human gut virome. Within human blood, the Anelloviridae virus family is most prominent, found in over 90% of human populations worldwide¹⁸, while human pegiviruses are present at only ~1–5%¹⁹. The association of anelloviruses with health or disease remains unknown, however, significantly elevated levels of Anelloviridae Torque teno viruses have been observed in breast cancer, Hodgkin’s lymphoma, and colorectal cancer patients²⁰.

Commensal viruses exert important health functions independent of commensal bacteria. In bacteria-depleted mice, commensal viruses maintained the homeostasis of intraepithelial lymphocytes within the gut lining compared with mice depleted in both bacteria and viruses²¹. Among commensal viruses, the dominant family members are Podoviridae, Siphoviridae, Myoviridae and Microviridae. Notably, the first three families have recently been abolished under the revised International Committee on Taxonomy of Viruses (ICTV) classification (https://ictv.global), highlighting another layer of complexity to virome characterization amid a constantly evolving taxonomy landscape.

To understand how commensal viruses are linked to human health, one goal of the HVP is identify viruses that may confer health benefits for therapeutic utilization similar to probiotics. These purported “provirotics” could enhance human health by synergizing with host tissues and the microbiome in niches across the human body. Likewise, an oral virome transplant—comparable to a fecal transplant—may address recalcitrant disease that does not respond to other treatment modalities.

There is renewed promise in phage therapy for treating individuals with multidrug-resistant infections. Phage therapy, in which viruses that infect bacteria are administered to drug-resistant patients, was first employed in the early 20th century but was largely abandoned as antibiotic-based therapies flourished in the Western world²². As cases of antibiotic resistance have increased due to overuse and lack of novel drug development, phage therapy has reemerged, correlating with bacterial pathogen clearance and improved clinical outcomes²². Antibiotic resistance serves as a cautionary tale for the future development of antiviral drugs, as overuse of antiviral agents could similarly drive antiviral resistance. Nevertheless, human virome characterization efforts hold great promise for expanding therapeutic avenues and safeguarding human health by leveraging phage therapies and beneficial viruses for clinical advantage. Phage therapy also suggests that personalized-based approaches involving individual-specific virome signatures may be effective, thus opening new avenues for disease treatment. Importantly, this strategy may also be applied to other diseases for which virome and bacteriome signatures are not yet understood.

The Oral Virome - Hiding in Plain Sight

The human body houses a fascinating array of biological systems and pathways, including the anatomic, circulatory, endocrine, immune, and neural systems that collectively transmit information and biomolecules throughout the body. The oral cavity, a primary entry point for viruses into the human body, hosts diverse microbial communities and is tightly connected to circulatory, digestive and neural pathways. These bidirectional communication axes facilitate microbe and metabolite transmission and are referred to as the Oral-Gut^23–27, Oral-Brain²⁸, and Gut-Brain^29–35 axes. Our VCC is investigating the Oral-Gut-Brain axis, which represents the combined effects across these three systems in regulating human health^36–41.

The Oral-Gut-Brain Axis bidirectionally links the oral and gut microbiomes with neural networks in which oral microbiota translocate to the gut and brain⁴², while neural signals and systemic inflammation can alter gut and oral microbial communities. This axis is key for oral pathogens to trigger inflammation linked to Alzheimer’s Disease, Parkinson’s Disease, and systemic diseases across the human body^{40, 42–44}. Generally, characterized viruses across the oral-gut-brain axis are bacteriophages, most notably Caudoviricetes^{16, 45, 46}. Common oral eukaryotic viruses include Anelloviridae, Herpesviridae, Myoviridae, Papillomaviridae, Podoviridae, Redondoviridae, while gut viruses include Adenoviridae, Anelloviridae, Calciviridae, Circoviridae, Herpesviridae, Microviridae, Myoviridae, Picornviridae, Podoviridae and Siphoviridae. Brain viruses are much less abundant overall but include Herpesviridae, Myoviridae, Podoviridae and Siphoviridae¹⁶ (Figure 4).

Figure 4. Common eukaryotic viruses identified across the Oral-Gut-Brain Axis.

Most common eukaryotic viruses are stratified by Brain, Oral Cavity and Gut regions of the human bodt.

Our VCC efforts involve generating virome atlases of oral tissues including saliva, dental plaque, teeth, gingival tissue, tears, and nasopharyngeal swabs (Figure 5A). We also aim to profile multiple oral specimens across individuals, including single-tooth resolution for teeth and dental plaque specimens, and then align the oral virome data with gut (colorectal tissue, stool), and brain (brain tissue, cerebrospinal fluid (CSF)) datasets. Finally, blood, skin swabs, and breastmilk viromes will be generated to further interconnect these transport systems with the oral-gut-brain axis.

Figure 5. Hiding in Plain Sight.

A). Oral specimens collected for virome profiling include saliva, oral swabs, dental plaque, nasopharyngeal swabs, extracted teeth, gingival tissue and gingival crevicular fluid. B). In addition to human (host) cells, small amounts of microbiota, including viruses, bacterial, fungi and archaea, are present and can be identified in virome characterization experiments.

Experimentally, human primary biospecimens contain small amounts of microbiota (viruses, bacteria, fungi, archaea) (Figure 5B) that carry through DNA and RNA extraction steps (Figure 6A). Viral content can be isolated using viral capture enrichment of bulk DNA/RNA followed by next-generation sequencing, or the viral-specific content can be informatically collected after short- or long-read metagenomic sequencing (Figure 6A). These data can be subsequently analyzed for novel viral species discovery and annotation, as well as the formation of Metagenome Assembled Genomes (MAGS).

Figure 6. Shedding Light on “Dark Matter”.

A) Upon procurement, oral cavity specimens contain a mixture of human cells along with viruses, bacteria, fungi, and archaea. Total DNA/RNA isolated from human tissues can be subject to viral capture enrichment or shotgun metagenomic short- or long-read sequencing to identify metagenomic content. B) Workflow of single-cell/nuclei based profiling. Cells/nuclei are dissociated and resuspended at the single cell/nuclei level. Cells/nuclei are input for a microfluidics-based merging with emulsions that contain sequencing library primers with cell/nuclei-specific barcodes. Once the libraries are prepared the emulsions are lysed and short- or long-read sequencing can be performed to identify cellular subgroups, heterogeneity and/or rare cell populations. C) Spatial transcriptomic workflow. A fixed tissue section is hybridized to arrayed library probes that include barcodes for two-dimensional mapping. After library preparation, short- or long-read sequencing can help to resolve spatially derived subgroups and heterogeneity.

Recent technological advancements have allowed sequencing data resolution at the single-cell level, both in cell/nuclei suspensions (Figure 6B) or spatially across a tissue section (Figure 6C). Single-cell/nuclei suspensions serve as inputs for microfluidics-based sorting in which cell-specific sequencing barcode emulsions are merged with each cell. After barcode ligation, emulsions are lysed and short- or long-read sequencing is performed to identify cellular subgroups, heterogeneity and rare populations (Figure 6B). Alternatively, spatial transcriptomic profiling utilizes spatially-barcoded library probe hybridization to fixed tissue specimens that allow the sequencing data to be interrogated in two-dimensional space, for the purposes of identifying spatially-resolved cell populations and tissue heterogeneity (Figure 6C).

Several key findings have emerged from initial attempts to define the virome in health and disease, including evidence for a spectrum of ecological niches that differ across the lifespan, complex interkingdom interactions between viruses, bacteria, and the host immune system, and the potential importance of commensal viruses^{13, 47–53}. Data from humans with chronic oral diseases (e.g., periodontal disease) and animal models of the same conditions point to a unique oral disease–associated virome^{39, 54}. Most existing human oral virome data have been derived from saliva samples^{17, 55, 56} and, to a limited extent, from dental plaque⁵⁷. In contrast, the gut virome is the best-studied and densely colonized of all body viral communities, whereas the brain and nervous system viromes in healthy humans remains among the least explored. The few prior investigations assessing viral communities within these regions have shown that, although they are commonly regarded as sterile, viruses are abundant in CSF, indicative of active connection points between oral-gut and brain-CSF viromes.

Several individual viruses have been linked to oral health, systemic diseases and human cancers (Table 1. Figure 7)^58–61. Among the most studied is Epstein-Barr virus (EBV), a ubiquitous human herpesvirus linked to multiple oral inflammatory diseases including periodontitis and Sjogren’s Syndrome⁶². EBV can also cause distinctive oral lesions such as oral hairy tongue leukoplakia⁶³ and is detected in the nasopharynx, oropharynx, sinus cavity, jaw, and tonsil tissues⁶⁴, demonstrating its persistence in diverse head-and-neck niches. Another notable virus is human papillomavirus (HPV) that has causative roles in oral cancers⁶⁵ and appears elevated in HIV-positive individuals (Figure 7A). Among the HPV genotypes, HPV-16 is the most oncogenic and is found in roughly 90% of all HPV-positive oral cancers⁶⁵. Interestingly, periodontitis or patients with gingival disease have higher risk of HPV infection than those without⁶⁶, and HPV infection is correlated with poorer oral health⁶⁷ and the presence of benign lesions in the oral cavity.

Table 1.

Common Viruses Found in the Oral Cavity

Virus	Genus	Description	Family	Genome	Presence and Role in Disease	Clinical Appearance or Manifestation
COVID-19		SARS-CoV-2	Coronaviridae	ssRNA (+ sense)	Infects oral cavity tissues and salivary glands	Oral lesions (ulcers, erosions, blisters and red/white spots on tongue and gingiva); taste disorders (dysgeusia), dry mouth (xerostomia), fungal infections, periodontal disease exacerbation
HSV-1	HHV-1	Herpes Simplex Virus Type 1	Herpesviridae (α-Virinae)	Linear dsDNA	Sensory ganglia latency; associated with Orofacial infections	Inflammation and ulcers on lips, mouth, tongue and gingiva (Figure 7B).
HSV-2	HHV-2	Herpes Simplex Virus Type 2	Herpesviridae (α-Virinae)	Linear dsDNA	Present in genital infections, orofacial lesions	Fluid-filled blisters on the lips, tongue, gums and mouth.
VSV	HHV-3	Varicella-Zoster Virus	Herpesviridae (α-Virinae)	Linear dsDNA	Varicella (chickenpox) in children, herpes zoster (shingles) in adults afterwards; possibly in oral cavity	Vesicles that develop into ulcers on the mouth palate, tongue, inner cheek (Figure 7C).
EBV	HHV-4	Epstein-Barr Virus	Herpesviridae (Ɣ-Virinae)	Linear dsDNA	Oral Malignancies, oral hairy leukoplakia, Sjogrens Syndrome	Plaque-like, white lesions with a hairy surface or shallow ulcers across the oral mucosa.
CMV	HHV-5	Cytomegalovirus	Herpesviridae (β-Virinae)	Linear dsDNA	Commonly found in gingival and salivary glands in the oral cavity	Ulcerated regions with well-defined structure located on tongue, gingiva, mouth floor and palate.
HHV-6	HHV-6	Human HerpesVirus 6	Herpesviridae (β-Virinae)	Linear dsDNA	Roseola infantum; latency in T-cells and monocytes	Erythematous papules/macules or ulcers on the uvular base and soft palate.
HHV-7	HHV-7	Human HerpesVirus 7	Herpesviridae (β-Virinae)	Linear dsDNA	Asymptomatic, may reactivate with oral manifestations	Linked to erosive oral lesions and oral inflammation (periodontitis).
HHV-8	HHV-8	Human HerpesVirus 8	Herpesviridae (Ɣ-Virinae)	Linear dsDNA	Kaposi’s Sarcoma Associated Herpes Virus (KSHV); Linked to Kaposi’s Sarcoma in immunocompromised patients	Purple to brown areas on the gingiva and mouth palate that can become ulcerated and result in bleeding (Figure 7D).
HAV		Hepatitis A Virus	Picornaviridae	ssRNA (+ sense)	Fecal-Oral Transmission; Found in oral secretions	Mouth pain, gum bleeding, burning sensation, dry mouth, altered taste and yellow-brown mucosa.
HBV		Hepatitis B Virus	Hepadnaviridae	dsDNA (partial)	Causes Hepatitis B; transmitted via saliva/blood	Oral mucosal erosions with swollen red-gray areas. Can also present with small red/purple spots, ulceration and leukoplakia.
HCV		Hepatitis C Virus	Flaviridae	ssRNA (+ sense)	Causes Chronic Hepatitis; present in oral fluids	White, interlacing lines or red ulcerated patches on tongue and buccal mucosa. Mucosa may also be swollen, grey/red color, with erosion and hemorrhages. Tongue and gingival areas can be dry, smooth and coated with bleeding.
HIV		Human Immunodeficiency Virus	Retroviridae	ssRNA (+ sense)	Host genome integration; leads to immunodeficiency. HIV-associated periodontal diseases include Linear Gingival Erythema, Necrotizing Ulcerative Gingivitis, Necrotizing Ulcerartive Periodontitis. Kaposi’s Sarcoma gingival lesions are also present. Image shows HIV-associated Candidiasis	White plaques and red patches on palate/buccal mucosa. Ulcers can present with white-grey base with red patches (Figure 7E).
HPV		Human Papillomaviruses	Papillomaviridae	Circular dsDNA	Specific for epithelial cells; has oncogenic potential	Pink/white growths with cauliflower or stalk-like appearances on the tongue, lips or palate. Can also have smooth, flat or domed appearance with ulceration, across the oral cavity (Figure 7A).
Adenovirus		Adenovirus	Adenoviridae	dsDNA	Linked to oral lesions, pharyngitis and conjunctivitis	Oral mucosa swelling and appearance of small vesicles on gingiva, lips, tongue and palate. Can form ulcers and erosions. Inflammation can also spread to uvula, tonsils and pharynx.
Molluscum Contagiosum Virus		Molluscum Contagiosum Virus	Poxviridae	dsDNA	Benign cutaneous/mucosal lesions in oral cavity	Pearl-shaped, flesh colored bumps on lips, tongue and inner cheek mucosa.
Redondovirus		Redondovirus	Redondoviridae	Circular ssDNA	Common in oral/respiratory tract	Strongly connected to periodontitis, found in saliva and gingival areas of the mouth. Do not cause direct disease symptoms with lesions, ulcers, etc.
Enterovirus		Enteroviruses	Picornaviridae	ssRNA (+ sense)	Causes Hand-foot-mouth disease; herpangina	Grey-colored vesicles that ultimately rupture and form ulcers that are located on the inner cheek, tongue and throat.
Mumps Virus		Mumps Virus	Paramyxoviridae	ssRNA (− sense)	Associated with Parotitis and orofacial symptoms	Salivary gland inflammation between ear and jaw.

Figure 7.

Clinical appearance of patients infected with oral viruses. A) Human Papillomavirus (HPV), B) Herpes Simplex Virus Type 1 (HSV-1), C) Varicella-Zoster Virus Type 2 (VSV), D) Human Herpesvirus 8 (HHV-8), and E) Human Immunodeficiency Virus (HIV). Descriptions are listed in Table 1.

Other common oral viruses include Herpes Viruses, SARS-CoV-2 (COVID-19), HIV, and others (Table 1, Figure 7)⁶⁰. Herpes Simplex Virus Type 1 (HSV-1) is known for causing cold sores presenting as lesions or blisters near the lips, mouth, or gums (Figure 7B). HSV-1 has lifelong latency within sensory neurons, where it remains dormant between outbreaks that occur in response to factors such as stress or immune suppression. Varicella-Zoster Virus (VSV, Figure 7C), presents as chickenpox in children and shingles in adults. Herpes Virus Type 8 (HHV-8) infections cause Kaposi’s Sarcoma that commonly occurs in HIV patients (Figure 7D). COVID-19 is abundant in the oral and nasopharyngeal regions of infected individuals, and patients have reported oral health challenges including oral lesions, orofacial pain and periodontitis-like symptoms. However, periodontal symptoms are not statistically associated with COVID-19 severity⁶⁸. HIV-associated oral diseases (Figure 7E) include linear gingival erythema (LGE; a band of redness along the gum line), necrotizing ulcerative gingivitis (NUG; painful, bleeding and ulcerative gums) and necrotizing ulcerative periodontitis (NUP; a more severe form involving tissue and bone destruction, typically seen in those with advanced immunosuppression).

Implications for the Dental Community

Oral cavity virome characterization is aimed to transform clinical dentistry by informing DMFS (Decayed, Missing, Filled, Surfaces) status, periodontal status, and unveiling the relationships between viral presence and systemic health. Oral specimens are abundant and non-invasively collected, and therefore, well positioned for rapid, chairside viral diagnostics and personalized data-driven patient care. Since oral pathogens are linked to cardiovascular, respiratory, renal, reproductive, arthritic, liver, circulatory and brain health, oral cavity viral biomarkers can be developed as surrogate measures of systemic disease (Figure 8). In addition, the synergy of biomarker discovery with AI-assisted bioinformatics and real-time monitoring using wearable device, smartphone and tablet technologies, will have a strong influence on global oral health (Figure 8).

Figure 8. The Future of Precision Dentistry based on Oral Viromics and Technological Advances.

Viruses characterized in oral cavity tissues and biofluids can be easily accessed to isolate and characterize novel biomarkers linked to oral health and systemic disease. Left- and right-edge icons: Current and future technological advancements (clockwise from upper right) can utilize oral viromics for floss-based vaccine delivery, phage therapy, molecular circuitry, DNA/RNA-based biomarkers, smart toothbrushes linked to phones and tablets, drug treatment data mining, wearable device tracking of oral health measures, AI-assisted informatics, telehealth and global, cloud-based data analyses and tracking. The tissue ring surrounding the oral cavity (clockwise from top) highlights the oral-systemic health axes that exist with brain, heart/cardiovascular health, respiratory, kidney/renal function, reproductive health, rheumatoid arthritis, liver function, and circulatory, endocrine, immune and neural pathways for oral microbe translocation across the human body.

The oral cavity also demonstrates potential as a therapeutic gateway. The innovative use of dental floss as a non-invasive, needle-free vaccine delivery system in mice⁶⁹ represents a promising new avenue for immunization (Figure 8). The gingival sulcus pockets, located between teeth and gums, readily absorb biomaterials that can enter systemic circulation. Harnessing this property could enable delivery of vaccines to counteract pathogenic viruses in addition to beneficial commensal viruses, emphasizing the importance of the oral cavity in safeguarding overall human health. The development of vaccines to target viruses linked to oral diseases and oral cancer is also promising for the future of dentistry. For instance, the introduction of mRNA-based vaccines⁷⁰ that were used during the COVID-19 pandemic can be quickly generated and distributed at a large scale.

Conclusions and Future Directions - Promises and Challenges

Virome characterization will profoundly advance our understanding of the roles of commensal viruses in oral health across the human body by elucidating the composition and the interconnectedness of viral communities across organ systems, cohorts, and the lifespan. These insights will help determine how pathogenic viruses promote disease states, how commensal viruses are altered during disease onset and progression, and how viruses are functionally involved in normal physiologic processes and intertwined in systemic health and disease. An advanced understanding of the human virome will provide an unprecedented foundation for improving global human health and strengthen preparedness for future viral pandemics.

While virome characterization holds great promise, overcoming numerous challenges are needed, including new tools and technologies for scientific observation, analysis, and interpretation to address the abundant viral dark matter. As our understanding of viral diversity expands and previously unknown viruses are brought to light, existing viral taxonomic frameworks must evolve to incorporate new data and classification criteria^{13, 53}. Coordinated efforts are needed to manage the growing volumes of new viral sequence data and to ensure consistent classification across databases. Functional assays will be essential to determine whether viral presence is correlative or causal with health and disease. Finally, careful attention is needed towards safely handling virus-based experimental protocols as there is currently no universal consensus on methods for virome characterization.

Our HVP Oral-Gut-Brain Axis VCC is set to profile thousands of biospecimens to develop standardized virome reference datasets. For the dental community, the oral virome will be essential for correlating viral signatures with patient health, treatment response, and predicting future risks to oral health.