938 D3000 new imprint Word template Vol 13, No 1 (2025) ISSN 2167-8677 (online) DOI 10.5195/d3000/2025.938 http://dentistry3000.pitt.edu Emerging Role of Viral Infection in Periodontal Disease Alaa W. Izzat1, Batool Hassan Al-Ghurabi1, Lina Sami Adham1, Zahraa F. Shaker2 1College of Den*stry, University of Baghdad, Baghdad, Iraq 2College of Den*stry, University of Al-Mustansiriyah, Baghdad, Iraq Abstract Periodontal disease is primarily linked to a bacterial infection, such as dental plaque, which harbors a broad microbial community and can induce numerous in- :lammatory responses in periodontal tissue. In numerous instances, the local bac- terial incursion and host-mediated immune reactions result in severe alveolar bone resorption. While researchers mainly concentrate on identifying periodon- topathogenic bacteria, recent investigations have suggested that several viruses may also play a role in the onset and advancement of periodontitis. Human viruses can induce cytokine release from both in:lammatory and non-in:lammatory cells, hence compromising periodontal immune protection. This review investigates the potential role of viral infection in the pathogenesis of periodontal disease. Open Access Cita%on: Izzat AW, et al. (2025) Emerging Role of Viral Infec%on in Periodontal Disease. Den%stry 3000. 1:a001 doi:10.5195/d3000.2025.938 Received: May 7, 2025 Accepted: May 31, 2025 Published: June 27, 2025 Copyright: ©2025 Izzat AW, et al. This is an open access ar%cle licensed under a Crea%ve Commons ASribu%on Work 4.0 United States License. Email: batoolamms@codental.uobaghdad.edu. Introduc)on Periodontal disease, or gum disease, com- prises a series of in5lammatory disorders that impact the tissues encircling the teeth [1,2]. In its initial phase, termed gingivitis, the gums exhibit swelling, redness, and po- tential bleeding. It is regarded as the primary cause of tooth loss among adults globally. In its advanced stage, known as periodontitis, the gums may retract from the tooth, result- ing in bone loss, and potentially causing teeth to become loose or dislodge [3]. Halito- sis (bad breath) may also occur [4]. Perio- dontal disease results from microbial infec- tion, which causes in5lammation and loss of connective tissue attachment as well as alve- olar bone around the teeth [3]. Bacterial plaque is a primary etiologic factor of perio- dontitis. In most cases, the bacteria are pro- teolytic, Gram-negative species that produce pathogenic factors that trigger host defense responses, causing in5lammation and tissue damage. Microbiological culture and culture- independent genetic investigations have rec- ognized around 1200 bacterial species and 18,000 phylotypes in the oral cavity and a minimum of 400 bacterial species in subgin- gival locations. Nevertheless, despite the ex- tensive enumeration of many bacteria asso- ciated with periodontitis, fewer than 20 spe- cies are classi5ied as principal periodontal pathogens. Plaque contains non-bacterial microorganisms, including viruses, myco- plasma, yeasts, and protozoa [5]. Multiple studies indicate that human viruses may contribute to the etiology of periodontitis by modifying immune defenses, triggering harmful host responses, or exerting direct lytic effects on periodontal tissues [6]. Sev- eral immune-compromising factors, includ- ing smoking, in5lammation, stress, trauma, and immunosuppressive disorders, may re- activate latent viruses residing in the body [7]. In numerous clinical studies, human viruses such as human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), and human immunode- 5iciency virus (HIV) have been implicated in the pathogenesis of periodontal disease [8]. In this research, we chose to shed light on the involvement of viruses in periodontal dis- ease due to the scarcity of previous studies on them and their importance in under- standing the basic mechanisms of immune responses to viral infection in the etiopatho- genesis of the disease. Material and Methods For this review, the authors executed an electronic search across many pertinent sci- enti5ic databases, including SCOPUS, Google Scholar, PubMed, and Web of Science. The preliminary evaluation comprised 46 publi- cations published between 2015 and 2025 that had the terms “periodontal disease,” “herpes viruses,” “periodontopathogenic Emerging Role of Viral InfecEon in Periodontal Disease Vol 13, No 1 (2025) DOI 10.5195/d3000/2025.938 http://dentistry3000.pitt.edu 2 bacteria,” and “in5lammatory response.” Eligibility criteria: This study included re- cent papers, reviews, and case-control stud- ies; all articles included in this review were published in English. Results/Discussion Figure 1 shows the work5low of this work. 46 articles were analyzed. Periodontal Diseases Periodontal infections represent one of the world's most prevalent chronic infectious con- ditions. Periodontitis is still one of the most common causes of tooth loss in adults. The primary etiological component of periodon- titis is subgingival bacteria and their toxins; however, the destruction of tissue that oc- curs is a result of host response activities that are induced by microbial factors [9]. Periodontitis is characterized by bone re- sorption, loss of attachment, and tooth mo- bility [10]. The periodontal diseases affect 20%-50% of the population in the world. They are associated with a wide spectrum of chronic systemic disorders, including diabe- tes, cardiovascular, renal, neurodegenera- tive diseases, in addition to immune-medi- ated rheumatic diseases, obesity, neoplastic disorders, hypertension, and adverse preg- nancy, chronic obstructive pulmonary dis- ease [11]. According to several researchers, untreated periodontal diseases has been linked to higher medical care costs for non- oral diseases. A periodontal disease is a risk factor for a variety of systemic diseases, in- cluding cardiovascular diseases and diabe- tes. The mechanisms underlying this obser- vation are unknown, but it is apparent that in5lammatory cytokines represent a signifi- cant link between periodontal and systemic diseases [12]. Many variables, including ge- netic, metabolic, immunological, and in5lam- matory elements, are linked to the progres- sion of periodontitis. Chronic periodontitis is an in5lammatory disease induced by bacte- ria, wherein the immune response signi5i- cantly contributes to the degradation of alve- olar bone. Appropriate cytokine production is thought to result in protective immunity, whereas inappropriate cytokine production results in tissue death and disease develop- ment [13]. Moreover, it is widely acknowl- edged that the regulation of the T helper 1 (Th1)/T helper 2 (Th2) cell equilibrium is critical to periodontal disease immunoregu- lation [11]. Most cases of periodontitis are historically classi5ied as either aggressive periodontitis or chronic periodontitis. Recently, it has be- come clear that insuf5icient evidence sup- ports this classi5ication based on factors such as varying clinical presentation and scienti5ic investigations. A de5iciency of distinct patho- biology-based differentiations among the speci5ied categories, diagnostic ambiguity, and obstacles in therapy execution. In perio- dontology, a new classi5ication was intro- duced despite the 1999 classi5ication have been used for the previous 17 years [14]. Bi- ological and clinical discoveries have revised the periodontal, peri-implant illness, and sta- tus classi5ication system, resulting in the 2017 World Workshop Classi5ication [15]. Pathophysiology of periodontal diseases Dental plaque is a microbial bio5ilm that ac- cumulates on the teeth and gingiva, which is the 5irst stage of gingivitis. In the absence of treatment, gingivitis can advance to perio- dontitis, a condition characterized by deep periodontal pockets that re5lect the illness and may result in the loss of teeth [16]. Inter- estingly, Studies estimate that a human host may have up to 150 different types of mi- crobes in their bio5ilm. In addition, human dental plaque contains over a thousand spe- cies [17]. Research on the healthy residen- tial microbiome using current DNA methods reveals an overabundance of Gram-positive microbes, despite the existence of periodon- tal pathogens [18]. This makes them symbi- onts, or obligate inhabitants of the subgingi- val and submarginal regions of the dental bio5ilm formation. Further spirochetes, vi- ruses, and Gram-negative anaerobic bacteria are all possible causative pathogens [19]. Particularly, Treponema denticola, Porphy- romonas gingivalis (P. gingivalis), and Tan- nerella forsythia are members of the red complicated collection of anaerobic microor- ganisms thought to be the effective bacterial species affecting the onset and progression of periodontal disease within the many dif- ferent and extensive range of bacteria resid- ing in subgingival bio5ilm formation. It is possible that microbial bio5ilm presence alone is insuf5icient for PD development. The disease develops when a microbial bio5ilm and its host have lost their equilibrium due to dysbiosis brought by the presence of "key- stone" bacteria or an excessive response of the immune system in the host to the exist- ence of microbes [20]. Moreover, in5lammation is triggered when the host reacts to the typical residing plaque as it builds, which alters the microbial ecol- ogy and dysbiosis. An "ecological catastro- phe" can be brought by a pathological mal- functioning of the immune response. An up- ward cycle of escalating dysbiosis feeds on it- self. In particular, the immune cell remnants (after apoptosis), the complete spectrum of host immune elements encompasses immu- noglobulins, complement, serum proteins, and cytokines. chemokines and collagen breakdown products are elevated during in- 5lammation. Furthermore, serum exudates are present in in5lamed pockets due to en- hanced capillary permeability. There is an in- crease in anaerobic bacteria because an an- oxic environment occurs in in5lammatory situations. Therefore, given the new environ- mental circumstances, certain symbionts be- come pathobionts, i.e., commensals become potentially pathogenic due to an aberration in homeostasis. Pathobionts' proliferation (such as P. gingivalis) can further provoke and exacerbate host in5lammatory re- sponses. A transcriptome investigation of subgingival microbiomes in periodontitis demonstrated elevated expression of genes encoding proteolytic enzymes, iron acquisi- tion, and lipopolysaccharide synthesis; this strongly suggests that numerous saccharo- lytic, anaerobic, and Gram-negative bacteria in periodontal in5lammation take advantage of ecological alterations for their nourishing and enormous requirements [21]. As perio- dontal in5lammation worsens, the bacterial biomass of bio5ilms is associated with human periodontitis development. Thus, the dysbio- sis and in5lammation encourage one another, creating a vicious cycle that could continue periodontal in5lammation and the disease's development [14]. The altered ecology then promotes the out- growth of pathobionts, which might exacer- bate in5lammatory reactions and prolong the disease's course. In addition to the subgingi- val bacterial bio5ilm on the tooth root surface and epithelial lining (a), genetic predisposi- tions and epigenetic modi5ications (b), life- style-related risk factors (c), systemic dis- eases (d), and other factors (e) have been recognized as causal risk factors for perio- dontitis [22]. Regarding the degradation of bone and con- nective tissue in periodontitis, the host re- sponse is thought to play a crucial role. Anti- gens of microbes and virulent elements trig- ger in5lammation and immunological re- sponses. These reactions include both innate and adaptive immune responses. Further- more, there is individual diversity in re- sponse due to differences in cytokine and other antimicrobial responses and the indi- vidual's environmental circumstances and genetic predispositions. The host's reaction to bacterial invasion entails activating and stimulating various in5lammatory cell types and resident tissue cells [23]. Role of viruses in periodontal disease Herpesviruses The Herpesviridae family, including EBV-1, HCMV, and herpes simplex virus (HSV), has been associated with several types of perio- dontal disease [24,25]. Research indicates that these viruses can infect and modify the functioning of polymorphonuclear leuko- cytes, lymphocytes, and macrophages, re- sulting in a reduced capacity to combat Emerging Role of Viral InfecEon in Periodontal Disease Vol 13, No 1 (2025) DOI 10.5195/d3000/2025.938 http://dentistry3000.pitt.edu 3 bacterial challenges [26]. This may augment the virulence of periodontopathogenic mi- crobiota. In contrast, the dysfunction of pol- ymorphonuclear leukocytes at periodontal sites can promote the proliferation of perio- dontopathic bacteria and the following pro- gression of destructive periodontal disease. Periodontal sites associated with the herpes virus typically exhibit increased concentra- tions of periodontopathic bacteria, such as P. gingivalis, Tannerella forsythia, Dialister pneumosintes, Dialister invisus, Prevotella intermedia, Prevotella nigrescens, Trepo- nema denticola, Campylobacter rectus, and Aggregatibacter actinomycetemcomitans [27]. The presence of periodontal HCMV, EBV, and maybe other viruses, local host immune re- sponses, and periodontopathic bacteria con- stitutes a fragile equilibrium that may result in periodontal damage [28]. The pathogenicity of the herpes virus is intri- cate, either through direct viral infection and reproduction or by a virally mediated modi- 5ication of the host's immunological system. The initial stages of periodontitis in immu- nologically naive hosts may primarily entail cytopathogenic occurrences, while most clinical manifestations in immunocompetent individuals are attributable to cellular or hu- moral immune responses [29]. Herpes viruses may exhibit periodonto- pathic potential through the following mech- anisms: Herpes viruses can directly elicit cy- topathic effects on keratinocytes, endothelial cells, 5ibroblasts, and in5lammatory cells, in- cluding polymorphonuclear leukocytes, lym- phocytes, macrophages, and possibly osteo- cytes. EBV and CMV can infect and alter the functions of monocytes, macrophages, and lymphocytes in periodontal lesions. Aggres- sive periodontitis lesions, potentially due to a herpes virus periodontal infection, exhibit a reduced number of viable cells, an in- creased presence of T-suppressor lympho- cytes, and a higher concentration of B lym- phocytes (EBV impact) compared to chronic periodontitis lesions or healthy periodontal sites. Cytopathic effects generated by the herpes virus may impede tissue turnover and repair [30]. 2. An infection with the periodontal herpes virus may augment the virulence of the peri- odontal microbiota. Proteins of the herpes virus synthesized on eukaryotic cell mem- branes may function as innovative bacterial binding sites. Cytomegalovirus can enhance the adherence of A. actinomycetemcomitans to primary epithelial cells from periodontal pockets and HeLa cells [31,32]. Herpes viruses may cause dysfunctions in the phagocytosis, adherence, chemotaxis, and bactericidal functions of polymorphonu- clear leukocytes, which are crucial for managing periodontopathic bacteria. Active Epstein-Barr virus infection can produce anti-neutrophilic antibodies, resulting in neutropenia, and can polyclonally increase the proliferation and differentiation of B cells. The pathogenic processes of herpesvi- ruses synergistically worsen illness; hence, a dual periodontal infection involving cyto- megalovirus and EBV, or CMV and HSV, is likely to manifest in severe forms of perio- dontitis [33]. Epstein-Barr virus (EBV) The Epstein-Barr virus, a common γ-HHV, in- fects around 95% of individuals asympto- matically and is generally transmitted by blood or oral secretions. The virus prolifer- ates in oropharyngeal epithelial cells or B lymphocytes. Nearly all seropositive individ- uals actively excrete viruses in their saliva [34]. While EBV infection in children is typi- cally subclinical, EBV infection in adults causes infectious mononucleosis. Fever, lym- phadenopathy, and pharyngitis are the pre- dominant symptoms of infectious mononu- cleosis. Oral ulcers, palatal petechiae, and, less frequently, gingival ulcerations may arise [33]. The most common EBV-related le- sion is oral hairy leukoplakia. Its presence usually indicates a relatively advanced stage of immunosuppression, such as in HIV infec- tion. HIV-infected patients’ T cells suppress EBV-infected B cells less effectively than im- munocompetent people’s T cells. Thus, HIV patients have 10–20 times the number of cir- culating EBV-infected B cells as healthy peo- ple [26]. According to the EBV status, there may be two dissimilar mechanisms involved in the pathogenesis of BL: virus-driven and mutational coding [35]. It induces latent infection in B-cells, with oc- casional lytic reactivation linked to the ter- minal differentiation of B-cells into plasma cells. Chronic latent EBV infection is associ- ated with lymphomas and carcinomas [36]. EBV is associated with several autoimmune disorders [37], serving as a direct cause of multiple sclerosis [38]. Recent studies re- vealed substantial insights into EBV's in- volvement in periodontitis [39]. They found that EBV commonly infects periodontal junc- tional Epithelial Cells [40]. Furthermore, it was determined that periodontitis lesions harbor signi5icant plasma cells, predomi- nantly exhibiting EBV positivity [41]. These 5indings provided the initial evidence of ac- tive EBV presence in periodontal lesions, in- dicating that it exacerbates local in5lamma- tion and contributes to the etiology of perio- dontitis [39]. Cytomegalovirus (CMV) Cytomegalovirus (CMV) infects T lympho- cytes, periodontal monocytes, and macro- phages [42]. The global seroprevalence of CMV infection varies from 0% to 95%, contingent upon the geographic region (de- veloped versus developing countries) [43]. The infection typically initiates during child- hood or even before birth, as the placenta plays a crucial role in the transmission of CMV to the fetus. Evidence indicates that CMV has developed several techniques to cir- cumvent the host immune response and has utilized the host immunological response to facilitate reactivation from dormancy and propagate infection [25,44]. Acute CMV infection is characterized by in- creased viral replication and dissemination to many organs. The pathogenesis of acute infection illustrates a correlation among viral replication levels, organ dysfunction, and disease in patients [32]. The pathogenesis of chronic infection involves a bi-directional re- lationship between viral gene expression and the host's in5lammatory response: the host's in5lammatory response facilitates vi- ral reactivation, while the virus provokes the host's in5lammatory response. In this case, the disease could be attributed to viral and host functions [45]. Consequently, CMV is frequently reactivated, leading to temporary immunosuppression and the proliferation of periodontal pathogenic bacteria. While it has been presumed that the pathogenesis of periodontitis is primarily due to bacterial in- fection on the tooth surface and within the gingival sulcus, numerous studies have demonstrated that host response factors, in- cluding in5lammatory responses and activa- tion of the innate immune system, are essen- tial to the development of periodontal dis- ease [26]. Human Immunode:iciency Virus (HIV) Periodontal pathology in HIV-infected pa- tients falls into three categories: (i) Linear gingival erythema, (ii) necrotizing ulcerative periodontal diseases, and (iii) enhanced pro- gression of chronic adult periodontitis [26]. In the mid-1980s, several reports described necrotic periodontitis and intense gingival erythema in HIV-infected patients. HIV-asso- ciated periodontitis (HIV-P) was named after these acute necrotic lesions, characterized by the loss of the underlying bone, and HIV-as- sociated gingivitis (HIV-G) was termed for a speci5ic kind of gingival erythema that proved resistant to conventional plaque treatment. The contemporary terminology utilized by the American Academy of Perio- dontology classi5ies HIV-G lesions as linear gingival erythema and HIV-P lesions as ne- crotizing ulcerative periodontitis. In addition to linear gingival erythema and necrotizing ulcerative periodontitis, these conditions were more common in patients with HIV. Ne- crotizing ulcerative gingivitis and necrotiz- ing ulcerative periodontitis are two perio- dontal conditions that have been identi5ied in both HIV-positive and HIV-negative Emerging Role of Viral InfecEon in Periodontal Disease Vol 13, No 1 (2025) DOI 10.5195/d3000/2025.938 http://dentistry3000.pitt.edu 4 patients. Necrotizing ulcerative gingivitis is characterized by interdental papilla ulcera- tion, gingival bleeding, and severe pain. The interproximal papilla is usually described as punched out and a 5ibrinous pseudo mem- brane typically covers the affected area [46]. The only difference between necrotizing ul- cerative periodontitis and necrotizing ulcer- ative gingivitis is that Lesions of necrotizing ulcerative periodontitis in5iltrate the alveo- lar bone. Necrotizing ulcerative periodonti- tis is distinguished by exposed bone, gingival recession, and tooth movement. Additional manifestations of necrotizing ulcerative gin- givitis or necrotizing periodontitis are halito- sis, lymphadenopathy, pyrexia, and general malaise [26]. Conclusions Herpes viruses may have a role in the eti- opathogenesis of destructive periodontal disease. Based on research completed over the last 15 years. 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Identi5ication Screening Illegibility Included Exclusion based on the year, title and abstract 14 Excluded after full text reading 12 Distinct titles, abstracts, and recent arti- cles after 2015 72 Full text reading 58 Final article se- lected 46